Psychopharmacology for Cocaine Dependence - Buspirone

• Cocaine-Stroop [ Time Frame: M, W, F @ 11:30 AM over 2 weeks ] [ Designated as safety issue: No ]
  The task assesses attentional biases to cocaine-related (drug-related) and rewarding (non-drug related) stimuli vs. neutral stimuli. Participants are instructed to respond to words shown in different colors on the screen, by pressing as quickly and accurately as possible on one of three colored buttons. The primary outcome measure is reaction times (RT), with attentional bias measured as the difference in RTs on cocaine vs. neutral words.
  
  
• Risky decision making [ Time Frame: M, W, F @ 11 AM over 2 weeks ] [ Designated as safety issue: No ]
  The task provides subjects with three choice options on each of 100 repeated trials. Options are low, moderate, and high risk, based on variance and probability in gain/loss amounts. The low risk option is more adaptive over many trials. Subjects start each test session with $5.00. End-of-session earnings can range from approximately +$12.00 to -$2.00. The outcome measure is a risk index (ranging from 0.33 to 100) that factors in tolerance for variability and amount of gains and losses across the three options.
  
  

• ARCI [ Time Frame: M, W, F @ 10 time points, over 2 weeks ] [ Designated as safety issue: No ]
  Addiction Research Center Inventory. The ARCI short form [173] will be used. It is a 49-item true / false questionnaire that has been empirically-derived to assess five different factors, including euphoria, sedation, and dysphoria [174]. The PCAG scale has proven to be a sensitive measure of subjective effects in many studies administering stimulant drugs [174, 175]. We have employed it extensively in our laboratory [155, 175].
  
  
• POMS [ Time Frame: M, W, F @ 10 time points, over 2 weeks ] [ Designated as safety issue: No ]
  Profile of Mood States. The POMS is a self-rating measure of current mood [176]. It consists of six subscales: depression, vigor, confusion, tension, anxiety, and fatigue. This instrument has been used in hundreds of studies in both clinical and healthy control populations, and has been demonstrated to be sensitive to a range of acute drug effects, including amphetamine [171], cocaine [38], and caffeine [108, 177]. We will use the 37-item short form of the POMS, which correlates highly with the full scale [178].
  
  
• DEQ [ Time Frame: M, W, F @ 10 time points, over 2 weeks ] [ Designated as safety issue: No ]
  Drug Effects Questionnaire. The DEQ (e.g., [95]) is visual analog scale questionnaire (Drug Effects Questionnaire, or DEQ) that assesses the extent to which subjects experience four subjective states: "Feel Drug", "Feel High", "Like Drug", and "Want More".
  
  
• VAS [ Time Frame: M, W, F @ 10 time points, over 2 weeks ] [ Designated as safety issue: No ]
  The VAS (e.g., [179]) presents 100-mm horizontal lines labeled with an adjective: "stimulated", "high", "anxious", "elated", "hungry", and "nauseated." The scale is anchored by "not at all" (0) on the left, and "extremely" (100) on the right.
  
  
• cardiovascular [ Time Frame: M, W, F @ 10 time points, over 2 weeks ] [ Designated as safety issue: Yes ]
  Participants' heart rate, systolic and diastolic blood pressure will be recorded.
  
  

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.