CiteULike: Tag dopamine

[Dopamine system genes and personality traits of extraversion and novelty seeking]

VE Golimbet — 2006-12-02T12:01:06-00:00

Zh Vyssh Nerv Deiat Im I P Pavlova, Vol. 56, No. 4. (g 2006), pp. 457-463.

Dopamine neurotransmissin is thought to play a relevant role in behavioral reinforcement system. Polymorphism of the genes involved in dopamine system has been reported for association with psychological traits related to impulsive and sensation seeking behaviors. The study was aimed at a search for association of catechol-O-metyltransferase (COMT) and dopamine receptor D4 (DRD4) gene polymorphism with personality traits in Russian population. A sample comprised 130 subjects. It was found that carriers of the Met/Met COMT genotype had higher scores of novelty seeking as compared to those with the Val/Val and Met/Met genotypes. The association was observed in women only. In the presence of the C allele of the DRD4 gene, females with the Met/Met genotype demonstrated higher scores on extraversion and hypomania. The results are consistent with the current theoretical concepts on the regulation of dopamine neurotransmission in the brain.

Drug addiction. Part II. Neurobiology of addiction.

J Vetulani — 2006-03-25T21:29:34-00:00

Pol J Pharmacol, Vol. 53, No. 4. (g 2001), pp. 303-317.

The drug addiction may be regarded as the disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the limbic structures of the brain. Its existence was proved by demonstration of the "pleasure centers," that were discovered as location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamine, but other monoamines and acetylcholine may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures. Several of those structures may be specifically involved in the reward produced by different substances, when anticipating the reward. The recent discovery of CART peptides may importantly expand our knowledge about the neurochemistry of reward. Natural rewarding activities and artificial chemical rewarding stimuli act at the same locations, but while natural activities are controlled by feedback mechanisms that activate aversive centers, no such restrictions bind the responses to artificial stimuli. There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behavior. The craving induced by substances of addiction inhibits other behaviors. The adaptation of an organism to a chronic intake of drugs involves development of adaptive changes, sensitization or tolerance. It is thought that the gap between sensitization developing for the incentive value of the drug and tolerance to the reward induced by its consumption underlies the vicious circle of events leading to drug dependence. The vulnerability to addiction is dependent not only on the environment, but also on genetic factors.

Is there a common molecular pathway for addiction?

Eric Nestler — 2005-10-27T05:37:51-00:00

Nature Neuroscience, Vol. 8, No. 11. (26 October 2005), pp. 1445-1449.

Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation.

JF Cheer — 2008-05-14T23:59:16-00:00

The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 27, No. 4. (24 January 2007), pp. 791-795.

Transient surges of dopamine in the nucleus accumbens are associated with drug seeking. Using a voltammetric sensor with high temporal and spatial resolution, we demonstrate differences in the temporal profile of dopamine concentration transients caused by acute doses of nicotine, ethanol, and cocaine in the nucleus accumbens shell of freely moving rats. Despite differential release dynamics, all drug effects are uniformly inhibited by administration of rimonabant, a cannabinoid receptor (CB1) antagonist, suggesting that an increase in endocannabinoid tone facilitates the effects of commonly abused drugs on subsecond dopamine release. These time-resolved chemical measurements provide unique insight into the neurobiological effectiveness of rimonabant in treating addictive disorders.

D1 Dopamine Receptors in Prefrontal Cortex: Involvement in Working Memory

Toshiyuki Sawaguchi — 2006-03-27T23:11:20-00:00

The prefrontal cortex is involved in the cognitive process of working memory. Local injections of SCH23390 and SCH39166, selective antagonists of the D1 dopamine receptor, into the prefrontal cortex of thesus monkeys induced errors and increased latency in performance on an oculomotor task that required memory-guided saccades. The deficit was dose-dependent and sensitive to the duration of the delay period. These D1 antagonists bad no effect on performance in a control task requiring visually guided saccades, indicating that sensory and motor functions were unaltered. Thus, D1 dopamine receptors play a selective role in the mnemonic, predictive functions of the primate prefrontal cortex.

Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction.

PS Goldman-Rakic — 2006-02-21T01:17:28-00:00

Psychopharmacology (Berl), Vol. 174, No. 1. (June 2004), pp. 3-16.

BACKGROUND AND RATIONALE: Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D(1) receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D(1) stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia. OBJECTIVES: This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D(1) signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function. RESULTS AND CONCLUSIONS: Dopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D(1) receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D(1) receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia.

Assessment of Stromal-Derived Inducing Activity in the Generation of Dopaminergic Neurons from Human Embryonic Stem Cells

Tandis Vazin — 2008-04-08T22:01:26-00:00

Stem Cells (3 April 2008), 2008-0039.

Producing dopaminergic (DA) neurons is a major goal of human embryonic stem cell (hESC) research. DA neurons can be differentiated from hESC by co-culture with the mouse PA6 stromal cell line; this differentiation-inducing effect is termed stromal-derived inducing activity (SDIA). The molecular and biochemical nature of SDIA is, however, unknown. Various studies have suggested that SDIA involves either a fixation-resistant component located on the PA6 cell surface, or factors secreted into the medium by PA6 cells. To address this question, hESC were co-cultured with PA6 cells for 12 days, then further differentiated with SHH, FGF-8 and glial cell line-derived neurotrophic factor. After 18 days, 34% of cells were tyrosine hydroxylase (TH)+. When PA6 cells were fixed or irradiated, the number of TH+ cells was decreased by 3-fold, while mitomycin-c treatment of feeder cells decreased the number of TH+ cells by 32%. The neural-inducing effect of PA6 cells, as monitored by beta-III-tubulin expression, was minimally affected by mitomycin-c treatment or fixation, but was decreased 50% by irradiation. Medium conditioned by PA6 cells was ineffective in differentiating TH+ cells when used alone. Conditioned medium combined with heparin and/or fixed PA6 cells produced TH+ cell differentiation, although less effectively than PA6 cell co-culture. Thus, PA6 cell surface activity is required for neural differentiation of hESC, but secreted factors are required for the specific DA neuron-inducing effect. 10.1634/stemcells.2008-0039

Provocative tests with psychostimulant drugs in schizophrenia.

JA Lieberman — 2007-12-11T07:09:38-00:00

Psychopharmacology (Berl), Vol. 91, No. 4. (1987), pp. 415-433.

The psychotogenic effects of psychostimulant drugs have provided a major line of evidence in support of the DA hypothesis of schizophrenia. To evaluate the effects of psychostimulant (PS) drug in schizophrenia and the clinical variables which may influence their expression, we reviewed 36 studies of PS drugs in patients with schizophrenia. Approximately 40% evidence a psychotogenic response to PS administration in doses that are subpsychotogenic in normals. Specific clinical variables appear to modify this response, including diagnosis, degree and type of psychopathology, stage of illness and pharmacologic status at the time of testing. Non-amphetamine-like PS drugs, e.g., methylphenidate, appear to have greater psychotogenic potency than amphetamine-like PS drugs. These results suggest the presence of a subgroup of schizophrenic patients who exhibit psychotic symptom activation with PS in a state dependent or independent fashion. This biologic phenomenon may be clinically exploitable and should be investigated further.

Nucleus accumbens dopamine release is necessary and sufficient to promote the behavioral response to reward-predictive cues.

SM Nicola — 2006-09-02T22:41:55-00:00

Neuroscience, Vol. 135, No. 4. (2005), pp. 1025-1033.

The nucleus accumbens is part of the neural circuit that controls reward-seeking in response to reward-predictive cues. Dopamine release in the accumbens is essential for the normal functioning of this circuit. Previous studies have shown that injection of dopamine receptor antagonists into the accumbens severely impairs an animal's ability to perform operant behaviors specified by predictive cues. Furthermore, excitations and inhibitions of accumbens neurons evoked by such cues are abolished by inactivation of the ventral tegmental area, the major dopaminergic input to the accumbens. These results indicate that dopamine is necessary to elicit neural activity in the accumbens that drives the behavioral response to cues. Here we show that accumbens dopamine release is causal to the rats' reward-seeking behavioral response by demonstrating that dopamine in this structure is both necessary and sufficient to promote the appropriate behavioral response to reward-predictive cues.

Characterization of unconditioned behavioral effects of dopamine D3/D2 receptor agonists.

B Geter-Douglass — 2006-09-15T19:15:22-00:00

J Pharmacol Exp Ther, Vol. 283, No. 1. (October 1997), pp. 7-15.

A series of experiments examined the ability of dopamine D3/D2 receptor agonists [(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]b enzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD 128,907), (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT), quinpirole and bromocriptine] to produce a variety of dopaminergically mediated behaviors. The effects of these drugs with selectivity for D3/D2 receptors over D1 receptors were compared with those produced by the selective D1 agonists [(+/-)-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393), (+/-)-6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepine hydrobromide (SKF 82958)], a nonselective dopaminergic agonist (apomorphine), and an indirect dopamine agonist (cocaine). The D3/D2 agonists decreased locomotor activity, had no effect on gnawing and only inconsistently induced climbing in mice. Further, these agonists dose-dependently produced scratching in squirrel monkeys. In contrast, the D1 agonists, SKF 82958 and SKF 38393, did not produce scratching in squirrel monkeys. Whereas the full D1 agonist, SKF 82958, produced increases in locomotor activity and in climbing and gnawing, the partial D1 agonist, SKF 38393, did not increase the frequencies of these behaviors. The nonselective dopamine agonist, apomorphine, produced decreases in locomotor activity and increases in climbing and gnawing in mice. Apomorphine dose-dependently produced scratching in squirrel monkeys. The indirect dopamine agonist, cocaine, produced increases in locomotor activity and climbing, but had no effect on climbing or gnawing in mice and did not produce scratching in squirrel monkeys. These findings suggest that D3/D2 agonists can be distinguished on various behavioral measures from the nonselective agonist, apomorphine (gnawing), D1 agonists (scratching) and the indirect agonist, cocaine (locomotor activity and scratching). Behaviors once attributed to stimulation of D2 (locomotor activity and scratching) or D1/D2 (climbing and gnawing) receptors may also involve dopamine D3 receptors.

In vivo striatal binding of the D1 antagonist SCH 23390 is not modified by changes in dopaminergic transmission.

F Thibaut — 2007-01-16T16:14:58-00:00

Neuropharmacology, Vol. 35, No. 3. (March 1996), pp. 267-272.

The in vivo striatal binding of [3H]SCH 23390, an antagonist of the D1 dopamine receptors, was investigated in mice submitted to pretreatment to either decrease (gammabutyrolactone 750 mg/kg, i.p.) or, increase (3,4-dihydroxyphenylalanine (L-DOPA) 200 mg/kg i.p. plus dexamphetamine 4 mg/kg, s.c.) dopaminergic transmission. Such conditions failed to modify [3H]SCH 23390 binding. However, we observed that dopamine (at concentrations > or = 1 microM), reduced the in vitro binding of [3H]SCH 23390 in membrane fractions. These results suggest that modifications in dopamine neurotransmission do not alter the in vivo quantification of D1 receptors with [3H]SCH 23390, for example, in studies that use positron emission tomography.

Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics

Pierre Sokoloff — 2007-05-10T15:52:49-00:00

Nature, Vol. 347, No. 6289. (1990), pp. 146-151.

SCH23390 causes persistent antidopaminergic effects in vivo: evidence for longterm occupation of receptors.

DW Schulz — 2007-01-16T16:12:56-00:00

Life Sci, Vol. 36, No. 20. (20 May 1985), pp. 1941-1948.

SCH23390 has neurochemical properties characteristic of a specific D1 dopamine receptor antagonist. However, it is a potent inhibitor of dopamine-mediated behaviors which previously had been thought to be linked to D2 receptors. The metabolism of SCH23390 following parenteral administration to rats was much more rapid in the periphery than in brain, and SCH23390 had behavioral effects long after its circulating concentration had declined below detectable levels. Furthermore, the stimulation of adenylate cyclase by dopamine was attenuated in striatal homogenates taken from rats treated with SCH23390 as much as twelve hours before sacrifice. Pretreatment with cis-flupenthixol, a compound with equivalent D1 potency in vitro, failed to inhibit dopamine-stimulated adenylate cyclase activity one or four hours following injection, despite the fact that this dose produced significant behavioral effects. These data indicate that SCH23390 may act with unusual tenacity at certain sites in the central nervous system.

Differential regional and cellular distribution of dopamine D2-like receptors: An immunocytochemical study of subtype-specific antibodies in rat and human brain

Zafar Khan — 2007-05-10T15:46:47-00:00

The Journal of Comparative Neurology, Vol. 402, No. 3. (1998), pp. 353-371.

Dopamine D2-like receptors (D2, D3, and D4) are major targets for action of typical and atypical neuroleptics, commonly used in the treatment of schizophrenia. To understand their individual functional contribution, subtype-selective anti-peptide antibodies were raised against D2, D3, and D4 receptor proteins. The antibodies were shown to be specific on immunoblots of rat brain membranes and immunoprecipitated the solubilized native dopamine receptors in an antibody concentration-dependent manner. In addition, they also bind selectively to the respective recombinant D2, D3, and D4 receptor membrane proteins from cDNA transfected cells. Immunolocalization studies show that the D2-like receptor proteins had differential regional and cellular distribution in the cerebral cortex, hippocampus, basal ganglia, cerebellum, and midbrain, thus providing anatomical substrate for area-specific regulation of the dopamine neurotransmission. In cortical neurons, D4 receptor protein was found in both pyramidal and nonpyramidal cells, whereas D2 and D3 seem to be mostly associated with nonpyramidal interneurons. In rat hippocampus, the expression pattern of D2-like receptors (D4>D3>D2) mirrored that obtained with immunoprecipitation studies. D2 and D4 receptor immunolabeling was observed in the thalamic reticular nucleus, which was negative for the D3 subtype. Species differences were also observed; for example, the D4 subtype receptor is the most highly expressed protein in the rat cortex, whereas it is significantly less in human cortex. Differential patterns of D2, D3, and D4 receptor expression in rat and human brain should shed light on the therapeutic actions of neuroleptic drugs and may lead to the development of more specifically targeted antipsychotic drugs. J. Comp. Neurol. 402:353-371, 1998. © 1998 Wiley-Liss, Inc.

Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus.

H Wang — 2006-08-24T21:10:14-00:00

J Comp Neurol, Vol. 442, No. 4. (21 January 2002), pp. 392-404.

Glutamatergic neurons within the deep layers of the prefrontal cortex and dopaminergic neurons of the substantia nigra pars compacta preferentially terminate in patch-like regions within the caudate putamen nucleus (CPN). Activation of dopamine D2 receptors is known to potently modulate striatal glutamatergic transmission and may play a role in reward-based motor learning. To determine the cellular substrate for D2-mediated regulation of prefrontal corticostriatal transmission in striatal patches, we combined anterograde transport of biotinylated dextran amine (BDA) with immunogold-silver labeling of a D2 receptor antipeptide antiserum in rat brain. Injections centered in deep layers of the dorsal part of the anterior cingulate cortex, one of the prefrontal cortical regions, produced varicose axonal BDA labeling in a patch-like distribution in the dorsomedial CPN. Electron microscopy showed that in these patch compartments, BDA labeling was present exclusively in axons and terminals (total number = 581), 9% of which contained detectable D2-like immunoreactivity. Thirty percent of the BDA-labeled terminals formed asymmetric excitatory synapses with dendritic spine heads, and the remainder were without recognizable junctions. The recipient spines were unlabeled or contained immunogold-silver particles for D2 receptors. A few of the D2-labeled spines also received convergent, often nonsynaptic contact from D2-labeled terminals resembling dopaminergic afferents. In addition, the corticostriatal terminals often apposed spiny and nonspiny neuronal profiles that contained D2 labeling. These results suggest that dopamine D2 receptors are strategically positioned for presynaptic and postsynaptic modulation of prefrontal corticostriatal excitation of spiny neurons in striatal patches. The findings have direct implications for D2-mediated control of reward-related motor learning.

NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine

A Verma — 2007-05-10T15:45:14-00:00

J. Neurosci., Vol. 16, No. 1. (1 January 1996), pp. 373-379.

Dopaminergic modulation of prefrontal cortical input to nucleus accumbens neurons in vivo.

AM Brady — 2006-08-29T00:08:19-00:00

J Neurosci, Vol. 24, No. 5. (4 February 2004), pp. 1040-1049.

Dopaminergic transmission in the nucleus accumbens has been proposed to modulate the effects of converging excitatory inputs from the cortex, hippocampus, and amygdala. Here, we used in vivo intracellular recording in anesthetized rats to examine the response of nucleus accumbens neurons to stimulation of the prefrontal cortex (PFC) and the ventral tegmental area (VTA). The EPSP elicited in accumbens neurons by PFC stimulation was attenuated by VTA train stimulation in a pattern mimicking dopamine cell burst firing. PFC-elicited EPSPs were smaller in amplitude and faster to decay after VTA stimulation. These changes could not be explained by membrane depolarization alone, because EPSPs evoked during the sustained depolarization after VTA stimulation were significantly smaller than EPSPs evoked during spontaneously occurring up states. Furthermore, no attenuation of PFC-elicited responses was observed during depolarization produced by positive current injection through the recording electrode. Administration of a D1 antagonist (SCH 23390; 0.5 mg/kg, i.p.) had no effect on the VTA reduction of PFC-elicited responses, whereas administration of a D2 antagonist (eticlopride; 0.5 mg/kg, i.p.) reversed the reduction of PFC inputs when the analysis was limited to comparisons with spontaneous up states. These results suggest that the ability of PFC inputs to drive accumbens neurons is dampened by dopamine acting primarily at D2 receptors. Along with previous reports of dopaminergic attenuation of limbic afferents to the accumbens, these findings support the hypothesis that dopamine mediates the selection and integration of excitatory inputs and thus shapes information processing in accumbens output neurons.

Selective responding of nucleus accumbens core and shell dopamine to aversively conditioned contextual and discrete stimuli

MA Pezze — 2007-01-31T01:51:50-00:00

Neuroscience, Vol. 108, No. 1. (5 December 2001), pp. 91-102.

Dopamine transmission within the nucleus accumbens has been implicated as a neurochemical substrate of associative learning processes. It has been suggested that the acquisition of classically conditioned fear to a specific environment, or context, differs fundamentally from the development of conditioned fear to a discrete stimulus, such as a light or a tone. In this study, we assessed extracellular dopamine in the rat nucleus accumbens shell and core during the expression of a conditioned fear response. Animals were aversively conditioned to either a context or a tone and extracellular dopamine was measured in the nucleus accumbens shell and core by in vivo microdialysis over the next 2 days as animals were returned first to the conditioning chamber (day 1: context test), and subsequently as animals were again returned to the chamber and presented with the conditioned tone stimulus (day 2: tone test). Dopamine levels in the core were significantly higher in the Context-Shock group compared to the Tone-Shock group during the 30-min exposure to context while dopamine levels in the nucleus accumbens shell did not differ significantly during the context test between groups. In contrast, extracellular dopamine in the shell but not the core of Tone-Shock animals increased significantly during presentation of the tone. Dopamine in both the shell and core remained unchanged during the tone test in the Context-Shock groups. These data suggest distinct roles for shell and core dopamine transmission in the expression of a conditioned emotional response. While dopamine increased in the shell primarily during the presentation of a discrete tone conditioned stimulus, core dopamine responded more to a contextual conditioned stimulus. These results may reflect differences in either the type of information acquired or the salience of the learned associations which are formed to a context vs. a discrete tone cue.

NMDA antagonist effects on striatal dopamine release: microdialysis studies in awake monkeys.

BW Adams — 2006-08-03T17:07:34-00:00

Synapse, Vol. 43, No. 1. (January 2002), pp. 12-18.

Brain imaging studies have suggested that the NMDA antagonist ketamine is as potent a releaser of striatal dopamine as amphetamine. This conclusion contradicts microdialysis findings in the rodent that NMDA antagonists, in contrast to amphetamine, have little or no effect on striatal dopamine release. The present study addressed two mechanisms that could account for this discrepancy: 1) whether there is a species difference, i.e., rodents vs. primates, in the responsivity of striatal dopamine to NMDA antagonists, and 2) whether rapid uptake of dopamine prevents reliable measures of synaptic dopamine release by microdialysis in response to NMDA antagonists. MRI-directed in vivo microdialysis was used to compare the effects of psychotomimetic NMDA antagonists phencyclidine (PCP), ketamine, and amphetamine on extracellular striatal dopamine levels in awake rhesus monkeys. The effect of PCP was also investigated in the presence of intrastriatally applied nomifensine, a dopamine uptake blocker. Amphetamine (0.1 or 0.4 mg/kg) produced robust and dose-dependent increases in dopamine release ranging 2-10-fold above baseline. PCP at 0.1 mg/kg had no effect and at 0.3 mg/kg produced a small 50% increase over baseline. Ketamine, at the relatively high dose of 5 mg/kg, produced only a 30% increase in dopamine release. Intrastriatal application of nomifensine did not influence the effect of PCP, suggesting that rapid uptake of dopamine is not preventing the detection of a PCP-induced increase in dopamine release. These findings suggest that in the primate, ketamine and PCP are not effective dopamine releasers, as has been suggested by previous imaging studies.

Ultrastructural features of the nitric oxide synthase-containing interneurons in the nucleus accumbens and their relationship with tyrosine hydroxylase-containing terminals.

S Hidaka — 2006-08-24T16:09:32-00:00

J Comp Neurol, Vol. 431, No. 2. (5 March 2001), pp. 139-154.

The ultrastructural features of neuronal nitric oxide synthase (NOS) -immunoreactive interneurons of rat nucleus accumbens shell and core were studied and compared. The NOS-containing subpopulation displayed characteristics similar to those previously described for nicotinamide adenine dinucleotide phosphate diaphorase-, neuropeptide Y, or somatostatin-containing striatal neurons, but also showed properties not previously associated with them, particularly the formation of both asymmetric and symmetric synaptic junctions. Inputs derived mainly from unlabeled terminals, but some contacts were made by NOS-immunolabeled terminals, by means of asymmetric synapses. Immunopositive endings that formed symmetric synapses were mainly onto dendritic shafts, whereas those that formed asymmetric synapses targeted spine heads. Morphometric analysis revealed that the core and shell NOS-stained neurons had subtly different innervation patterns and that immunostained terminals were significantly larger in the shell. A parallel investigation explored synaptic associations with dopaminergic innervation identified by labeling with an antibody against tyrosine hydroxylase (TH). In both shell and core, TH-positive boutons formed symmetric synapses onto NOS-containing dendrites, and in the core, TH- and NOS-immunolabeled terminals converged on both a single spiny dendrite and a spine. These results suggest that, in the rat nucleus accumbens, NOS-containing neurons may be further partitioned into subtypes, with differing connectivities in shell and core regions. These NOS-containing neurons may be influenced by a dopaminergic input. Recent studies suggest that nitric oxide potentiates dopamine release and the current study identifies the medium-sized, densely spiny neurons as a possible site of such an interaction.

Anatomical substrates for glutamate-dopamine interactions: evidence for specificity of connections and extrasynaptic actions.

SR Sesack — 2006-08-24T15:37:33-00:00

Ann N Y Acad Sci, Vol. 1003 (November 2003), pp. 36-52.

For normal regulation of motor, affective, and cognitive functions, dopamine provides an essential modulation of glutamate transmission within multiple brain regions. This paper will review three principal anatomical substrates for such interactions. First, dopamine modulates the activity of glutamate neurons within the cerebral cortex. Evidence will be reviewed for dopamine regulation of pyramidal neurons in the prefrontal cortex via synaptic and extrasynaptic mechanisms and through indirect effects mediated by GABA cells. Second, glutamate neurons innervate dopamine cells within the ventral tegmental area. Evidence will be described for selective glutamate input from the prefrontal cortex or the brain stem tegmentum to different populations of dopamine cells. The third level of interaction occurs within target regions via convergent synaptic or extrasynaptic regulation of common neurons. Such convergence will be reviewed for the basal ganglia, prefrontal cortex, and amygdala. Together, these substrates for glutamate-dopamine interactions provide several mechanisms for normal regulation of brain function. Sites of modulatory interaction between dopamine and glutamate also suggest circuit alterations that might contribute to the pathophysiology of mental health disorders and provide potential sites for therapeutic intervention in these conditions.

Overlapping intracellular and differential synaptic distributions of dopamine D1 and glutamate N-methyl-D-aspartate receptors in rat nucleus accumbens.

Y Hara — 2006-08-24T15:13:04-00:00

J Comp Neurol, Vol. 492, No. 4. (28 November 2005), pp. 442-455.

The dopamine D1 receptor (D1R) in the nucleus accumbens (Acb) shell is highly implicated in psychostimulant-evoked locomotor activity and reward, whereas the D1R in the Acb core is more crucial for appetitive instrumental learning. These behavioral effects depend in part on interactions involving glutamatergic N-methyl-D-aspartate (NMDA) receptors, whose essential NR1 subunit has physical associations with the D1R. To determine the relevant sites for D1R activation and interactions involving NMDA receptors, we examined the electron microscopic immunolabeling of D1R and NR1 C-terminal peptides in rat Acb shell and core. In each Acb subdivision, the D1Rs were located principally on extrasynaptic plasma membranes of dendritic shafts and spines and more rarely were associated with cytoplasmic endomembranes. Many D1R-labeled somata and dendrites also contained NR1 immunoreactivity. In comparison with D1R, NR1 immunoreactivity was more often seen in the cytoplasm and near asymmetric synapses on somatodendritic profiles. In these profiles, notable overlapping distributions of D1R and NR1 occurred near endomembranes. The exclusively D1R- or D1R- and NR1-containing dendrites were most prevalent in the Acb shell, but were also present in the Acb core. In each region, NR1 was also detected in axon terminals without D1R, which formed excitatory-type synapses with D1R-labeled dendrites. These results provide ultrastructural evidence that D1Rs in the Acb have subcellular distributions supporting, 1) intracellular cotrafficking with NR1 and 2) modulation of the postsynaptic excitability in spiny neurons affected by presynaptic NMDA receptor activation. The region-specific differences in receptor distributions suggest a major, but not exclusive, involvement of Acb D1R in reward-related processing.

Distinct functions of the two isoforms of dopamine D2 receptors

Alessandro Usiello — 2006-08-09T21:41:44-00:00

Nature, Vol. 408, No. 6809. (November 2000), pp. 199-203.

Input from the amygdala to the rat nucleus accumbens: its relationship with tyrosine hydroxylase immunoreactivity and identified neurons.

LR Johnson — 2006-08-24T14:56:42-00:00

Neuroscience, Vol. 61, No. 4. (August 1994), pp. 851-865.

Both tyrosine hydroxylase-positive fibres from the mesolimbic dopamine system and amygdala projection fibres from the basolateral nucleus are known to terminate heavily in the nucleus accumbens. Caudal amygdala fibres travelling dorsally via the stria terminalis project densely to the nucleus accumbens shell, especially in the dopamine rich septal hook. The amygdala has been associated with the recognition of emotionally relevant stimuli while the mesolimbic dopamine system is implicated with reward mechanisms. There is behavioural and electrophysiological evidence that the amygdala input to the nucleus accumbens is modulated by the mesolimbic dopamine input, but it is not known how these pathways interact anatomically within the nucleus accumbens. Using a variety of neuroanatomical techniques including anterograde and retrograde tracing, immunocytochemistry and intracellular filling, we have demonstrated convergence of these inputs on to medium-sized spiny neurons. The terminals of the basolateral amygdala projection make asymmetrical synapses predominantly on the heads of spines which also receive on their necks or adjacent dendrites, symmetrical synaptic input from the mesolimbic dopamine system. Some of these neurons have also been identified as projection neurons, possibly to the ventral pallidum. We have shown a synaptic level how dopamine is positioned to modulate excitatory limbic input in the nucleus accumbens.

Repeated exposure to amphetamine disrupts dopaminergic modulation of excitatory synaptic plasticity and neurotransmission in nucleus accumbens

Yong Li — 2007-06-07T14:03:24-00:00

Synapse, Vol. 51, No. 1. (2004), pp. 1-10.

The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse perturb the normal functioning of this pathway. The nucleus accumbens (NAc) is a major terminal field of the mesolimbic dopamine neurons and modifications in neuronal structure and function in NAc accompany repeated exposure to psychomotor stimulants and other addictive drugs. Glutamatergic afferents to the NAc are thought to be crucial to the development of several aspects of addictive behavior, including behavioral sensitization and relapse to cocaine self-administration. Here we examine glutamatergic neurotransmission and synaptic plasticity in NAc neurons in vitro before and after repeated amphetamine treatment in vivo. We find that dopamine attenuates the response of NAc neurons to repetitive activation of glutamatergic afferents and thereby blocks long-term potentiation (LTP) induced by high-frequency afferent stimulation. Dopamine's effects are mimicked by dopamine receptor agonists and by amphetamine. In a second set of experiments, animals were treated with amphetamine daily for 6 days and brain slices were prepared after 8-10 days of withdrawal. In these slices, LTP in the NAc appears normal. However, acute exposure of such slices to amphetamine no longer modulates synaptic transmission or LTP induction. Thus, repeated exposure to amphetamine produces long-lasting changes in the modulation of glutamatergic synaptic transmission by amphetamine in the NAc. Our results support the notion that after psychostimulant exposure, excitatory synapses on NAc neurons alter their response to further psychostimulant for long periods of time. Synapse 51:1-10, 2004. © 2003 Wiley-Liss, Inc.

A Postsynaptic Interaction between Dopamine D1 and NMDA Receptors Promotes Presynaptic Inhibition in the Rat Nucleus Accumbens via Adenosine Release

Jenni Harvey — 2007-02-03T21:24:50-00:00

J. Neurosci., Vol. 17, No. 14. (15 July 1997), pp. 5271-5280.

Electrophysiological evidence for the existence of both D-1 and D-2 dopamine receptors in the rat nucleus accumbens

Fj White — 2006-09-17T19:25:03-00:00

J. Neurosci., Vol. 6, No. 1. (1 January 1986), pp. 274-280.

Comparison of effects of D-1 and D-2 dopamine receptor agonists on neurons in the rat caudate putamen: an electrophysiological study

Xt Hu — 2006-09-17T19:20:49-00:00

J. Neurosci., Vol. 8, No. 11. (1 November 1988), pp. 4340-4348.

The duration of the effects of a single administration of dopamine antagonists on ambulatory activity and motor coordination.

A Agmo — 2007-01-16T16:16:57-00:00

J Neural Transm, Vol. 106, No. 3-4. (1999), pp. 219-227.

Pimozide, cis(Z)-flupenthixol, SCH 23390 and sulpiride were administered to male rats. Each subject received a single drug injection, and tests for ambulatory activity and motor coordination were performed 1, 24, 48 and 72 hrs later. All drugs reduced ambulatory activity at the test 1 hr postinjection. Pimozide and SCH 23390 continued to reduce ambulatory activity at the test 24 hrs after injection. All drugs impaired motor coordination 1 hr after injection and, with the exception of SCH 23390, were also effective at the 24 hrs test. Flupenthixol, 2 mg/kg, continued to impair motor coordination also at the 48 hrs test. These data show that effects of dopamine antagonists on motor functions may persist for much longer than is generally believed. That should be important to take into account in experimental designs where repeated drug administration is employed.

Multi-walled carbon nanotubes with poly(methylene blue) composite film for the enhancement and separation of electroanalytical responses of catecholamine and ascorbic acid

Umasankar Yogeswaran — 2008-03-07T06:15:34-00:00

Sensors and Actuators B: Chemical, Vol. In Press, Corrected Proof

A novel conductive composite film containing multi-walled carbon nanotubes (MWCNTs) with poly(methylene blue) (PMB) has been synthesized on glassy carbon electrode (GCE), gold and indium tin oxide electrodes by potentiostatic methods. The presence of MWCNTs in the composite film enhance the surface coverage concentration ([Gamma]) of PMB, increased the electron transfer rate constant (Ks) by 44.53% and decreased the degradation of PMB during the cycling. The composite film exhibits a promising higher electrocatalytic activity towards the oxidation of ascorbic acid (AA), epinephrine (EP) and dopamine (DA) present in pH 7.4 aqueous solution. The presence of PMB in the composite film enhances the functional properties and overall increase in the sensitivity of the composite film modified electrodes. Both, the cyclic voltammetry (CV) and square wave voltammetry (SWV) have been used for the measurement of electroanalytical properties of analytes by means of composite film modified electrodes. In CV, well-separated voltammetric peaks have been obtained at the composite film modified GCEs for AA-EP and AA-DA mixture with a peak separation of 144.36 and 164.00 mV, respectively. The detection limit values obtained are equivalent to the concentrations found in physiological conditions. Similar sensitivity values have been observed in CV and semi-derivative SWV. Further, the electrochemical quartz crystal microbalance and scanning electron microscopy have been used to reveal the enhancements in functional properties and surface morphology of the composite film.

Separation and concentration effect of f-MWCNTs on electrocatalytic responses of ascorbic acid, dopamine and uric acid at f-MWCNTs incorporated with poly (neutral red) composite films

Umasankar Yogeswaran — 2008-03-06T18:24:53-00:00

Electrochimica Acta, Vol. 52, No. 19. (25 May 2007), pp. 5985-5996.

A novel conductive composite film containing functionalized multi-walled carbon nanotubes (f-MWCNTs) with poly (neutral red) (PNR) was synthesized on glassy carbon electrodes (GC) by potentiostatic method. The composite film exhibited promising electrocatalytic oxidation of mixture of biochemical compounds such as ascorbic acid (AA), dopamine (DA) and uric acid (UA) in pH 4.0 aqueous solutions. It was also produced on gold electrodes by using electrochemical quartz crystal microbalance technique, which revealed that the functional properties of composite film were enhanced because of the presence of both f-MWCNTs and PNR. The surface morphology of the polymer and composite film deposited on transparent semiconductor tin oxide electrodes were studied using scanning electron microscopy and atomic force microscopy. These two techniques showed that the PNR was fibrous and incorporated on f-MWCNTs. The electrocatalytic responses of neurotransmitters at composite films were measured using both cyclic voltammetry (CV) and differential pulse voltammetry (DPV). These experiments revealed that the difference in f-MWCNTs loading present in the composite film affected the electrocatalysis in such a way, that higher the loading showed an enhanced electrocatalytic activity. From further electrocatalysis studies, well separated voltammetric peaks were obtained at the composite film modified GC for AA, DA and UA with the peak separation of 0.17 V between AA-DA and 0.15 V between DA-UA. The sensitivity of the composite film towards AA, DA and UA in DPV technique was found to be 0.028, 0.146 and 0.084 [mu]A [mu]M-1, respectively.

D1-Like Dopamine Receptor Activation Modulates GABAergic Inhibition But Not Electrical Coupling between Neocortical Fast-Spiking Interneurons

Stephen Towers — 2008-03-06T14:18:15-00:00

J. Neurosci., Vol. 28, No. 10. (5 March 2008), pp. 2633-2641.

Dopamine, acting through D1 receptors, is thought to play an important role in cognitive functions of the frontal cortex such as working memory. D1 receptors are widely expressed in fast-spiking (FS) interneurons, a prominent class of inhibitory cells that exert a powerful control of neuronal firing through proximal synapses on their postsynaptic targets. FS cells are extensively mutually interconnected by both GABAA receptor-mediated synapses and gap junction-mediated electrical synapses, and networks of FS cells play a crucial role in the generation of rhythmic synchronous activity. Although recent studies have documented the effects of dopamine modulation of neocortical synaptic connections among excitatory cells and between excitatory and various inhibitory cells, the effects of dopamine receptor activation on GABAergic and electrical interactions among FS cells is not known. To resolve this, we recorded from pairs of FS cells in the infragranular layers of mouse neocortical slices and tested the effects of D1-like (D1/D5) receptor activation on these connections. We found that D1-like receptor activation modulated GABAergic but not electrical connections between them. A D1-like receptor agonist preserved the strength of electrical coupling but reduced the amplitude of IPSPs and IPSCs between FS cells. Our results suggest that D1-like receptor activation has synapse-specific effects within networks of FS cells, with potential implications for the generation of rhythmic activity in the neocortex. 10.1523/JNEUROSCI.5079-07.2008

Dopamine Receptor Activation Is Required for Corticostriatal Spike-Timing-Dependent Plasticity

Verena Pawlak — 2008-03-06T14:16:09-00:00

J. Neurosci., Vol. 28, No. 10. (5 March 2008), pp. 2435-2446.

Single action potentials (APs) backpropagate into the higher-order dendrites of striatal spiny projection neurons during cortically driven "up" states. The timing of these backpropagating APs relative to the arriving corticostriatal excitatory inputs determines changes in dendritic calcium concentration. The question arises to whether this spike-timing relative to cortical excitatory inputs can also induce synaptic plasticity at corticostriatal synapses. Here we show that timing of single postsynaptic APs relative to the cortically evoked EPSP determines both the direction and the strength of synaptic plasticity in spiny projection neurons. Single APs occurring 30 ms before the cortically evoked EPSP induced long-term depression (LTD), whereas APs occurring 10 ms after the EPSP induced long-term potentiation (LTP). The amount of plasticity decreased as the time between the APs and EPSPs was increased, with the resulting spike-timing window being broader for LTD than for LTP. In addition, we show that dopamine receptor activation is required for this spike-timing-dependent plasticity (STDP). Blocking dopamine D1/D5 receptors prevented both LTD and LTP induction. In contrast, blocking dopamine D2 receptors delayed, but did not prevent, LTD and sped induction of LTP. We conclude (1) that, in combination with cortical inputs, single APs evoked in spiny projection neurons can induce both LTP and LTD of the corticostriatal pathway; (2) that the strength and direction of these synaptic changes depend deterministically on the AP timing relative to the arriving cortical inputs; (3) that, whereas dopamine D2 receptor activation modulates the initial phase of striatal STDP, dopamine D1/D5 receptor activation is critically required for striatal STDP. Thus, the timing of APs relative to cortical inputs alone is not enough to induce corticostriatal plasticity, implying that ongoing activity does not affect synaptic strength unless dopamine receptors are activated. 10.1523/JNEUROSCI.4402-07.2008

Interplay between neuromodulator-induced switching of short-term plasticity at sensorimotor synapses in the neonatal rat spinal cord

Barriere — 2008-04-03T18:15:18-00:00

The Journal of Physiology, Vol. 586, No. 7. (April 2008), pp. 1903-1920.

Rat-PET study without anesthesia: anesthetics modify the dopamine D1 receptor binding in rat brain.

S Momosaki — 2008-06-12T09:04:35-00:00

Synapse (New York, N.Y.), Vol. 54, No. 4. (15 December 2004), pp. 207-213.

Positron emission tomography (PET) measurements in 6-month-old F344/N rats were performed in the conscious state and the influence of chloral hydrate, ketamine, and pentobarbital anesthesia on dopamine D(1) (DA-D(1)) receptor binding was evaluated using [(11)C]SCH23390, a selective DA-D(1) receptor ligand. To perform the PET study in conscious rats, an original fixation apparatus was developed and the animals were trained to acclimate to the scanning atmosphere for 3 h. This training was carried out twice a day for 2 weeks. PET measurements in conscious rats were successful, since the trained rats scarcely moved during the scanning (as monitored by video camera) and since highly reproducible measurements of binding potential (BP) were derived from their scanning. Chloral hydrate and ketamine anesthesia significantly increased the striatal BP of DA-D(1) receptors by 36% and 46%, respectively, compared to that observed in the conscious state. In contrast, pentobarbital markedly decreased the BP by 41%. These BP values of DA-D(1) receptors were calculated using a curve-fitting method. Our results indicate that PET studies in rats should be performed in the conscious state since the anesthetics dramatically modified ligand-receptor bindings, such as DA-D(1) receptor binding, in rat brain.

Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine.

R Kuczenski — 2008-06-03T13:55:47-00:00

The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 15, No. 2. (February 1995), pp. 1308-1317.

Microdialysis in behaving animals was used to concomitantly characterize the dopamine and 5-HT responses in the caudate and the norepinephrine response in the hippocampus to the D- and L-isomers of amphetamine and methamphetamine. Doses of all four drugs which promoted similar stereotypy responses produced a D-amphetamine-like response profile of dopamine and dopamine metabolites, suggesting that all these drugs interact with dopamine systems to facilitate the release of transmitter. However, in contrast to the similar behavioral profiles, the magnitude of the dopamine responses diverged significantly. In addition, all four drugs increased extracellular norepinephrine and 5-HT, but the relative responses differed markedly from dopamine and from each other. The contrasting structure-activity relationships for these drugs likely reflect their differential potency at the various neuronal uptake transporters in promoting either transmitter release, and/or uptake blockade. In addition, the interaction of each drug at the vesicular transporters, as well as the availability of a cytoplasmic pool of transmitter likely also contribute to the neurotransmitter response. Because of the particularly divergent transmitter response profiles exhibited by L-methamphetamine, its behavioral and neurotransmitter effects were characterized over a more extended range of doses. Although the duration of the increase in extracellular dopamine was clearly proportional to dose, the dose-dependent increases in the magnitude of the dopamine response did not parallel the behavioral profiles. The results of these studies indicate that, while the dopamine, norepinephrine and 5-HT responses to these drugs probably contribute to the expression of stimulant-induced behaviors, simple relationships between the neurotransmitter responses and the behavioral profiles were not evident.

Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum.

AK Cadogan — 2008-06-03T13:40:12-00:00

Journal of neurochemistry, Vol. 69, No. 3. (September 1997), pp. 1131-1137.

Using the endogenous cannabinoid receptor agonist anandamide, the synthetic agonist CP 55940 [[1alpha,2beta(R)5alpha]-(-)-5-(1,1-dimethylheptyl+ ++)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and the specific antagonist SR 141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride], second messenger activation of the central cannabinoid receptor (CB1) was examined in rat striatal and cortical slices. The effects of these cannabinoid ligands on electrically evoked dopamine (DA) release from [3H] dopamine-prelabelled striatal slices were also investigated. CP 55940 (1 microM) and anandamide (10 microM) caused significant reductions in forskolin-stimulated cyclic AMP accumulation in rat striatal slices, which were reversed in the presence of SR 141716 (1 microM). CP 55940 (1 microM) had no effect on either KCl- or neurotransmitter-stimulated 3H-inositol phosphate accumulation in rat cortical slices. CP 55940 and anandamide caused significant reductions in the release of dopamine after electrical stimulation of [3H]dopamine-prelabelied striatal slices, which were antagonised by SR 141716. SR 141716 alone had no effect on electrically evoked dopamine release from rat striatal slices. These data indicate that the CB1 receptors in rat striatum are negatively linked to adenylyl cyclase and dopamine release. That the CB1 receptor may influence dopamine release in the striatum suggests that cannabinoids play a modulatory role in dopaminergic neuronal pathways.

Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine.

R Kuczenski — 2008-06-03T13:37:22-00:00

Journal of neurochemistry, Vol. 68, No. 5. (May 1997), pp. 2032-2037.

Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.

A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study.

JS Markowitz — 2008-06-03T12:43:38-00:00

Journal of child and adolescent psychopharmacology, Vol. 16, No. 6. (December 2006), pp. 687-698.

dl-Methylphenidate (MPH) has been widely used to treat attention-deficit/hyperactivity disorder (ADHD) for the last half century. It had been exclusively available in the racemic form, i.e., a 50:50 mixture of d- and l-isomers. However, a single enantiomer formulation, d-MPH (dexmethylphenidate), became available for general clinical use in 2002. For this reason, the intrinsic pharmacological differences in the effects of d- and l-MPH have recently come under intense investigation. The primary therapeutic effects of MPH are generally recognized to reside in the d-isomer. The present investigation provides quantitative values for a broad range of receptor-level interactions of the individual MPH isomers to better characterize the distinction between dl-MPH versus d-MPH versus l-MPH as it relates to binding affinity at sites associated with relevant central nervous system (CNS) pharmacology, as well as peripheral physiology. Overall, there were few differences in binding affinities between d-MPH and the racemate whereas there were more apparent differences between d-MPH and l-MPH. d-MPH exhibited prominent affinity at the norepinephrine transporter (NET) site, even exceeding such affinity at the dopamine transporter (DAT). These results further demonstrate that affinity for catecholaminergic sites largely resides in the d-MPH isomer. Although binding affinity was not demonstrable at the serotonin (5-HT) transporter site (SERT), novel findings of the study included affinity for the 5-HT1A and 5-HT2B receptor sites for both d- and l-MPH, with d-MPH exerting by far the most predominant effects at these sites. Thus, the emerging data of favorable therapeutic effects of ADHD treatment with d-MPH (and dl-MPH) may be underpinned by affinity and potential pharmacologic effects at NET and DAT sites, as well as sites relevant to serotonergic neurotransmission that may modulate mood, cognition, and motor behavior. However, the present exploratory studies reflect receptor binding affinities only. The specific pharmacological activities (i.e., agonism vs. antagonism) of these compounds await further exploration.

Imaging the Dopamine System with In Vivo [11C]raclopride Displacement Studies: Understanding the True Mechanism.

N Ginovart — 2008-01-28T15:50:19-00:00

Mol Imaging Biol, Vol. 7, No. 1. (b 2005), pp. 45-52.

Measuring changes in dopamine (DA) levels in humans using radioligand-displacement studies and positron emission tomography (PET) has provided important empirical findings in diseases and normal neurophysiology. These studies are based on the assumption that DA exerts a competitive inhibition on D(2)-radioligand binding. However, the transfer of this hypothesis to a proven mechanism has not been fully achieved yet and an accumulating number of studies challenge it. In addition, new evidence suggests that DA exerts a noncompetitive inhibition on D(2)-radioligand binding under amphetamine conditions. This article reviews the theoretical basis for the DA competition hypothesis, the in vivo and in vitro evidences supporting a noncompetitive action of DA on D(2)-radioligand binding under amphetamine conditions, and discusses possible mechanisms underlying this noncompetitive interaction. Finally, we propose that such noncompetitive interactions may have important implications for how one interprets findings obtained from radioligand-displacement PET studies in neuropsychiatric diseases, especially in schizophrenia in which a dysregulation of the DA-promoted internalization of D(2) receptors was recently suggested.

Amphetamine induces dopamine efflux through a dopamine transporter channel.

KM Kahlig — 2008-05-07T09:32:09-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 9. (1 March 2005), pp. 3495-3500.

Drugs of abuse, including cocaine, amphetamine (AMPH), and heroin, elevate extracellular dopamine (DA) levels in the brain, thereby altering the activity/plasticity of reward circuits and precipitating addiction. The physiological release of DA occurs through the calcium-dependent fusion of a synaptic vesicle with the plasma membrane. Extracellular DA is cleared by uptake through the Na+/Cl- -dependent DA transporter (DAT). In contrast, the substrate AMPH induces nonvesicular release of DA mediated by DAT. Extracellular AMPH is generally believed to trigger DA efflux through DAT by facilitating exchange for cytosolic DA. Here, in outside-out patches from heterologous cells stably expressing DAT or from dopaminergic neurons, by using ionic conditions in the patch pipette that mimic those produced by AMPH stimulation, we report that AMPH causes DAT-mediated DA efflux by two independent mechanisms: (i) a slow process consistent with an exchange mechanism and (ii) a process that results in rapid (millisecond) bursts of DA efflux through a channel-like mode of DAT. Because channel-like release of DA induced by AMPH is rapid and contains a large number of DA molecules, with a single burst of DA on par with a quantum of DA from exocytotic release of a vesicle, this burst mode of release may play a role in the synaptic actions and psychostimulant properties of AMPH and related compounds. Unlike AMPH, the endogenous substrate DA, when present on both sides of the plasma membrane, inhibits this channel-like activity, thereby suggesting that the DAT channel-like mode cannot accumulate DA against a concentration gradient.

Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine.

JM Williams — 2008-05-07T09:28:45-00:00

PLoS biology, Vol. 5, No. 10. (16 October 2007), pp. 2369-2378.

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level-dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders.

Sex differences in amphetamine-induced displacement of [(18)F]fallypride in striatal and extrastriatal regions: a PET study.

P Riccardi — 2008-02-21T15:43:48-00:00

Am J Psychiatry, Vol. 163, No. 9. (September 2006), pp. 1639-1641.

OBJECTIVE: The authors examined gender differences in d-amphetamine-induced displacements of [(18)F]fallypride in the striatal and extrastriatal brain regions and the correlations of these displacements with cognition and sensation seeking. METHOD: Six women and seven men underwent positron emission tomography (PET) with [(18)F]fallypride before and after an oral dose of d-amphetamine. Percent displacements were calculated using regions of interest and parametric images of dopamine 2 (D(2)) receptor binding potential. RESULTS: Parametric images of dopamine release suggest that the female subjects had greater dopamine release than the male subjects in the right globus pallidus and right inferior frontal gyrus. Gender differences were observed in correlations of changes in cognition and sensation seeking with regional dopamine release. CONCLUSION: Findings revealed a greater dopamine release in women as well as gender differences in the relationship between regional dopamine release and sensation seeking and cognition.

A neural substrate of prediction and reward.

W Schultz — 2005-03-11T16:16:49-00:00

Science, Vol. 275, No. 5306. (14 March 1997), pp. 1593-1599.

The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.

Dopamine neurons and their role in reward mechanisms.

W Schultz — 2008-03-04T10:53:20-00:00

Curr Opin Neurobiol, Vol. 7, No. 2. (April 1997), pp. 191-197.

Information related to rewards is processed by a limited number of brain structures. Recent studies have demonstrated that dopamine neurons respond to appetitive events, such as primary rewards and reward-predicting stimuli. Rather than responding unconditionally, these neurons signal deviations from the prediction of future appetitive events. These reward-related responses correspond formally to concepts of behavioral and computational learning theories and may thus constitute teaching signals for appetitive learning.

The Reward Signal of Midbrain Dopamine Neurons.

Wolfram Schultz — 2008-03-04T10:48:46-00:00

News Physiol Sci, Vol. 14 (December 1999), pp. 249-255.

Dopamine projections from the midbrain to striatum and frontal cortex play a major role in behavioral reactions controlled by rewards. Recent experiments have shown that dopamine neurons code the discrepancy between the prediction and occurrence of rewards and in this way signal a crucial learning term for approach behavior.

Dopamine responses comply with basic assumptions of formal learning theory.

P Waelti — 2005-04-08T21:45:00-00:00

Nature, Vol. 412, No. 6842. (5 July 2001), pp. 43-48.

According to contemporary learning theories, the discrepancy, or error, between the actual and predicted reward determines whether learning occurs when a stimulus is paired with a reward. The role of prediction errors is directly demonstrated by the observation that learning is blocked when the stimulus is paired with a fully predicted reward. By using this blocking procedure, we show that the responses of dopamine neurons to conditioned stimuli was governed differentially by the occurrence of reward prediction errors rather than stimulus-reward associations alone, as was the learning of behavioural reactions. Both behavioural and neuronal learning occurred predominantly when dopamine neurons registered a reward prediction error at the time of the reward. Our data indicate that the use of analytical tests derived from formal behavioural learning theory provides a powerful approach for studying the role of single neurons in learning.

Reward signaling by dopamine neurons.

W Schultz — 2008-03-04T10:46:54-00:00

Neuroscientist, Vol. 7, No. 4. (August 2001), pp. 293-302.

Dopamine projections from the midbrain to the striatum and frontal cortex are involved in behavioral reactions controlled by rewards, as inferred from deficits in parkinsonism, schizophrenia, and drug addiction. Recent experiments have shown that dopamine neurons are not directly modulated in relation to movements. Rather, they appear to code the rewarding aspects of environmental stimuli. They show short, phasic increases of activity following primary food and liquid rewards ("unconditioned stimuli") and conditioned, reward-predicting stimuli of visual, auditory, and somatosensory modalities. They also display smaller activation-depression sequences after stimuli resembling rewards and after novel or particularly intense stimuli. Rewards are only reported as far as they occur differently than predicted. According to learning theories, a "prediction error" message may constitute a powerful teaching signal for behavior and learning. The phasic reward message is different from the more tonic enabling function of dopamine that is deficient in Parkinson's disease, indicating that dopamine neurons subserve different functions at different time scales. Neurons in other brain structures, such as the striatum, orbitofrontal cortex, and amygdala, code the quality, quantity, and preference of rewards. The dopamine reward prediction error signal may cooperate with these reward perception signals during the learning and performance of behavioral reactions to motivating environmental stimuli.