Health & Medical Neurological Conditions

Adenosinergic System: Therapeutics for Drug Addiction

Adenosinergic System: Therapeutics for Drug Addiction

Adenosine & Cocaine


Chronic use of psychostimulants such as cocaine results in the development of profound cravings for the drug, which was reported to be mediated in part by an enhanced ability of the stimulant to increase synaptic levels of DA in the nucleus accumbens and thus induce distinct hyperactivity in animals. A growing body of evidence suggests that adenosine is involved in cocaine dependence and that adenosine signaling pathways may offer new targets for treatment of cocaine addiction. Moreover, adenosine uptake was shown to be augmented after cocaine withdrawal. Adenosine receptor antagonists were shown to decrease the expression of conditioned place preference induced by cocaine in rats, whereas only lower doses of agonists were able to show a similar response. Similarly, cocaine-induced locomotor hyperactivity was dose-dependently reduced by adenosine receptor agonists, and the effect was more pronounced with a selective adenosine A1 agonist at the low doses. In one study, adenosine receptor antagonists caffeine and CGS15943 were shown to reinstate cocaine-seeking behavior in non-human primates, which was decreased by pretreatment with an adenosine A2 agonist. Therefore, adenosine antagonists were considered to function as reinforcers and also strengthen the evidence for the role of adenosine mechanisms in the reinstatement of cocaine-seeking behavior. The adenosine A1 and A2A receptor antagonists were also shown to produce high levels of drug-lever selection when substituted for cocaine in rats trained to discriminate cocaine from saline under a fixed-ratio schedule of food presentation. Surprisingly, the adenosine receptor antagonists also potentiated the discriminative-stimulus actions of cocaine at lower levels, which was explained by the ability of cocaine to increase extracellular concentrations of adenosine. The neurobiological mechanisms involved in these effects need to be discerned.

One study, performed on nucleus accumbens tissue extracted from experimental animals that had been withdrawn for 3 weeks from chronic cocaine exposure, showed an induction of adenosine A1 receptor protein and mRNA. However, increased total adenosine A1 protein was not considered proportional with increased functional adenosine A1 receptors, and thus may result in enhanced DA D1 function. On the other hand, in spite of increase in the synthesis of adenosine A1 protein, a functional attenuation of adenosine A1 receptor stimulation via reduction in adenosine A1 receptor-stimulated G-protein coupling was observed in the nucleus accumbens of rats withdrawn from repeated cocaine treatment. The repeated cocaine administration was shown to reduce the relative concentration of adenosine A1 receptors at the cell surface and increase the concentration in the endoplasmic reticulum/golgi compartment.

Direct physical interaction between adenosine A2A and DA D2/3 receptors, and the existence of A2A–D2 heteromeric receptor complexes with reciprocal antagonistic interactions was reported based on the colocalization of adenosine A2A receptors with DA D2 receptors on nucleus accumbens of medium spiny neurons. Thus, adenosine A2A receptors represent a target for reducing enhanced DA D2 receptor sensitivity, that contributes to cocaine relapse. Furthermore, systemic adenosine A2A receptor stimulation was shown to impair cocaine sensitization, and the reinstatement of cocaine-seeking behavior. In addition, numerous studies have reported that the reinforcing efficacy of cocaine is decreased in animals lacking adenosine A2A receptors. Mice with a specific genetic deletion of the adenosine A2A receptors in the striatum were found to display the opposite phenotype compared with mice with a forebrain-specific deletion when challenged with cocaine. Adenosine A2A receptor knockout mice also displayed a marked reduction in cocaine intake, and thus a difference in the operant self-administration induced by cocaine. In one recent study, a decrease in acute systemic cocaine-mediated dopaminergic neurotransmission in the nucleus accumbens was found in animals lacking adenosine A2A receptors. Moreover, the locomotor stimulant activity of cocaine was also diminished in these global adenosine A2A receptor knockout mice. On the other hand, pharmacological manipulation of adenosine A2A receptors in the nucleus accumbens was shown to alter cocaine-seeking behavior whereby stimulation of these receptors in the nucleus accumbens attenuates drug-seeking behavior in rats trained to lever press for cocaine. This indicates that adenosine A2A receptors are potential targets for restricting drug-relapse.

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