Psychopharmacology for Cocaine Dependence - Buspirone

Chronic cocaine use may produce disruption of monoamine systems (including dopamine). This
may in turn contribute to measurable dysfunction in important cognitive and behavioral
processes. Pharmacotherapy with stimulants that enhance dopamine (DA) function has shown
efficacy in treating cocaine dependence and improving behavioral function -- supporting the
notion that these processes are related. In the development of novel pharmacotherapies for
cocaine dependence, an important step is a full characterization of the
psychopharmacological properties of potential medications for cocaine dependence, including
subjective, physiological, and behavioral effects. Selective medications may play a key role
in the modulation of DA neurotransmission by enhancing DA receptor activation.

The D3 receptor is an autoreceptor that may function to control phasic DA activity and
mediate sensitization of DA agonists, thus playing a role in conditioning of drugs of abuse
like cocaine. Growing evidence suggests that D3 receptor antagonists may be targets for
pharmacotherapy for substance dependence, and particularly for stimulant drugs like cocaine,
which disrupt normal DA function. Importantly, administration of D3 antagonists may disrupt
reactivity (attention) to drug cues and attenuate cue-induced craving. Buspirone is
currently the only available D3 antagonist approved for human administration, and is thus a
viable investigational compound.

This project proposes to evaluate the potential pharmacotherapeutic action of the D3
antagonist buspirone. The DA-modulating effects of buspirone may help with affective and
behavioral deficiencies related to DA depletion. Accordingly, the project aims to
characterize the psychopharmacology of buspirone in individuals with cocaine dependence.
Employing chronic dosing designs within an acute stimulant challenge (methylphenidate), the
experiment will be conducted using well-established psychopharmacological methods in order
to characterize the shape and magnitude of chronic pretreatment-mediated change in the
methylphenidate dose-response curve. Measures will include subjective effects,
cardiovascular effects, and behavioral effects (attentional bias to drug cues and risky
decision making). These data will compliment and provide valuable information to clinical
trials using these agents to treat cocaine dependence.

Inclusion Criteria:

- cocaine dependent subjects, non-treatment seeking

- meet current DSM-IV criteria for cocaine dependence disorder

- report using cocaine within the past 30 days

- at least 1 positive urine toxicology screen for the cocaine metabolite
benzoylecgonine (BE) [300 ng/mL, during the initial (2-4 day) screening period

- acceptable health on the basis of interview, medical history, and physical exam

- able to understand the consent form and provide written informed consent.

Exclusion Criteria:

- currently dependent on any psychoactive substance other than cocaine or nicotine

- current DSM-IV diagnosed major psychiatric disorder (e.g., psychosis, bipolar, major
depressive disorder)

- any medical condition that would contraindicate administration of medications

- taking medications known to have significant drug interactions study medications

- probation / parole requiring reports of drug use to court officers

- pregnant or nursing for female patients

- cannot read, write, or speak English.