oxadiazoles and Alcoholism

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Adult; Aged; Alcoholism; Animals; Anxiety; Azabicyclo Compounds; Craving; Disease Models, Animal; Double-Blind Method; Female; Humans; Hydrocortisone; Image Processing, Computer-Assisted; Imagery, Psychotherapy; Middle Aged; Oxadiazoles; Oxygen; Psychiatric Status Rating Scales; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Retrospective Studies; Single-Blind Method; Young Adult

The density and affinity of sites labeled by the 1,4-dihydropyridines, [3H]nitrendipine and (+) [3H]PN 200-110, were not significantly different in superior frontal and parietal cortical membranes from alcoholic patients and nonalcoholic control patients. This is in contrast to the increased number of dihydropyridine receptors and increased functional activity of calcium channels reported in brain from rats treated chronically with ethanol and in neural cell lines grown in the presence of ethanol. These results indicate that 1,4-dihydropyridine-sensitive calcium channels (L type) in the brain, despite possible acute changes, are unaltered following long-term ethanol exposure in humans.

Topics: Alcoholism; Cerebral Cortex; Dihydropyridines; Humans; Isradipine; Male; Middle Aged; Nitrendipine; Oxadiazoles

Exposure to ethanol for days to weeks enhances the expression of voltage-dependent Ca2+ channels in the brains of experimental animals and in cultured neural cell lines. To determine if similar changes occur in the brains of alcoholic patients, we measured the binding of (+)-[3H]PN 200-110 to cerebral cortex samples obtained at autopsy from alcoholic and non-alcoholic patients. No difference in (+)-[3H]PN 200-110 binding was observed, suggesting that ethanol-induced changes in Ca2+ channel expression are more likely to be related to acute withdrawal than to chronic ethanol exposure alone.

Topics: Aged; Alcoholism; Calcium Channel Blockers; Calcium Channels; Frontal Lobe; Humans; Isradipine; Middle Aged; Oxadiazoles

The influence of white rats of alcohol abuse formation of immunization by covalent conjugates of serum albumin with psychostimulant sydnophen was investigated. Immunization by conjugates where the molar sydnophen: protein ratio was 18:1-33: 1 results in significant depression of 15% ethanol consumption (in the condition of free choice between water and ethanol solution).

Topics: Alcoholism; Animals; Antidepressive Agents; Drug Evaluation, Preclinical; Haptens; Immunization; Male; Oxadiazoles; Rats; Serum Albumin; Sydnones; Time Factors