The goal of this research is to clarify the role of the serotonin (5-HT) and dopamine (DA) systems in mediating the effects of cocaine in humans. While the role of DA in mediating cocaine's effects has long been recognized interest in 5-HT has recently burgeoned. Previous work by our group has suggested that disruption of 5-HT function attenuates cocaine- induced euphoria. The present studies make use of the novel atypical neuroleptic risperidone, which has a unique pharmacological profile that includes significant antagonism at both the 5-HT2 and D2 receptors. Clozapine, which has a somewhat similar profile, is not suitable for studies of this type because of its significant adverse effects and toxicity. Preclinical findings suggest that 5-HT2/D2 receptor antagonism should be associated with an ability to block the effects of cocaine. Two studies are proposed to test this possibility. In the first, 15 subjects will undergo double-blind randomization to receive acute pretreatment with a single dose of risperidone 0, 2, or 4 mg, followed two hours later by a single challenge dose of intranasal cocaine. Responses to cocaine will be assessed in order to ascertain the effects of acute risperidone pretreatment. In the second study, 30 drug-free subjects will receive a single challenge dose of intranasal cocaine followed by double-blind parallel-groups randomization to two weeks of chronic treatment with risperidone or placebo. At the end of the risperidone treatment period, subjects will undergo a second intranasal cocaine challenge in order to ascertain the effects of chronic risperidone pretreatment on responses to cocaine. Physiological, behavioral, and psychological variables will be comprehensively assessed and systematically monitored during these studies. Neurobiological measures will include the following neurotransmitter systems indices: (1) DA--plasma homovanillic acid (HVA), growth hormone (GH), and prolactin; (2) 5-HT--cortisol and ACTH. Cocaine plasma levels will be assessed to control for pharmacokinetic effects and risperidone levels measured to control for bioavailability. We hypothesize that both acute and chronic administration of risperidone will antagonize the euphorigenic and other effects of cocaine. In addition to providing important data on cocaine's mechanism of action, these studies will be directly relevant to the development of risperidone as a possible clinical treatment for cocaine dependence.
