CiteULike: awooga's dopamine

Dopamine receptor pharmacology.

P Seeman — 2008-07-30T12:51:24-00:00

Current opinion in neurology and neurosurgery, Vol. 6, No. 4. (August 1993), pp. 602-608.

Although antipsychotic drugs originally helped to discover dopamine receptors, the five dopamine receptors presently identified and cloned are facilitating the search for and discovery of more selective antipsychotic and antiparkinson drugs. The D1-like dopamine receptors, D1 and D5, are sensitive to the same drugs as the D1 receptor in native tissues, but D5 is about 10 times more sensitive to dopamine than D1. The D2-like receptors, D2, D3, and D4, have approximately similar sensitivities to dopamine, but bromocriptine and raclopride are both about two orders of magnitude weaker at D4, whereas clozapine is one order more potent at D4, as compared with D2 and D3. The human dopamine D4 receptor has many variants. The sensitivities to clozapine of human variants D4.2, D4.4, and D4.7 are approximately similar, with dissociation constants between 5 and 24 nM, matching the spinal fluid concentration of clozapine under therapeutic conditions. Thus antipsychotic action may be effected through blockade of either dopamine D2 or D4 receptors.

Firing modes of midbrain dopamine cells in the freely moving rat

BI Hyland — 2008-06-27T05:34:19-00:00

Neuroscience, Vol. 114, No. 2. (1 October 2002), pp. 475-492.

There is a large body of data on the firing properties of dopamine cells in anaesthetised rats or rat brain slices. However, the extent to which these data relate to more natural conditions is uncertain, as there is little quantitative information available on the firing properties of these cells in freely moving rats. We examined this by recording from the midbrain dopamine cell fields using chronically implanted microwire electrodes. (1) In most cases, slowly firing cells with broad action potentials were profoundly inhibited by the dopamine agonist apomorphine, consistent with previously accepted criteria. However, a small group of cells was found that were difficult to classify because of ambiguous combinations of properties. (2) Presumed dopamine cells could be divided into low and high bursting (>40% of their spikes in bursts) groups, with the majority having low bursting rates. The distribution of burst incidence was similar to that previously reported with chloral hydrate anaesthesia, but the average intraburst frequency was higher in the conscious animal at rest and was higher again in bursts triggered by salient stimuli. (3) There was no evidence for spike frequency adaptation within bursts on average, consistent with the hypothesis that afterhyperpolarisation currents may be disabled during behaviourally induced bursting. (4) Presumed dopamine cells responded to reward-related stimuli with increased bursting rates and significantly higher intraburst frequencies compared to bursts emitted outside task context, indicating that modulation of afferent activity might not only trigger bursting, but may also regulate burst intensity. (5) In addition to the irregular single spike and bursting modes we found that extremely regular (clock-like) firing, previously only described for dopamine cells in reduced preparations, can also be expressed in the freely moving animal. (6) Cross-correlation analysis of activity recorded from simultaneously recorded neurones revealed coordinated activity in a quarter of dopamine cell pairs consistent with at least [`]functional' connectivity. On the other hand, most dopamine cell pairs showed no correlation, leaving open the possibility of functional sub-groupings within the dopamine cell fields. Taken together, the data suggest that the basic firing modes described for dopamine cells in reduced or anaesthetised preparations do reflect natural patterns of activity for these neurones, but also that the details of this activity are dependent upon modulation of afferent inputs by behavioural stimuli.

Interaction between diffusion and Michaelis-Menten uptake of dopamine after iontophoresis in striatum.

C Nicholson — 2007-12-19T09:24:23-00:00

Biophys J, Vol. 68, No. 5. (May 1995), pp. 1699-1715.

A quantitative description of the behavior of a neurotransmitter in the brain extracellular microenvironment requires an understanding of the relative importance of diffusion versus uptake processes. This paper models the behavior of dopamine released from a small iontophoresis electrode and its voltammetric detection by a carbon fiber sensor 100 microns away as a basis for developing a new paradigm for measuring dopamine kinetics in intact rat neostriatum. The diffusion equation incorporating uptake, characterized by a maximum velocity Vmax and a Michaelis-Menten constant Km, was transformed to an integral equation and solved numerically for the dopamine concentration, C. Analytical solutions were derived for limiting cases of a steady-state free-boundary problem when C >> Km and the linear time-dependent problem when C << Km. These solutions were compared with complete numerical solutions, both for normal uptake (Vmax = 0.2 or 0.8 microM s-1; Km = 0.15 microM), and in the presence of the uptake blocker nomifensine (Km = 6 microM). The results suggest that an experimental strategy for the quantitative analysis of dopamine, and other compounds, in living tissue is to fit a family of concentration versus time curves generated with different iontophoretic current strengths and recorded with a microsensor, to the numerical solution of the diffusion-uptake equation.

Prominent Burst Firing of Dopaminergic Neurons in the Ventral Tegmental Area during Paradoxical Sleep

Lionel Dahan — 2006-12-07T00:45:12-00:00

Neuropsychopharmacology, Vol. aop, No. current.

Heterogeneous Targets of Dopamine Synapses in Monkey Prefrontal Cortex Demonstrated by Serial Section Electron Microscopy: A Laminar Analysis Using the Silver-enhanced Diaminobenzidine Sulfide (SEDS) Immunolabeling Technique

John Smiley — 2008-06-21T04:13:30-00:00

Cereb. Cortex, Vol. 3, No. 3. (1 May 1993), pp. 223-238.

Dopamine projections to the cerebral cortex have been implicated in normal and pathological cognitive processes, notably, Parkinson's disease and schizophrenia. To help elucidate the function of these dopamine axons, they were characterized by serial section electron microscopy in individual layers of monkey prefrontal cortex. Dopamine immunoreactivity was visualized with a silver precipitation technique that allowed clear resolution of the internal structures and cell membranes of labeled axons. Apart from the occasional large microtubule-filled axon, dopamine axons were thin and varicose with many clear synaptic vesicles and fewer densecore vesicles. With few exceptions, dopamine synapses were symmetric and quite small, seen in only one to three serial sections. A determination of the "synaptic incidence" showed that only 39% of labeled varicosities formed identifiable synapses. However, it is certain that some small synapses could not be visualized even in serial sections, and it is possible that the vast majority if not all varicosities form synapses. Except for one soma, dendritic spines and shafts were the recipients of dopamine synapses. Many postsynaptic shafts were small and spiny, indicating that they were distal pyramidal dendrites. However, some postsynaptic shafts especially in supragranular layers had distinctly nonpyramidal features. These lacked spines, had a high density of synaptic inputs, and often had a strikingly varicose morphology. The data suggest that the majority of dopamine synapses in all layers are on pyramidal cells, but that a significant fraction are on presumed GA-BAergic nonpyramidal cells. 10.1093/cercor/3.3.223

DARPP-32 is a robust integrator of dopamine and glutamate signals.

E Fernandez — 2007-10-15T15:29:02-00:00

PLoS Comput Biol, Vol. 2, No. 12. (22 December 2006)

Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca(2+) signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca(2+) signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but that its response also depends on the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute effect on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the influence of the delay between dopamine and glutamate, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca(2+) regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons.

Food Reward in the Absence of Taste Receptor Signaling

Ivan de Araujo — 2008-03-31T11:10:48-00:00

Neuron, Vol. 57, No. 6. (27 March 2008), pp. 930-941.

Summary Food palatability and hedonic value play central roles in nutrient intake. However, postingestive effects can influence food preferences independently of palatability, although the neurobiological bases of such mechanisms remain poorly understood. Of central interest is whether the same brain reward circuitry that is responsive to palatable rewards also encodes metabolic value independently of taste signaling. Here we show that trpm5-/- mice, which lack the cellular machinery required for sweet taste transduction, can develop a robust preference for sucrose solutions based solely on caloric content. Sucrose intake induced dopamine release in the ventral striatum of these sweet-blind mice, a pattern usually associated with receipt of palatable rewards. Furthermore, single neurons in this same ventral striatal region showed increased sensitivity to caloric intake even in the absence of gustatory inputs. Our findings suggest that calorie-rich nutrients can directly influence brain reward circuits that control food intake independently of palatability or functional taste transduction.

Unique Properties of Mesoprefrontal Neurons within a Dual Mesocorticolimbic Dopamine System

Stephan Lammel — 2008-03-13T00:38:04-00:00

Neuron, Vol. 57, No. 5. (13 March 2008), pp. 760-773.

Summary The mesocorticolimbic dopamine system is essential for cognitive and emotive brain functions and is thus an important target in major brain diseases like schizophrenia, drug addiction, and attention deficit hyperactivity disorder. However, the cellular basis for the diversity in behavioral functions and associated dopamine-release pattern within the mesocorticolimbic system has remained unclear. Here, we report the identification of a type of dopaminergic neuron within the mesocorticolimbic dopamine system with unconventional fast-firing properties and small DAT/TH mRNA expression ratios that selectively projects to prefrontal cortex and nucleus accumbens core and medial shell as well as to basolateral amygdala. In contrast, well-described conventional slow-firing dopamine midbrain neurons only project to the lateral shell of the nucleus accumbens and the dorsolateral striatum. Among this dual dopamine midbrain system defined in this study by converging anatomical, electrophysiological, and molecular properties, mesoprefrontal dopaminergic neurons are unique, as only they do not possess functional somatodendritic Girk2-coupled dopamine D2 autoreceptors.

Effects of Dopaminergic Modulation on the Integrative Properties of the Ventral Striatal Medium Spiny Neuron

Jason Moyer — 2008-03-04T03:40:49-00:00

J Neurophysiol, Vol. 98, No. 6. (1 December 2007), pp. 3731-3748.

Dopaminergic modulation produces a variety of functional changes in the principal cell of the striatum, the medium spiny neuron (MSN). Using a 189-compartment computational model of a ventral striatal MSN, we simulated whole cell D1- and D2-receptormediated modulation of both intrinsic (sodium, calcium, and potassium) and synaptic currents (AMPA and NMDA). Dopamine (DA) modulations in the model were based on a review of published experiments in both ventral and dorsal striatum. To objectively assess the net effects of DA modulation, we combined reported individual channel modulations into either D1- or D2-receptor modulation conditions and studied them separately. Contrary to previous suggestions, we found that D1 modulation had no effect on MSN nonlinearity and could not induce bistability. In agreement with previous suggestions, we found that dopaminergic modulation leads to changes in input filtering and neuronal excitability. Importantly, the changes in neuronal excitability agree with the classical model of basal ganglia function. We also found that DA modulation can alter the integration time window of the MSN. Interestingly, the effects of DA modulation of synaptic properties opposed the effects of DA modulation of intrinsic properties, with the synaptic modulations generally dominating the net effect. We interpret this lack of synergy to suggest that the regulation of whole cell integrative properties is not the primary functional purpose of DA. We suggest that D1 modulation might instead primarily regulate calcium influx to dendritic spines through NMDA and L-type calcium channels, by both direct and indirect mechanisms. 10.1152/jn.00335.2007

Reward Prediction Error Computation in the Pedunculopontine Tegmental Nucleus Neurons

Yasushi Kobayashi — 2007-06-29T02:35:43-00:00

Annals of the New York Academy of Sciences, Vol. 1104, No. 1. (May 2007), pp. 310-323.

Dopamine-containing ventral tegmental area neurons in freely moving cats: Activity during the sleep-waking cycle and effects of stress

Michael Trulson — 2008-03-07T17:22:07-00:00

Experimental Neurology, Vol. 83, No. 2. (February 1984), pp. 367-377.

Abstract The activity of dopamine-containing ventral tegmental area (VTA) units was recorded by means of movable 32- and 64-[mu]m-diameter insulated Nichrome wires in freely moving cats. The VTA units displayed a slow, somewhat irregular activity during quiet waking (mean 3.63 +/- 0.41 spikes/s) and showed no significant change in activity during slow-wave sleep or REM sleep. Although VTA unit activity was somewhat higher and more erratic during active waking, there was no relationship between unit discharge and phasic movement. These neurons were inhibited (-87%) by small doses of apomorphine (1.0 mg/kg, i.p.) and excited (+43%) by small doses of haloperidol (0.5 mg/kg, i.p.). The stress of a conditioned emotional reaction (CER) paradigm resulted in a significant increase in the discharge rate of VTA neurons (+39%), compared with the quiet-waking baseline. The CER paradigm increased plasma glucocorticoids by 74%. Neurochemical studies revealed that the CER paradigm resulted in a significant decrease of dopamine in the limbic forebrain (-31%), whereas both homovanillic acid (+47%) and dihydroxyphenylacetic acid (+43%) concentrations were increased. No significant changes in dopamine metabolism were observed in the striatum under the CER situation. These data have implications in relation to the role of stress and dopamine in mediating certain psychiatric disorders.

Interleukin-2 decreases accumbal dopamine efflux and responding for rewarding lateral hypothalamic stimulation

Hymie Anisman — 2008-03-07T12:28:16-00:00

Brain Research, Vol. 731, No. 1-2. (26 August 1996), pp. 1-11.

Systemic administration of interleukin-2 (IL-2) provoked marked alterations of responding for rewarding brain stimulation from the medial forebrain bundle (MFB). In particular, when animals were tested for ICSS immediately following IL-2 treatment only a modest disturbance of responding was evident. However, if animals were subsequently exposed to repeated daily ICSS sessions (24-168 h) in the drug-free state, rightward shifts in the rate intensity functions and significant increases in reward thresholds were apparent. These results were dependent upon the presence of IL-2 during the initial ICSS session. If animals were tested for ICSS 24 h after IL-2 administration, without an intervening test, performance was unaffected. Evaluation of nonreinforced behavior after IL-2 treatment revealed that ICSS remained under stimulus control and the cytokine did not provoke reward-unrelated performance deficits. Dopamine (DA) activity in the nucleus accumbens has been implicated in goal-directed responding to positively reinforcing stimuli and in the present investigation, using in vivo microdialysis, it was observed that IL-2 markedly reduced DA release from this region. It was suggested that the protracted consequences of IL-2 on ICSS likely do not involve motoric, soporific, attentional or cognitive changes, but may be attributable to its specific actions on motivational arousal, possibly engendered by the cytokine-induced diminution of accumbal DA efflux.

Interleukin-1 beta augments release of norepinephrine, dopamine, and serotonin in the rat anterior hypothalamus

F Shintani — 2008-03-07T12:29:37-00:00

J. Neurosci., Vol. 13, No. 8. (1 August 1993), pp. 3574-3581.

Matching Behavior and the Representation of Value in the Parietal Cortex

Leo Sugrue — 2005-02-01T17:44:21-00:00

Science, Vol. 304, No. 5678. (18 June 2004), pp. 1782-1787.

Psychologists and economists have long appreciated the contribution of reward history and expectation to decision-making. Yet we know little about how specific histories of choice and reward lead to an internal representation of the "value" of possible actions. We approached this problem through an integrated application of behavioral, computational, and physiological techniques. Monkeys were placed in a dynamic foraging environment in which they had to track the changing values of alternative choices through time. In this context, the monkeys' foraging behavior provided a window into their subjective valuation. We found that a simple model based on reward history can duplicate this behavior and that neurons in the parietal cortex represent the relative value of competing actions predicted by this model.

Activity in posterior parietal cortex is correlated with the relative subjective desirability of action.

MC Dorris — 2005-02-04T21:13:00-00:00

Neuron, Vol. 44, No. 2. (14 October 2004), pp. 365-378.

Behavioral studies suggest that making a decision involves representing the overall desirability of all available actions and then selecting that action that is most desirable. Physiological studies have proposed that neurons in the parietal cortex play a role in selecting movements for execution. To test the hypothesis that these parietal neurons encode the subjective desirability of making particular movements, we exploited Nash's game theoretic equilibrium, during which the subjective desirability of multiple actions should be equal for human players. Behavior measured during a strategic game suggests that monkeys' choices, like those of humans, are guided by subjective desirability. Under these conditions, activity in the parietal cortex was correlated with the relative subjective desirability of actions irrespective of the specific combination of reward magnitude, reward probability, and response probability associated with each action. These observations may help place many recent findings regarding the posterior parietal cortex into a common conceptual framework.

Neural correlates of decision variables in parietal cortex.

ML Platt — 2005-02-01T19:51:55-00:00

Nature, Vol. 400, No. 6741. (15 July 1999), pp. 233-238.

Decision theory proposes that humans and animals decide what to do in a given situation by assessing the relative value of each possible response. This assessment can be computed, in part, from the probability that each action will result in a gain and the magnitude of the gain expected. Here we show that the gain (or reward) a monkey can expect to realize from an eye-movement response modulates the activity of neurons in the lateral intraparietal area, an area of primate cortex that is thought to transform visual signals into eye-movement commands. We also show that the activity of these neurons is sensitive to the probability that a particular response will result in a gain. When animals can choose freely between two alternative responses, the choices subjects make and neuronal activation in this area are both correlated with the relative amount of gain that the animal can expect from each response. Our data indicate that a decision-theoretic model may provide a powerful new framework for studying the neural processes that intervene between sensation and action.

The computational neurobiology of learning and reward

Nathaniel Daw — 2007-04-19T16:11:56-00:00

Current Opinion in Neurobiology, Vol. 16, No. 2. (April 2006), pp. 199-204.

Following the suggestion that midbrain dopaminergic neurons encode a signal, known as a `reward prediction error', used by artificial intelligence algorithms for learning to choose advantageous actions, the study of the neural substrates for reward-based learning has been strongly influenced by computational theories. In recent work, such theories have been increasingly integrated into experimental design and analysis. Such hybrid approaches have offered detailed new insights into the function of a number of brain areas, especially the cortex and basal ganglia. In part this is because these approaches enable the study of neural correlates of subjective factors (such as a participant's beliefs about the reward to be received for performing some action) that the computational theories purport to quantify.

Serotonin-dopamine interaction in the rat ventral tegmental area: an electrophysiological study in vivo.

S Prisco — 2008-03-06T14:00:30-00:00

J Pharmacol Exp Ther, Vol. 271, No. 1. (October 1994), pp. 83-90.

Electrophysiological techniques were used to study the effects of various serotonin (5-HT) agonists and antagonists on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) of rats. Systemic administration of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.25-80 micrograms/kg i.v.) increased the firing rate of the majority (75%) of DA cells studied and stimulated their bursting activity. A subpopulation (25%) of DA neurons was inhibited by 8-OH-DPAT. Selective lesions of 5-HT neurons by the neurotoxin 5-7-dihydroxytryptamine abolished completely the excitatory effect of 8-OH-DPAT on both firing rate and bursting activity of DA neurons. Microiontophoretic application of 8-OH-DPAT into the VTA did not cause any change in the firing rate of DA neurons. Treatment with the selective 5-HT1B agonist CGS 12066B (7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrolo[1,2-a] quinoxaline 1:2 maleate salt) (1.25-160 micrograms/kg i.v.) did not cause any change in basal firing rate of VTA DA cells. Systemic administration of trifluoromethylphenylpiperazine (TFMPP) (1.25-160 micrograms/kg i.v.) and m-chlorophenylpiperazine (mCPP) (1.25-320 micrograms/kg i.v.), two mixed 5-HT1B/5-HT1C receptor agonists, significantly reduced the firing rate of all VTA DA neurons studied. The effect of mCPP (maximal inhibition, 40%) was more pronounced compared to that of TFMPP (maximal inhibition, 25%). Microiontophoretic application of mCPP into the VTA caused a marked inhibition of the basal activity of DA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of 5-HT2C receptors in the control of central dopamine function

Vincenzo Di Matteo — 2008-03-06T14:00:35-00:00

Trends in Pharmacological Sciences, Vol. 22, No. 5. (1 May 2001), pp. 229-232.

Substantial evidence suggests that the functional status of the mesocorticolimbic dopamine (DA) system originating in the ventral tegmental area is under a phasic and tonic inhibitory control by the 5-HT system that acts by stimulating 5-HT2C receptor subtypes. Indeed, electrophysiological and biochemical data demonstrate that 5-HT2C receptor agonists decrease, whereas 5-HT2C receptor antagonists enhance, mesocorticolimbic DA function. However, 5-HT2C receptors do not appear to play a relevant role in the control of the nigrostriatal DA system originating in the substantia nigra pars compacta. In this article, the role of 5-HT2C receptors in the control of brain DA function will be reviewed, and the search for new therapies for neuropsychiatric disorders, such as depression, schizophrenia and drug addiction, based on these findings will be discussed.

The involvement of dopamine in the modulation of sleep and waking

Jaime Monti — 2008-03-06T11:56:23-00:00

Sleep Medicine Reviews, Vol. 11, No. 2. (April 2007), pp. 113-133.

Summary Dopamine (DA)-containing neurons involved in the regulation of sleep and waking (W) arise in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc). The VTA and SNc cells have efferent and afferent connections with the dorsal raphe nucleus (DRN), the pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT), the locus coeruleus (LC), the lateral and posterior hypothalamus (LH), the basal forebrain (BFB), and the thalamus. Molecular cloning techniques have enabled the characterization of two distinct groups of DA receptors, D1-like and D2-like receptors. The D1 subfamily includes the D1 and D5 receptors, whereas the D2 subfamily comprises the D2, D3, and D4 receptors. Systemic administration of a selective D1 receptor agonist induces behavioral arousal, together with an increase of W and a reduction of slow wave sleep (SWS) and REM sleep (REMS). Systemic injection of a DA D2 receptor agonist induces biphasic effects, such that low doses reduce W and increase SWS and REMS (predominant activation of the D2 autoreceptor), whereas large doses induce the opposite effect (predominant facilitation of the D2 postsynaptic receptor). Compounds with DA D1 or D2 receptor blocking properties augment non-REMS and reduce W. Preliminary findings tend to indicate that the administration of a DA D3-preferring agonist induces somnolence and sleep in laboratory animals and man. DA neurons in the VTA and the SNc do not change their mean firing rate across the sleep-wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep-wake cycle. The available evidence tends to indicate that during W there occurs an increase of burst firing activity of DA neurons, and an enhanced release of DA in the VTA, the nucleus accumbens (NAc), and a number of forebrain structures. A series of structures relevant for the regulation of the behavioral state, including the DRN, LDT/PPT, LC, and LH, could be partly responsible for the changes in the temporal pattern of activity of DA neurons.

Dopaminergic and Serotonergic Neurotransmission Systems Are Differentially Involved in Auditory Cortex Learning: A Long-Term Microdialysis Study of Metabolites

Holger Stark — 2008-03-06T11:06:34-00:00

Journal of Neurochemistry, Vol. 68, No. 2. (1997), pp. 691-697.

Abstract: Auditory cortex has been shown to be a site of widespread neuronal learning processes even in the context of simple auditory conditioning behavior. In view of their presumed role in determining behavioral and motivational relevance of incoming information we investigated whether the dopaminergic and serotonergic systems are involved in auditory cortex learning. Using a chronic brain microdialysis technique over 4 days, samples from auditory cortex were obtained before, during, and after daily footshock avoidance training simultaneously from trained gerbils and passive control animals or pseudotrained animals. Because of detection limits of dopamine and serotonin in auditory cortex, the response profiles of extracellular homovanillic acid as the metabolite of the dopaminergic system and of 5-hydroxyindoleacetic acid as the metabolite of the serotonergic system were determined from consecutive dialysis samples each day. The response of the dopaminergic system appeared to reflect the initial formation of the behaviorally relevant association exclusively during the first training day, whereas the serotonergic response appeared to correlate with the stress level of animals.

BOLD Responses Reflecting Dopaminergic Signals in the Human Ventral Tegmental Area

Kimberlee D'Ardenne — 2008-02-29T10:21:12-00:00

Science, Vol. 319, No. 5867. (29 February 2008), pp. 1264-1267.

Current theories hypothesize that dopamine neuronal firing encodes reward prediction errors. Although studies in nonhuman species provide direct support for this theory, functional magnetic resonance imaging (fMRI) studies in humans have focused on brain areas targeted by dopamine neurons [ventral striatum (VStr)] rather than on brainstem dopaminergic nuclei [ventral tegmental area (VTA) and substantia nigra]. We used fMRI tailored to directly image the brainstem. When primary rewards were used in an experiment, the VTA blood oxygen leveldependent (BOLD) response reflected a positive reward prediction error, whereas the VStr encoded positive and negative reward prediction errors. When monetary gains and losses were used, VTA BOLD responses reflected positive reward prediction errors modulated by the probability of winning. We detected no significant VTA BOLD response to nonrewarding events. 10.1126/science.1150605

A critical review of the function of neuromelanin and an attempt to provide a unified theory

Bruno Nicolaus — 2008-02-27T17:16:18-00:00

Medical Hypotheses, Vol. 65, No. 4. (2005), pp. 791-796.

Summary This paper provides a critical review of the numerous and various biological functions so far attributed to neuromelanin and an attempt to provide a unified theory based on the peculiar physical and chemical properties of the black particle (the neuromelanin cage). It is stressed that neuromelanin is not homogeneous, as is commonly accepted, but is made up of different substrate specific black pigments formed by the oxidation of o.diphenols or other oxygenated precursors (substantia nigra melanin, locus coeruleus melanin, retinal pigmented epithelium or ocular melanin, inner-ear melanin, and so on). Ocular melanin is believed to protect the eye by trapping metals and free radicals. The paper shows that this unconfirmed mechanism is a rather fortuitous irreversible molecular accident, which at times may prove itself deleterious. Albinism often leads to deafness in animals, indicating a genetic correlation. These two conditions appear to be correlated at a molecular level to eye/ear pigmentation and suggest verifying this hypothesis in normal and albino human individuals. Skin and ocular melanin are chemically different. However, they are both involved in light absorption/dissipation. The black particle structure (melanin cage) is believed to be fundamental to this process because there is a common bioelectric mechanism. The latter is worth of further investigation. It is also proposed checking how ocular melanin dissipates the excessive absorbed light (as heat or as current?). It has been claimed that inner-ear melanin mutes acoustic waves. This paper suggests investigating the underlying mechanism and also studying whether this pigment is bio-electrically involved in audiology. According to numerous authors, substantia nigra melanin is only biological garbage. This view is rejected, and it is stressed that intracellular melanogenesis is a fundamental and genetically controlled physiological process. It has been repeatedly claimed that the binding of iron, heavy metals, free radicals and harmful chemicals by substantia nigra melanin is fundamental to body detoxification/protection. Presumably, such irreversible and generic binding mechanisms have no physiological foundation; it is suggested the alternative that, substantia nigra melanin acts as semiconductor, transmitting and modulating nervous impulses, in a reversible way. In fact, substantia nigra melanin is absent or significantly scarce in two conditions of life in which the coordination of movement is either inefficient (newborn babies) or strongly compromised (Parkinson). To check this assumption, further investigation of nucleus caudatus, putamen, globus pallidus, substantia nigra pars compacta and reticulata, nucleus hypothalamicus is recommended.

Dopaminergic input is required for increases in serotonin output produced by behavioral activation: an in vivo microdialysis study in rat forebrain

A Mendlin — 2008-02-26T17:05:19-00:00

Neuroscience, Vol. 93, No. 3. (August 1999), pp. 897-905.

Previous research has demonstrated that pharmacological stimulation of postsynaptic dopamine D2 receptors produces increases in serotonin output. The present study explored whether this relationship also holds under physiological conditions. Accordingly, we examined the effects of D2 receptor blockade or unilateral dopamine depletion on behaviorally induced increases in extracellular serotonin levels in the corpus striatum and prefrontal cortex of freely moving rats using in vivo microdialysis. Extracellular levels of dopamine and serotonin, as well as behavioral activity, were increased by both mild tail pinch and the light-dark transition. Tail pinch-induced increases in serotonin levels (39+/-3% and 53+/-5% in the corpus striatum and prefrontal cortex, respectively), but not the accompanying behavioral changes, were blocked by local application of the D2 receptor antagonist raclopride (10 [mu]M). D2 receptor blockade also disrupted the positive relationship between striatal serotonin levels and behavioral activity of animals across the light-dark transition (r=0.93 without raclopride, r=0.24 in presence of raclopride). Unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic system also abolished increases in striatal serotonin output induced by both tail pinch and light-dark transition. A negative correlation was observed between the degree of striatal dopamine depletion and tail pinch-induced increases in serotonin efflux (r=-0.88). Thus, both a local blockade of postsynaptic D2 receptors and striatal dopamine depletion prevented increases in serotonin output that normally accompany behavioral activation. These data indicate that the increases in the forebrain serotonin output produced by two distinct physiological/environmental manipulations appear to be largely dependent upon intact local dopaminergic neurotransmission.

Cellular colocalization of dopamine D1 and D2 receptors in rat medial prefrontal cortex.

SL Vincent — 2007-11-26T13:04:38-00:00

Synapse, Vol. 19, No. 2. (February 1995), pp. 112-120.

In a recent study in rat medial prefrontal cortex (mPFC), a fluorescently coupled, high-affinity ligand for the D1 receptor subtype was localized to nonpyramidal neurons, while a ligand selective for the D2 subtype was found on neurons with a size distribution overlapping with both small pyramidal and large nonpyramidal cells. These observations raised the possibility that a subpopulation of cortical neurons with an intermediate size range may coexpress both the D1 and D2 receptor subtypes. In the present study, the D1 and D2 receptor subtypes have been simultaneously localized in layer VI of rat mPFC using 20 nM SCH 23390-Bodipy and 20 nM N-(p-aminophenethyl) spiperone-Texas red, respectively, in the presence of 100 nM mianserin (5-HT2 receptor antagonist). The localization of receptor binding fluorescence was assessed in paired images using fluoroscein isothiocyanate (FITC) and rhodamine dichroic filters for the D1 and D2 subtypes, respectively. Under the conditions employed here, most cell bodies showed either D1-like or D2-like receptor binding fluorescence, while a colocalization of both fluoroprobes was observed on only 25% of the labeled cells. When the size of each single-labeled cell body was measured using the respective FITC (D1-probe) and rhodamine (D2-probe) epifluorescence filters, the distribution of cells showing only D1-like receptor binding fluorescence was similar to nonpyramidal neurons (68.6 +/- 1.8 microns 2), while that for cells showing only D2-like receptor binding fluorescence was similar to that of both large interneurons and small pyramidal cells (106.9 +/- 2.4 microns 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Subpopulations of cortical GABAergic interneurons differ by their expression of D1 and D2 dopamine receptor subtypes.

C Le Moine — 2007-11-26T13:04:03-00:00

Brain Res Mol Brain Res, Vol. 58, No. 1-2. (15 July 1998), pp. 231-236.

D1 and D2 receptors have been described in different populations of efferent pyramidal neurons of the rat frontal cortex. Combined in situ hybridization and immunocytochemistry show here that these two subtypes are expressed in cortical GABAergic interneurons, with D1 and D2 mainly found in a subpopulation containing parvalbumin, whereas only 10% of the calbindin neurons express D1 receptors. These data indicate that various DA agonists may influence inhibitory circuits by distinct dopamine receptor subtypes.

D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons.

P Gaspar — 2007-11-26T13:03:01-00:00

Eur J Neurosci, Vol. 7, No. 5. (1 May 1995), pp. 1050-1063.

The dopaminergic input to the frontal cortex has an important role in motor and cognitive functions. These effects are mediated by dopamine receptors both of type D1 and of type D2, although the neural circuits involved are not completely understood. We used in situ hybridization to determine the cellular localization of D1 and D2 receptor mRNAs in the rat frontal cortex. Retrograde tracing was used in the same animals to identify the main cortical efferent populations. Fluorogold was injected into the different cortical targets of the frontal cortex and sections were hybridized with D1 and D2 35S-labelled cRNA probes. D1 and D2 mRNA-containing neurons were present in all the cortical areas investigated, with greater expression in the medial prefrontal, insular and cingulate cortexes and lower expression in the motor and parietal cortexes. Neurons containing D1 mRNA were most abundant in layer VIb; they were also present in layers VIa and V of all cortical layers and in layer II of the medial prefrontal, cingulate and insular areas. Double labelling with fluorogold demonstrated that D1 mRNA was present in corticocortical, corticothalamic and corticostriatal neurons. Neurons containing D2 mRNA were essentially restricted to layer V, but only in corticostriatal and corticocortical neurons. Neither D1 nor D2 mRNA was found in corticospinal or corticopontine neurons. The present results demonstrate that D1 and D2 receptor genes are expressed in efferent cortical populations, with higher expression for D1. In spite of an overlap in some cortical layers, the expression of D1 and D2 receptor genes is specific for different categories of pyramidal neurons.

Subcellular localization of the dopamine D<SUB><FONT SIZE='-1'>2</FONT></SUB> receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex

Laszlo Negyessy — 2007-11-26T12:57:54-00:00

The Journal of Comparative Neurology, Vol. 488, No. 4. (2005), pp. 464-475.

Structures of the cerebral cortex expressing the D2 dopamine receptor subtype (D2) are important sites of action of antipsychotic drugs. It has also been repeatedly suggested that the prefrontal cortex plays a significant role in neuropsychiatric disorders, including schizophrenia. Here, by using single and double immunohistochemical techniques with electron microscopy, we investigated in the primate prefrontal cortex the ultrastructural localization of D2 and we compared it with that of the neuronal calcium sensor-1 (NCS-1), a neuron-specific calcium-binding and D2-interacting protein. D2 immunoreactivity, revealed with preembedding immunoperoxidase in single labeling and with preembedding immunogold for double labeling, was localized in cell bodies with ultrastructural characteristics of both neurons and astroglia. D2 was localized in pre- and postsynaptic structures, including spines and dendrites, and in both excitatory- and inhibitory-like axon terminals. Immunogold labeling revealed peri- and extrasynaptic localization of D2 in postsynaptic structures, whereas extrasynaptic labeling was typically found in boutons. NSC-1 immunoreactivity was abundant in pre- and postsynaptic structures, in which it was also colocalized with D2. With the present strategy (that has high resolution but relatively limited sensitivity), NSC-1 was observed in about 10% of the D2-immunopositive spines and in a lower proportion of D2-immunopositive dendrites and boutons. The data demonstrate the localization of D2 in pre- and postsynaptic as well as extra- and perisynaptic structures of the primate prefrontal cortex. The data also show the coexistence of NCS-1 and D2 at the ultrastructural level. The latter finding suggests a role for NCS-1 in desensitization of D2 in the prefrontal cortex. J. Comp. Neurol. 488:464-475, 2005. © 2005 Wiley-Liss, Inc.

D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines.

JF Smiley — 2007-11-26T12:53:53-00:00

Proc Natl Acad Sci U S A, Vol. 91, No. 12. (7 June 1994), pp. 5720-5724.

Antibodies to the D1 dopamine receptor were used to localize this protein in several areas of human and monkey cerebral cortex with light and electron microscopy. In addition to cell body labeling in monkeys, all areas of humans and monkeys had a neuropil label with a laminar distribution predicted by previous D1 receptor autoradiography studies. Using electron microscopy, this neuropil label was seen in numerous dendritic spines, in dendritic shafts, and in occasional axon terminals. While labeled spines were common, they represented only a subset of all cortical spines. Serial sectioning through labeled spines showed that the diaminobenzidine reaction product was usually not at postsynaptic densities but instead was displaced to the side of the large asymmetric (presumed glutamatergic) synapse. Furthermore, most labeled spines did not receive synapses with dopaminergic features, suggesting that many D1 receptors are at extrasynaptic sites, possibly receiving dopamine via diffusion in the neuropil. Similarly, double labeling failed to reveal D1 labeling at synapses of tyrosine hydroxylase immunoreactive axons. Localization to numerous dendritic spines suggests that a primary role of D1 receptors is modulation of glutamatergic input to cortical pyramidal cells.

The neural basis of human error processing: reinforcement learning, dopamine, and the error-related negativity.

CB Holroyd — 2006-02-20T20:56:12-00:00

Psychol Rev, Vol. 109, No. 4. (October 2002), pp. 679-709.

The authors present a unified account of 2 neural systems concerned with the development and expression of adaptive behaviors: a mesencephalic dopamine system for reinforcement learning and a "generic" error-processing system associated with the anterior cingulate cortex. The existence of the error-processing system has been inferred from the error-related negativity (ERN), a component of the event-related brain potential elicited when human participants commit errors in reaction-time tasks. The authors propose that the ERN is generated when a negative reinforcement learning signal is conveyed to the anterior cingulate cortex via the mesencephalic dopamine system and that this signal is used by the anterior cingulate cortex to modify performance on the task at hand. They provide support for this proposal using both computational modeling and psychophysiological experimentation.

Reinforcement-related brain potentials from medial frontal cortex: origins and functional significance.

S Nieuwenhuis — 2007-02-21T01:25:44-00:00

Neurosci Biobehav Rev, Vol. 28, No. 4. (July 2004), pp. 441-448.

The development of the field of cognitive neuroscience has inspired a revival of interest in the brain mechanisms involved in the processing of rewards, punishments, and abstract performance feedback. One fruitful line of research in this area was initiated by the report of an electrophysiological brain potential in humans that was differentially sensitive to negative and positive performance feedback [J. Cogn. Neurosci. 9 (1997) 788]. Here we review current knowledge regarding the neural basis and functional significance of this feedback-evoked 'error-related negativity' (ERN). Our review is organized around a set of predictions derived from a recent theory, which holds that the ERN is associated with the arrival of a negative reward prediction error signal in anterior cingulate cortex.

Learning in Spiking Neural Networks by Reinforcement of Stochastic Synaptic Transmission

Sebastian Seung — 2006-10-05T12:48:49-00:00

Neuron, Vol. 40, No. 6. (18 December 2003), pp. 1063-1073.

It is well-known that chemical synaptic transmission is an unreliable process, but the function of such unreliability remains unclear. Here I consider the hypothesis that the randomness of synaptic transmission is harnessed by the brain for learning, in analogy to the way that genetic mutation is utilized by Darwinian evolution. This is possible if synapses are "hedonistic," responding to a global reward signal by increasing their probabilities of vesicle release or failure, depending on which action immediately preceded reward. Hedonistic synapses learn by computing a stochastic approximation to the gradient of the average reward. They are compatible with synaptic dynamics such as short-term facilitation and depression and with the intricacies of dendritic integration and action potential generation. A network of hedonistic synapses can be trained to perform a desired computation by administering reward appropriately, as illustrated here through numerical simulations of integrate-and-fire model neurons.

Dopamine and the Origins of Human Intelligence

Fred Previc — 2007-11-16T13:52:42-00:00

Brain and Cognition, Vol. 41, No. 3. (December 1999), pp. 299-350.

A general theory is proposed that attributes the origins of human intelligence to an expansion of dopaminergic systems in human cognition. Dopamine is postulated to be the key neurotransmitter regulating six predominantly left-hemispheric cognitive skills critical to human language and thought: motor planning, working memory, cognitive flexibility, abstract reasoning, temporal analysis/sequencing, and generativity. A dopaminergic expansion during early hominid evolution could have enabled successful chase-hunting in the savannas of sub-Saharan Africa, given the critical role of dopamine in counteracting hyperthermia during endurance activity. In turn, changes in physical activity and diet may have further increased cortical dopamine levels by augmenting tyrosine and its conversion to dopamine in the central nervous system (CNS). By means of the regulatory action of dopamine and other substances, the physiological and dietary changes may have contributed to the vertical elongation of the body, increased brain size, and increased cortical convolutedness that occurred during human evolution. Finally, emphasizing the role of dopamine in human intelligence may offer a new perspective on the advanced cognitive reasoning skills in nonprimate lineages such as cetaceans and avians, whose cortical anatomy differs radically from that of primates.

THE CATECHOLAMINE HYPOTHESIS OF AFFECTIVE DISORDERS: A REVIEW OF SUPPORTING EVIDENCE

Joseph Schildkraut — 2007-10-03T15:31:45-00:00

Am J Psychiatry, Vol. 122, No. 5. (1 November 1965), pp. 509-522.

The "catecholamine hypothesis of affective disorders" proposes that some, if not all, depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines. Evidence supporting this hypothesis was reviewed.Data from pharmacological studies, mainly in animals, suggest that the actions of both major classes of antidepressant drugs are mediated through the catecholamines. The monoamine oxidase inhibitors increase brain concentrations of norepinephrine while imipramine-like agents potentiate the physiological effects of norepinephrine. Reserpine, a drug which can cause clinical depression, depletes catecholamines, but other amines may also be involved in its mechanism of action. A rigorous extrapolation from pharmacological studies to pathophysiology clearly cannot be made. Clinical studies relevant to the catecholamime hypothesis are limited and the findings are inconclusive.It is not possible, therefore, to confirm definitively or to reject the catecholamine hypothesis on the basis of data currently available. In our present state of knowledge, however, the catecholamine hypothesis is of considerable heuristic value, providing the investigator and the clinician with a frame of reference integrating much of our experience with those pharmacological agents which produce alterations in human affective states. 10.1176/appi.ajp.122.5.509

Statistics of Midbrain Dopamine Neuron Spike Trains in the Awake Primate

Hannah Bayer — 2007-07-19T11:11:14-00:00

J Neurophysiol (5 July 2007), 01140.2006.

Work in behaving primates indicates that midbrain dopamine neurons encode a prediction error, the difference between an obtained reward and the reward expected. Studies of dopamine action potential timing in the alert and anaesthetized rat indicate that dopamine neurons respond in tonic and phasic modes, a distinction that has been less well characterized in the primates. We used spike train models to examine the relationship between the tonic and burst modes of activity in dopamine neurons while monkeys were performing a reinforced visuo-saccadic movement task. We studied spiking activity during four task-related intervals; two of these were intervals during which no task-related events occurred, while two were periods marked by task-related phasic activity. We found that dopamine neuron spike trains during the intervals when no events occurred were well described as tonic. Action potentials appeared to be independent, to occur at low frequency, and to be almost equally well described by Gaussian and Poisson-like (Gamma) processes. Unlike in the rat, interspike intervals as low as 20 ms were often observed during these presumptively tonic epochs. Having identified these periods of presumptively tonic activity we were able to quantitatively define phasic modulations (both increases and decreases in activity) during the intervals in which task-related events occurred. This analysis revealed that the phasic modulations of these neurons include both bursting, as has been described previously, and pausing. Together bursts and pauses seemed to provide a continuous, although non-linear, representation of the theoretically defined reward prediction error of reinforcement learning. 10.1152/jn.01140.2006

Dopamine neuron systems in the brain: an update

Anders Bjorklund — 2007-04-04T11:31:06-00:00

Trends in Neurosciences, Vol. In Press, Corrected Proof

The basic organization of the catecholamine-containing neuronal systems and their axonal projections in the brain was initially worked out using classical histofluorescence techniques during the 1960s and 1970s. The introduction of more versatile immunohistochemical methods, along with a range of highly sensitive tract-tracing techniques, has provided a progressively more detailed picture, making the dopamine system one of the best known, and most completely mapped, neurotransmitter systems in the brain. The purpose of the present review is to summarize our current knowledge of the diversity and neurochemical features of the nine dopamine-containing neuronal cell groups in the mammalian brain, their distinctive cellular properties, and their ability to regulate their dopaminergic transmitter machinery in response to altered functional demands and aging.

Dopaminergic neurones: much more than dopamine?

Vincent Seutin — 2007-09-03T17:09:03-00:00

Br J Pharmacol, Vol. 146, No. 2. (11 July 2005), pp. 167-169.

Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus

Paola Devoto — 2007-09-03T17:06:14-00:00

BMC Neuroscience, Vol. 6, No. 1. (2005)

BACKGROUND:Previous studies by our group suggest that extracellular dopamine (DA) and noradrenaline (NA) may be co-released from noradrenergic nerve terminals in the cerebral cortex. We recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral cortex by electrical stimulation of the locus coeruleus (LC). This study analyses the effect of both single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal cortex (mPFC), occipital cortex (Occ), and caudate nucleus. To rule out possible stressful effects of electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats.RESULTS:Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within 20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation. Local perfusion with tetrodotoxin (TTX, 10 muM) markedly reduced baseline NA and DA in the mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas.A sequence of five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to the same extent and duration as the first stimulus, whereas DA remained elevated at the time next stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach about 130 and 200% the initial level, respectively.In the presence of the NA transport (NAT) blocker desipramine (DMI, 100 muM), multiple LC stimulation still increased extracellular NA and DA levels.Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to modify DA level.CONCLUSION:The results confirm and extend that LC stimulation induces a concomitant release of DA and NA in the mPFC and Occ.The different time-course of LC-induced elevation of DA and NA suggests that their co-release may be differentially controlled.

Neuromodulation of the prefrontal cortex during sleep: a microdialysis study in rats.

Z de Saint Hilaire — 2007-08-27T20:32:05-00:00

Neuroreport, Vol. 11, No. 8. (5 June 2000), pp. 1619-1624.

To test the hypothesis that biogenic amines of the prefrontal cortex are involved in state-dependent cortical and behavioural activation, changes in extracellular levels of serotonin (5-HT), dopamine (DA), and noradrenaline (NA) were determined during the sleep-wake cycle in freely moving rats using microdialysis probes with parallel EEG recording. Serotonin gradually increased up to 450% during wakefulness (W) as compared to slow wave sleep (SWS), before decreasing toward stable levels during the next episode of SWS. Dopamine and its metabolite homovanillic acid (HVA) were reduced during W as compared to SWS. Although contradictory with the generally admitted enhancement of DA activity related to vigilance, this may be due to the particular role of DA neurons in the prefrontal cortex. However, DA and HVA showed dramatic changes announcing the transition between SWS and W. During paradoxical sleep (PS), DA and 5-HT showed complex changes, the direction of which depended on whether PS was followed by SWS or W. Biogenic amines of the prefrontal cortex are probably involved in cortical and behavioural activation.

Serotonin, but not dopamine, metabolites are increased in selected brain regions of subordinate male rats in a colony environment

Caroline Blanchard — 2007-08-27T20:27:10-00:00

Brain Research, Vol. 568, No. 1-2. (24 December 1991), pp. 61-66.

Subordinate male laboratory rats maintained in mixed-sex groups in a Visible Burrow System habitat show a complex pattern of stress-related changes including enhanced defensive behavior, early mortality and increased voluntary ethanol consumption. Analysis of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels indicated that 5-HT levels do not differ between colony subordinates, colony dominants, and singly-housed control animals. However, 5-HIAA levels were higher in subordinates than either dominants or control animals in the preoptic area, amygdala, hippocampus, and spinal cord, and, were higher than dominants only, in entorhinal cortex. Subordinates' regional 5-HIAA/5-HT ratios were reliably higher than those of dominant or control animals in midbrain and spinal cord and reliably higher than dominants only, in hypothalamus. Dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels and DA/DOPAC ratios were affected neither in hypothalamus nor midbrain. These findings suggest that a consistent increase of 5-HIAA levels in selected brain regions of subordinate rats may represent a biological substrate for a well-characterized pattern of alterations in defensive behaviors for these animals.

Acetylcholine Release in Ventral Tegmental Area by Hypothalamic Self-Stimulation, Eating, and Drinking

Pedro Rada — 2007-08-27T20:23:32-00:00

Pharmacology Biochemistry and Behavior, Vol. 65, No. 3. (March 2000), pp. 375-379.

Evidence is presented for an acetylcholine (ACh) input to the midbrain ventral tegmental area (VTA) as part of a system for self-stimulation and ingestive behavior. Male rats were prepared with an electrode in the perifornical lateral hypothalamus and an ipsilateral guideshaft for microdialysis in the VTA. Extracellular ACh increased in the VTA during self-stimulation, auto-stimulation, eating, or drinking. Infusion of atropine into the VTA via the microdialysis probe was sufficient to stop self-stimulation and reduce intake of food. It is concluded that ACh acts at muscarinic receptors in the VTA as part of a circuit that modulates hypothalamic self-stimulation and ingestive behavior.

The two faces of Eve: dopamine's modulation of wakefulness and sleep.

DB Rye — 2007-08-27T20:22:20-00:00

Neurology, Vol. 63, No. 8 Suppl 3. (26 October 2004)

In Parkinson's disease (PD), waking is frequently punctuated by sleep episodes, including rapid eye movement (REM) (i.e., dream) sleep, and sleep is interrupted by motor activities such as periodic limb movements and REM sleep behavior disorder. Because these pathologic behaviors are unaccounted for by contemporary models, this review summarizes the complex effects of dopamine (DA) on normal and pathological waking-sleeping. Maintenance of wakefulness is probably promoted by mesocorticolimbic DA circuits, and suppression of nocturnal movement appears to be influenced by indirect pathways linking midbrain DA neurons with pre-motor structures in the mesopontine tegmentum and ventromedial medulla. A diencephalospinal DA system may have an additional important role in mediating state-specific sensorimotor activity that is relevant to periodic limb movements and restless legs syndrome.

A Role for Hypocretin (Orexin) in Male Sexual Behavior

John Muschamp — 2007-08-27T20:18:14-00:00

J. Neurosci., Vol. 27, No. 11. (14 March 2007), pp. 2837-2845.

The role of hypocretin (orexin; hcrt/orx) neurons in regulation of arousal is well established. Recently, hcrt/orx has been implicated in food reward and drug-seeking behavior. We report here that in male rats, Fos immunoreactivity (ir) in hcrt/orx neurons increases markedly during copulation, whereas castration produces decreases in hcrt/orx neuron cell counts and protein levels in a time course consistent with postcastration impairments in copulatory behavior. This effect was reversed by estradiol replacement. Immunolabeling for androgen (AR) and estrogen (ERalpha) receptors revealed no colocalization of hcrt/orx with AR and few hcrt/orx neurons expressing ERalpha, suggesting that hormonal regulation of hcrt/orx expression is via afferents from neurons containing those receptors. We also demonstrate that systemic administration of the orexin-1 receptor antagonist SB 334867 [N-(2-methyl-6-benzoxazolyl)-N”-1,5-naphthyridin-4-yl urea] impairs copulatory behavior. One locus for the prosexual effects of hcrt/orx may be the ventral tegmental area (VTA). We show here that hcrt-1/orx-A produces dose-dependent increases in firing rate and population activity of VTA dopamine (DA) neurons in vivo. Activation of hcrt/orx during copulation, and in turn, excitation of VTA DA neurons by hcrt/orx, may contribute to the robust increases in nucleus accumbens DA previously observed during male sexual behavior. Subsequent triple immunolabeling in anterior VTA showed that Fos-ir in tyrosine hydroxylase-positive neurons apposed to hcrt/orx fibers increases during copulation. Together, these data support the view that hcrt/orx peptides may act in a steroid-sensitive manner to facilitate the energized pursuit of natural rewards like sex via activation of the mesolimbic DA system. 10.1523/JNEUROSCI.4121-06.2007

Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins.

TM Korotkova — 2006-12-01T01:47:37-00:00

J Neurosci, Vol. 23, No. 1. (1 January 2003), pp. 7-11.

Orexins/hypocretins are involved in mechanisms of emotional arousal and short-term regulation of feeding. The dense projection of orexin neurons from the lateral hypothalamus to mesocorticolimbic dopaminergic neurons in the ventral tegmental area (VTA) is likely to be important in both of these processes. We used single-unit extracellular and whole-cell patch-clamp recordings to examine the effects of orexins (A and B) and melanin-concentrating hormone (MCH) on neurons in this region. Orexins caused an increase in firing frequency (EC(50) 78 nm), burst firing, or no change in firing in different groups of A10 dopamine neurons. Neurons showing oscillatory firing in response to orexins had smaller afterhyperpolarizations than the other groups of dopamine neurons. Orexins (100 nm) also increased the firing frequency of nondopaminergic neurons in the VTA. In the presence of tetrodotoxin (0.5 microm), orexins depolarized both dopaminergic and nondopaminergic neurons, indicating a direct postsynaptic effect. Unlike the orexins, MCH did not affect the firing of either group of neurons. Single-cell PCR experiments showed that orexin receptors were expressed in both dopaminergic and nondopaminergic neurons and that the calcium binding protein calbindin was only expressed in neurons, which also expressed orexin receptors. In narcolepsy, in which the orexin system is disrupted, dysfunction of the orexin modulation of VTA neurons may be important in triggering attacks of cataplexy.

Multiple reward signals in the brain.

W Schultz — 2005-04-08T21:46:07-00:00

Nat Rev Neurosci, Vol. 1, No. 3. (December 2000), pp. 199-207.

The fundamental biological importance of rewards has created an increasing interest in the neuronal processing of reward information. The suggestion that the mechanisms underlying drug addiction might involve natural reward systems has also stimulated interest. This article focuses on recent neurophysiological studies in primates that have revealed that neurons in a limited number of brain structures carry specific signals about past and future rewards. This research provides the first step towards an understanding of how rewards influence behaviour before they are received and how the brain might use reward information to control learning and goal-directed behaviour.

Transient Calcium and Dopamine Increase PKA Activity and DARPP-32 Phosphorylation

Maria Lindskog — 2007-08-24T16:10:11-00:00

PLoS Computational Biology, Vol. 2, No. 9. (1 September 2006), e119.

Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.

Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system

EK Richfield — 2007-08-17T13:02:45-00:00

Neuroscience, Vol. 30, No. 3. (1989), pp. 767-777.

The anatomical distributions and affinity states of dopamine D1 and D2 receptors were compared in the rat central nervous system using quantitative autoradiography. [3H]SCH23390 and [3H]spiperone (in the presence of 100 nM mianserin) were used to label the D1, and D2 receptors, respectively. The densities of D1 and D2 receptors displayed a positive correlation among 21 brain regions (Pearson correlation coefficient, r = 0.80, P < 0.001). The affinity states for the D1 and D2 receptors were found to be quite different from each other, and different from the results obtained by others using homogenate preparations. Both the D1 and D2 receptors were best modeled using a two-state model. In the absence of exogenous guanine nucleotides and using the nonselective agonist dopamine as the competitor, the D1 receptor was primarily in a low affinity agonist state (RH = 21 +/- 6%), whereas the D2 receptor was primarily in the high affinity agonist state (RH = 77 +/- 3%). In the presence of 10 [mu]M guanylyl-imidodiphosphate orguanosine-5'-O-(2-thiophosphate) both the D1 and the D2 receptor were completely in a low affinity agonist state (RL = 100%). These affinity states were found both in the nucleus accumbens and olfactory tubercle using dopamine as the competitor and in the striatum using selective D1 or D2 agonists as competitors. Receptor occupancy of the D2 receptor with either an agonist or antagonist did not alter the affinity states of the D1 receptor, and conversely, receptor occupancy of the D1 receptor did not alter the affinity states of the D2 receptor. The correlation between densities of D1 and D2 receptors provides an anatomical framework for evaluating behavioral and electrophysiological evidence of an interaction between the two dopamine receptor subtypes. This interaction does not appear to be due to a sharing or coupling of G-proteins in such a way that binding to one dopamine receptor subtype alters the affinity state of the other receptor subtype. The differences between dopamine receptor distributions described by labeled agonists and antagonists may be due in part to differences in their affinity states. The low proportion of high affinity state D1 receptors may explain some of the difficulties in assigning specific behavioral roles to the D1 receptor.