CiteULike: awooga's adenosine

Differential effects of caffeine on dopamine and acetylcholine transmission in brain areas of drug-naive and caffeine-pretreated rats.

E Acquas — 2007-06-20T13:33:35-00:00

Neuropsychopharmacology, Vol. 27, No. 2. (August 2002), pp. 182-193.

The effects of caffeine on extracellular dopamine and acetylcholine have been studied in freely moving rats implanted with concentric microdialysis probes in the nucleus accumbens shell and core and in the medial prefrontal cortex. Intravenous administration of caffeine (0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg) dose-dependently increased dopamine and acetylcholine dialysate concentrations in the medial prefrontal cortex, while it did not affect dialysate dopamine in the shell and core of the nucleus accumbens. Intraperitoneal administration of caffeine (1.5, 3, 10, 30 mg/kg) also failed to affect DA in the shell and core of the nucleus accumbens. Such effects were duplicated by intravenous administration of DPCPX, a selective antagonist of adenosine A1 receptors, and of SCH 58261, an antagonist of A2a receptors. The effect of caffeine on prefrontal dopamine and acetylcholine transmission was also studied in rats chronically administered with caffeine (25 mg/kg, twice a day for seven days). At the end of this treatment rats became tolerant to the locomotor stimulating effects of a dose of 1 and 2.5 mg/kg i.v. of caffeine; these doses, however, still increased dialysate acetylcholine but did not affect dopamine in the prefrontal cortex. Therefore, in rats made tolerant to the locomotor stimulant effects of caffeine, tolerance developed to the dopamine stimulant but not to the acetylcholine stimulant effect of caffeine in the prefrontal cortex. The lack of acute stimulation of dopamine release in the nucleus accumbens shell by caffeine is relevant to the issue of its addictive properties and of the role of DA in drug- and substance-addiction. On the other hand, the dissociation between tolerance to the locomotor effects of caffeine and stimulation of acetylcholine release in the prefrontal cortex suggests that this effect might be correlated to the arousing effects of caffeine as distinct from its locomotor stimulant properties.

DARPP-32 mediates the actions of multiple drugs of abuse.

P Svenningsson — 2007-06-11T16:53:00-00:00

AAPS J, Vol. 7, No. 2. (2005)

Drugs of abuse share the ability to enhance dopaminergic neurotransmission in the dorsal and ventral striatum. The action of dopamine is modulated by additional neurotransmitters, including glutamate, serotonin and adenosine. All these neurotransmitters regulate the phosphorylation state of Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32). Phosphorylation at Thr(34) by protein kinase A converts DARPP-32 into a potent inhibitor of the multifunctional serine/threonine protein phosphatase, PP-1. Phosphorylation at Thr(75) by Cdk5 converts DARPP-32 into an inhibitor of protein kinase A. The state of phosphorylation of DARPP-32 at Thr(34) also depends on the phosphorylation state of Ser(97) and Ser(130), which are phosphorylated by CK2 and CK1, respectively. By virtue of regulation of these 4 phosphorylation sites, and through its ability to modulate the activity of PP-1 and protein kinase A, DARPP-32 plays a key role in integrating a variety of biochemical, electrophysiological, and behavioral responses controlled by dopamine and other neurotransmitters. Importantly, there is now a large body of evidence that supports a key role for DARPP-32-dependent signaling in mediating the actions of multiple drugs of abuse including cocaine, amphetamine, nicotine, caffeine, LSD, PCP, ethanol and morphine.

DARPP-32: an integrator of neurotransmission.

P Svenningsson — 2007-06-11T16:14:28-00:00

Annu Rev Pharmacol Toxicol, Vol. 44 (2004), pp. 269-296.

Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified initially as a major target for dopamine and protein kinase A (PKA) in striatum. However, recent advances now indicate that regulation of the state of DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34 and thereby converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5 and this converts DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. The state of phosphorylation of DARPP-32 at Thr34 depends on the phosphorylation state of two serine residues, Ser102 and Ser137, which are phosphorylated by CK2 and CK1, respectively. By virtue of its ability to modulate the activity of PP-1 and PKA, DARPP-32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse.

Caffeine as a psychomotor stimulant: mechanism of action

G Fisone — 2007-06-11T13:23:17-00:00

Cellular and Molecular Life Sciences (CMLS), Vol. 61, No. 7. (1 April 2004), pp. 857-872.

The popularity of caffeine as a psychoactive drug is due to its stimulant properties, which depend on its ability to reduce adenosine transmission in the brain. Adenosine A 1 and A 2A receptors are expressed in the basal ganglia, a group of structures involved in various aspects of motor control. Caffeine acts as an antagonist to both types of receptors. Increasing evidence indicates that the psychomotor stimulant effect of caffeine is generated by affecting a particular group of projection neurons located in the striatum, the main receiving area of the basal ganglia. These cells express high levels of adenosine A 2A receptors, which are involved in various intracellular processes, including the expression of immediate early genes and regulation of the dopamine- and cyclic AMP-regulated 32-kDa phosphoprotein DARPP-32. The present review focuses on the effects of caffeine on striatal signal transduction and on their involvement in caffeine-mediated motor stimulation.

Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Bertil Fredholm — 2007-06-11T13:21:57-00:00

Pharmacol Rev, Vol. 51, No. 1. (1 March 1999), pp. 83-133.

I. Introduction II. Consumption and Metabolism of Caffeine A. Sources of Caffeine B. Caffeine Absorption, Distribution, and Pharmacokinetics C. Caffeine Metabolism III. Molecular and Cellular Action of Caffeine in the Brain A. Fundamental Biochemical Actions B. Adenosine Levels in Brain and Other Tissues C. Adenosine Acts on Several Types of G-Protein-Coupled Receptors 1. Receptor Subtypes. 2. Receptor Distribution. D. Caffeine Affects Transmitter Release and Neuronal Firing Rates via Actions on Adenosine A1 Receptors E. Caffeine Effects on Dopaminergic Transmission Are Exerted Mainly via Actions on Adenosine A2A Receptors F. Identifying the Neuronal Substrates For Caffeine by Examining Changes in Immediate Early Genes[---]High Dose Effects G. Low Doses of Caffeine Selectively Decrease the Activity of Striatopallidal Neurons in the Striatum and Their Counterparts in the Nucleus Accumbens IV. Actions of Caffeine on Brain Functions and Behavior A. Activation of Dopaminergic Transmission and Effects on Motor Behavior B. Caffeine and Mood C. Effects of Caffeine in the Cortex and Hippocampus[---]Information Processing and Performance D. Effects on Sleep E. Effects of Caffeine on Cerebral Blood Flow and Metabolism F. Other Effects V. Addiction and Drug Dependence A. Definitions B. On the Neuronal and Molecular Basis of Drug Reinforcement and Addiction VI. Caffeine Withdrawal and Relief of Abstinence Symptoms by Caffeine A. Animal Studies on Caffeine Withdrawal B. Human Studies C. Effect of Caffeine on Withdrawal Symptoms VII. Tolerance to the Effects of Caffeine A. Cardiovascular Effects B. Effects on Sleep C. Effects on Mood D. Other Central Effects E. Differences between Acute and Long-Term Administration[---]Effect Inversion VIII. Caffeine Discrimination and Dose Adjustment in Animals and Humans A. Caffeine Discrimination in Animals B. Caffeine Discrimination in humans C. Dose Adjustment IX. Reinforcing Effects of Caffeine A. Reinforcement in Animals 1. Intravenous and Oral Self-Administration. 2. Reinforcing Effects of Caffeine: Place Conditioning. B. Reinforcement in Humans X. Possible Reinforcing Effects of Coffee, Independent of Caffeine Content XI. Comparisons with Known Addictive Compounds and Interactions between Caffeine and Addictive Drugs A. General Considerations B. Interactions between Caffeine and Cocaine or Amphetamine C. Interactions between Caffeine and Ethanol D. Interactions between Caffeine and Nicotine XII. Possible Harmful Effects of Caffeine at the Individual or Social Level[---]Abuse or Misuse XIII. Conclusions Acknowledgments References