5-HT1A agonist/antagonist modification of cocaine stimulant effects: implications for cocaine mechanisms.

The 5-HT1A receptor site has been demonstrated to be an important pharmacological target in the modulation of unconditioned behavioral effects induced by cocaine. In this study, separate groups of rats (n=7) received a series of the 5-HT1A agonist treatments, 8-OHDPAT (0.2,0.4 mg/kg) in combination with saline or cocaine (10 mg/kg). Using a crossover design, the treatments were subsequently switched to the 5-HT1A antagonist, WAY 100635 (0.4,0.8 mg/kg) and then, switched back again to 8-OHDPAT (0.2,0.4 mg/kg). When the 8-OHDPAT was given in combination with cocaine, locomotion was substantially enhanced but when the treatment was switched to WAY 100635, the cocaine induced locomotion was suppressed. Neither the 8-OHDPAT or WAY 100635 given with saline affected locomotion as compared to saline treated animals. These findings indicated a reciprocal facilitatory/inhibitory influence of 5-HT1A agonists/antagonists upon cocaine induced locomotion. The 8-OHDPAT treatments, however, did not enhance all cocaine behavioral responses. Initially, 8-OHDPAT suppressed cocaine induced rearing and central zone entry, but with repeated treatments, these response suppression effects subsided. As a consequence, the facilitative influence of 8-OHDPAT upon cocaine induced locomotion could not be attributed to response redistribution effects. While WAY 100635 markedly reduced cocaine induced locomotion and rearing to nearly saline response levels, the same WAY 100635 treatments did not modify locomotor stimulant effects induced by caffeine (10 mg/kg). In that caffeine stimulant effects are not directly linked to serotonergic mechanisms, the absence of an influence of WAY 100635 upon caffeine induced locomotor stimulation lent further support to the proposition that the 5-HT1A receptor site contributes to locomotor behavior in situations where the serotonergic system is pharmacologically activated by drugs such as cocaine. These findings point to a potential role for 5-HT1A antagonists in treatment of cocaine abuse.