Objectives: 5-HT6 receptor distribution is limited to nervous system and largely superimposable to that of dopamine. This distribution predicts a role of 5-HT receptors in reward and reinforcement and in extrapyramidal motor functions. Methods: We reviewed the reports found on the PubMed database, as well the unpublished observations made in our laboratory. Results: The 5HT6 receptor agonist ST1936. (SigmaTau, Pomezia, Italy) dose-dependently increased extracellular dopamine and noradrenaline in the prefrontal cortex and preferentially in the nucleus accumbens shell as compared to the core. These effects were prevented by pretreatment with the 5-HT6 antagonist SB271046. No changes in 5-HT were observed. ST1936 was self-administered at moderate rate on a continuous reinforcement schedule (FR1) and on a progressive ratio schedule and induced conditioned place preference e conditioned saccharin aversion, effects prevented by 5-HT6 receptor blockade. The 5-HT6 antagonist SB271046 reduced the increase of dialysate DA by cocaine in the shell of the accumbens but not in the prefrontal cortex. These observations indicate that ST1936 is provided with moderate rewarding and reinforcing properties. On the other hand SB271046, a 5-HT6 receptor blocker, impaired responding for amphetamine and cocaine i.v. self-administration, cocaine-conditioned place-preference and cocaine-stimulated locomotion. Conclusions: 5-HT6 receptor stimulation exerts reinforcing and rewarding effects via stimulation of dopamine release in the nucleus accumbens shell; thus, agonists of 5-HT6 receptors constitute a novel class of indirect psychostimulants. The available evidence indicates that 5-HT6 receptors play a modulatory role in the mechanisms of psychostimulant reinforcement and suggests testing of 5-HT6 antagonists as pharmacotherapeutic agents for cocaine dependence.
Possibile ruolo dei recettori 5-HT6 nelle dipendenze - Possible role of 5-HT6 receptors in addictions
DI CHIARA, GAETANO;VALENTINI, VALENTINA;DE LUCA, MARIA ANTONIETTA;FENU, SANDRO
2011-01-01
Abstract
Objectives: 5-HT6 receptor distribution is limited to nervous system and largely superimposable to that of dopamine. This distribution predicts a role of 5-HT receptors in reward and reinforcement and in extrapyramidal motor functions. Methods: We reviewed the reports found on the PubMed database, as well the unpublished observations made in our laboratory. Results: The 5HT6 receptor agonist ST1936. (SigmaTau, Pomezia, Italy) dose-dependently increased extracellular dopamine and noradrenaline in the prefrontal cortex and preferentially in the nucleus accumbens shell as compared to the core. These effects were prevented by pretreatment with the 5-HT6 antagonist SB271046. No changes in 5-HT were observed. ST1936 was self-administered at moderate rate on a continuous reinforcement schedule (FR1) and on a progressive ratio schedule and induced conditioned place preference e conditioned saccharin aversion, effects prevented by 5-HT6 receptor blockade. The 5-HT6 antagonist SB271046 reduced the increase of dialysate DA by cocaine in the shell of the accumbens but not in the prefrontal cortex. These observations indicate that ST1936 is provided with moderate rewarding and reinforcing properties. On the other hand SB271046, a 5-HT6 receptor blocker, impaired responding for amphetamine and cocaine i.v. self-administration, cocaine-conditioned place-preference and cocaine-stimulated locomotion. Conclusions: 5-HT6 receptor stimulation exerts reinforcing and rewarding effects via stimulation of dopamine release in the nucleus accumbens shell; thus, agonists of 5-HT6 receptors constitute a novel class of indirect psychostimulants. The available evidence indicates that 5-HT6 receptors play a modulatory role in the mechanisms of psychostimulant reinforcement and suggests testing of 5-HT6 antagonists as pharmacotherapeutic agents for cocaine dependence.
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