Cholinergic and 5HT3 Receptor Mechanisms in Cocaine Dependence (NIDA)
The limbic system is an integrated brain area involved in the regulation of reward, motivation, emotional expression, and memory. These regions are considered critical to the development and persistence of addiction. In our previous work, the regional cerebral blood flow (rCBF) response to the limbic stimulant procaine was assessed relative to saline in cocaine-addicted subjects and healthy controls. Our findings revealed that cocaine-addicted men and women exhibit a blunted limbic rCBF response to procaine compared to age and gender matched controls. Procaine, unlike cocaine, has minimal interaction with the monoamine transporters, but has potent affinity with both cholinergic and 5HT3 receptors. Preclinical studies indicate that these latter receptor systems are altered following the acute and chronic administration of cocaine, and disruptions in these systems may modulate subsequent drug reinforcement. Our competitive renewal is designed to further elucidate the putative neurobiologic differences in the cholinergic and 5HT3 systems revealed by procaine. Hypotheses: We hypothesize that cocaine-addicted subjects will demonstrate impairment of the cholinergic and 5HT3 receptor systems. Methods: Male and female cocaine-addicted subjects between two and six weeks abstinence will be compared to age and gender matched controls. All subjects will receive physostigmine, scopolamine, ondansetron, and saline. Single photon emission computed tomography (SPECT) and SPM analytic techniques will be used to assess rCBF and differences within and between groups. Significance: The cholinergic and 5HT3 receptor systems have not previously been studied in cocaine-addicted subjects using neuroimaging techniques. Our competing renewal will be used to identify specific changes in these neuroreceptor systems, providing avenues for new pharmacologic investigations in the treatment of cocaine dependence.

fMRI of Stress, HPA Axis, and Limbic Function in Alcoholism (NIAAA)
The chronic ingestion of alcohol disrupts the physiologic response to stress. Hypothalamic-pituitary-adrenal (HPA) axis suppression, and specifically adrenocortical hyposensitivity, is a key component of the altered stress response in recently alcohol-dependent subjects. Diminished HPA axis responsiveness during abstinence may impair the central nervous system's ability to mount an appropriate defense to environmental stressors, thus heightening the probability of relapse. In the proposed study, we will use functional magnetic resonance imaging (fMRI) to investigate the interaction between HPA axis disruption and limbic brain activation following a laboratory stressor. We propose that the alcohol-induced diminution of glucocorticoid responsivity in abstinent alcohol-dependent subjects will alter the amygdalar and hippocampal response to a laboratory stressor. Methods: Ten one-month abstinent alcohol dependent subjects and ten healthy controls will be studied. A stressor consisting of both a noxious thermal stimulus and anticipatory anxiety will be used to stimulate the HPA axis. The stressor will be repeated thirty minutes later, during the anticipated peak of the cortisol response. Using event-related analytic methods, the amygdalar, hippocampal, and other limbic regional brain response will be assessed during the initial (prior to HPA axis activation) and second (during the peak glucocorticoid response) stressor. In addition, brain responses during both a control task and a memory task will be assessed by fMRI at the two time points. Hormonal measures of ACTH, cortisol, and 3 ,5 -reduced neurosteroids will be measured during the stressors in addition to subjective anxiety, heart rate, and galvanic skin response. Genotyping and linkage analysis will also be obtained. Hypothesis: Diminished stress-induced HPA axis responsivity in the alcohol-dependent subjects will be associated with an increase in hippocampal activation and a decrease in amygdalar activation during stress relative to the healthy controls. Significance: The amgydalar and hippocampal regions are critical in mediating both the stress response and repeated drug administration. Dysfunctional alcohol-induced neuroadaptions in these and other limbic regions may impair the abstinent patient's ability to respond to stress, increasing their vulnerability of relapse. An understanding of the systemic disruptions in the stress response following long-term alcohol ingestion may therefore yield important avenues of future treatment intervention.

Impulsivity, Neural Deficits, and Relapse in Cocaine Addiction
The often impulsive nature of drug use has directed the field to develop a concept of relapse involving unconscious, automatic processes and/or impaired decision-making. These constructs hypothesize that addicted patients return to substance use because of either an impairment in the attentional and behavioral processes involved in inhibiting detrimental behaviors (i.e. impulsivity) and/or because of deficits in appropriately assessing the benefits and consequences of their decisions (i.e. decision-making). An impulsive relapse is perhaps best characterized by Tiffany's concept of "automaticity," a stereotyped, stimulus bound, effortless behavior accompanied by a lack of awareness and control. Alterations in impulsivity/decision-making are posited to be a result of altered neural circuitry involving the orbitofrontal cortex (OFC), anterior cingulate, amygdala, nucleus accumbens, insular cortex, mesial prefrontal cortex (PFC), inferior PFC and other related limbic/paralimbic regions. This proposal will elucidate the neurocognitive and associated neural mechanisms involved in the increased impulsivity and impaired decision-making in cocaine addiction, coupled with both an empirical and prospective assessment of their tendency to relapse impulsively. State-of-the-art functional magnetic resonance imaging (fMRI) will be used to monitor the central nervous system response during specific tasks of both impulsivity and decision-making. Impulsivity will be assessed using a task of response inhibition, which measures the ability to rapidly inhibit, or gate, pre-potent responses. Decision-making will be assessed using a task of response reversal, which measures the ability to assess response contingencies and then reverse cognitive and behavioral strategies to suppress a course of action that is no longer appropriate. The association of co-existing deficits in cognitive processes and brain activation with relapse risk would implicate these processes as critical mechanisms in the addictive process.