Mixed D2/5-HT2A antagonism of cocaine-induced facilitation of brain stimulation reward.

Previous behavioral, neurochemical and neurophysiological experiments have shown that selective 5-HT2A and mixed D2/5-HT2A antagonists can attenuate some, but not all, responses to amphetamine. The generality of these findings were determined in the present experiment by assessing the effect of mixed D2/5-HT2A antagonists on cocaine-induced facilitation of ventral tegmental area self-stimulation in rats. Although amphetamine and cocaine influence activity in monoaminergic neurons through different mechanisms, our previous research has shown that selective D2 and 5-HT2A antagonists have similar effects on behavioral responses to these psychostimulants. Therefore, we expected a similar pattern of results using mixed D2/5-HT2A antagonists. As shown previously, cocaine decreased self-stimulation threshold in a dose-dependent manner. Haloperidol and the mixed D2/5-HT2A antagonists risperidone and MDL 28, 133A antagonized cocaine-induced facilitation of self-stimulation, but only at doses that increased baseline self-stimulation threshold. There was a significant correlation (r = 0.87, p < 0.001) between antagonist-induced change in baseline threshold and attenuation of cocaine's effect on threshold. Taken together, the results of this and previous experiments support the importance of D2 receptors in the mechanisms of brain stimulation reward. 5-HT2A receptors appear not to be involved in mediation of both brain stimulation reward and amphetamine- and cocaine-induced facilitation of brain stimulation reward.

Reinstatement and spontaneous recovery of nicotine seeking in rats.

Reinstatement and spontaneous recovery of previously extinguished nicotine-taking behavior were examined in rats. Male subjects were trained to self-administer nicotine (30 microg/kg per infusion, IV; one 60-min session per day for 3 weeks). Extinction sessions were then given for 5-10 days during which saline was substituted for nicotine. Subsequently, in the first set of tests for nicotine seeking, the reinstatement of lever presses that previously delivered nicotine was examined after priming injections of saline and nicotine (75, 150 and 300 microg/kg, SC; and 30 and 60 microg/kg, IV). In the second set of tests for nicotine-seeking, rats were tested after an additional 21-day drug-free period during which they were not exposed to the self-administration chambers (a test for the spontaneous recovery of drug seeking), and after priming injections of nicotine (150 and 300 microg/kg, SC). Reinstatement of extinguished food-reinforced behavior after exposure to nicotine was also determined. Priming injections of nicotine reinstated nicotine seeking regardless of the route of administration. In addition, previously extinguished nicotine seeking recovered spontaneously after a 21-day period during which rats were not exposed to the drug-taking environment. Nicotine also reinstated extinguished food-reinforced behavior in rats with a history of nicotine self-administration, but not in drug-naive rats. The present results extend previous work with opioid and stimulant drugs on reinstatement of drug seeking by the self-administered drug. It also appears that, as with other positive reinforcers, the mere passage of time is a sufficient condition for the spontaneous recovery of extinguished nicotine seeking.

Mixed D2/5-HT2A antagonism of amphetamine-induced facilitation of brain stimulation reward.

Recent experiments have demonstrated that 5-HT2A antagonists can modify electrophysiological, neurochemical, and behavioral responses to psychostimulants. These findings led to an interest in using 5-HT2A antagonists to block the effects of psychostimulants on brain reward mechanisms. The present experiments assessed the ability of mixed D2/5-HT2A antagonists to reverse amphetamine-induced facilitation of self-stimulation. The D2/5-HT2A antagonists MDL 28,133A and risperidone attenuated the effects of cocaine and amphetamine, but only at antagonist doses that elevated baseline self-stimulation thresholds. A comparison of the effects of the mixed antagonists to those of haloperidol and eticlopride revealed that all four antagonists produced similar anti-stimulant effects when the influence of the drugs on baseline responding was considered. The D2 activity of the antagonists appears to account for their ability to reduce the effects of psychostimulants on self-stimulation. 5-HT2A antagonism makes a negligible contribution to the anti-amphetamine effects.