Evidence for a role of a dopamine/5-HT6 receptor interaction in cocaine reinforcement.

The putative 5-HT6 receptor agonist ST1936 has been shown to increase extracellular dopamine (DA) in the n.accumbens (NAc) shell and in the medial prefrontal cortex (PFCX). These observations suggest that 5-HT6 receptors modulate DA transmission in mesolimbic and mesocortical terminal DA areas. To investigate the behavioral counterpart of this interaction we studied in rats 1) the ability of ST1936 to maintain i.v. self-administration in fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement; 2) the effect of 5-HT6 receptor blockade on cocaine stimulated overflow of DA in dialysates from the PFCX and from the NAc shell and on cocaine i.v. self-administration. ST1936 was i.v. self-administered at unitary doses of 0.5-1 mg/kg on an FR1 and PR schedule of reinforcement, with breaking point of about 4. Pretreatment with the 5-HT6 antagonist SB271046 reduced by about 80% responding for ST1936. SB271046 also reduced cocaine-induced increase of dialysate DA in the NAc shell but not in the PFCX and impaired i.v. cocaine self-administration. These observations indicate that ST1936 behaves as a weak reinforcer and suggest that 5-HT6 receptors play a role in cocaine reinforcement via their facilitatory interaction with DA projections to the NAc shell. This novel 5-HT/DA interaction might provide the basis for a new pharmacotherapeutic strategy of cocaine addiction.