5-HT6 antagonism attenuates cue-induced relapse to cocaine seeking without affecting cocaine reinforcement

Re-exposure to drug-related cues elicits drug-seeking behaviour and relapse in humans even after months of abstinence. Similarly, in laboratory rats, drug-associated stimuli reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study mechanisms underlying cocaine relapse. 5-HT6 receptors (5-HT6Rs) are abundantly expressed in brain areas such as the nucleus accumbens and prefrontal cortex, which are critically involved in cocaine reinforcement and relapse. Nevertheless, the role of 5-HT6Rs in relapse mechanisms has not been investigated. We report here that the 5-HT6R antagonists SB-271046 and Ro-04-6790 significantly attenuate cue-induced cocaine seeking. However, effective doses of both 5-HT6R antagonists did not affect cocaine self-administration. This indicates that 5-HT6Rs are specifically involved in the secondary reinforcing properties of cocaine, leaving primary reinforcement and ability to perform an operant response unaffected. As such, 5-HT6Rs may represent a novel target for the prevention of relapse to cocaine seeking. © 2010 CINP

Insulin Modulates Cocaine-Sensitive Monoamine Transporter Function and Impulsive Behavior

Because insulin acutely enhances the function of dopamine transporters, the tyrosine kinase receptors activated by this hormone may modulate transporter-dependent neurochemical and behavioral effects of psychoactive drugs. In this respect, we examined the effects of insulin on exocytotic monoamine release and the efficacy of the monoamine transporter blocker cocaine in rat nucleus accumbens. Whereas insulin reduced electrically evoked exocytotic

Pharmacological manipulation of memory reconsolidation: towards a novel treatment of pathogenic memories

Well-consolidated memories, when retrieved, may return to a transiently fragile state, and need to be consolidated again in order to be maintained. This process has been referred to as memory reconsolidation and presumably serves to modify or strengthen memory traces. In recent years, our understanding of the neurobiological mechanisms underlying this phenomenon has increased rapidly. Here, we will briefly review some of the pharmacological evidence, stressing a crucial role for the brain's major neurotransmitter systems, such as glutamate and noradrenaline, in memory reconsolidation. Pharmacological intervention of reconsolidation processes may have clinical relevance, especially for the treatment of psychiatric disorders that are characterized by pathological memories, including post-traumatic stress disorder and addictive behaviour. © 2008 Elsevier B.V. All rights reserved

Platelet adenylyl cyclase activity as a biochemical trait marker for predisposition to alcoholism.

Previous studies demonstrated a reduced G(s)-protein stimulated adenylyl cyclase activity in the brain and blood cells of alcoholics. We investigated this phenomenon in platelets of children of alcoholics (COA), i.e., of children at high risk for the acquisition of alcoholism and (as yet) not regularly consuming alcohol. G(s)-protein mediated stimulation of adenylyl cyclase by 30 mM NaF and 50 μM forskolin stimulated adenylyl cyclase activity were assessed in platelet membranes of 23 (male and female) COA and 20 control children. G(s)-protein stimulated cAMP production by NaF, unlike that induced by direct stimulation of adenylyl cyclase with forskolin, in platelet membranes of COA was profoundly lower than in platelet membranes of control children. Moreover, such a reduced G(s)-protein functioning was only observed in platelet membranes of COA with a multigenerational family history of alcoholism. A reduction of G(s)protein stimulated adenylyl cyclase activity, in platelets may represent a sensitive and gender-independent trait marker for predisposition to alcoholism, rather than a state marker for alcoholism

Morphine causes a delayed increase in glutamate receptor functioning in the nucleus accumbens core

Enhanced excitatory neurotransmission in the mesocorticolimbic system may contribute to the persistence of addiction behaviour. Here, we demonstrated that glutamate-, N-methyl-d-aspartate (NMDA)- and α-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid (AMPA)-induced

Neuroadaptive effects of active versus passive drug administration in addiction research

Increasing knowledge of the genome sequences of several organisms and the development of genome-wide, high-throughput screening techniques for gene expression are likely to generate a vast amount of data aimed at elucidating the molecular mechanisms of addiction. These findings are likely to have potential for future addiction pharmacotherapies. However, it is important to employ animal models that dissociate the molecular and cellular consequences of the direct pharmacological effects of addictive drugs from those that result from the cognitive processes associated with self-administration of these drugs. In this article, we suggest that the short-term and long-term neuroadaptive effects of addictive drugs in the brain depend crucially on the drug-exposure paradigm used [i.e. passive (non-contingent) drug exposure and active (contingent) self-administration]. This has important ramifications for future molecular and cellular studies of drug addiction