Background: A family history of alcoholism is a risk factor for the development of alcohol problems. Factors that modulate the positive and negative reward valence of alcohol effects may influence the likelihood of repeated and or problematic use, and are therefore of interest. Alcohol has multiple targets in the brain that independently contribute to its behavioral effects. Studies with various pharmacological probes including alcohol, ketamine and benzodiazepines suggest differences between healthy individuals with a family history positive (FHP) or negative (FHN) for alcoholism. There is growing preclinical evidence suggesting involvement of brain cannabinoid receptor (CB-1R) function in the pharmacological actions of alcohol and in alcohol-drinking behaviors. Cannabinoids and alcohol activate the same reward pathways. CB-1R agonists stimulate while CB-1R antagonists suppress, alcohol self-administration and the motivational properties of alcohol. Comparison to wild type mice, CB-1R knockout mice show 1) significantly lower levels of alcohol preference and consumption, 2) slower rate of acquisition of alcohol drinking behavior, 3) lower alcohol sensitivity, and 4) blunted alcohol-induced dopamine release in the nucleus accumbens. Finally, alcohol preferring mice have a significantly lower level of CB-1R binding sites and higher affinity for CB-1R agonist than alcohol-avoiding mice. Despite these preclinical data, there is a paucity of clinical research in this area. ? ? Hypotheses: Individuals with a family history of alcoholism (FHP) will exhibit blunted 1) euphoric, 2) perceptual and 3) amnestic effects in response to ?-9-tetrahydrocannabinol (?9-THC) administration compared to individuals without a family history of alcoholism (FHN). ? ? Methods: An equal number (n=18) of healthy FHN and FHP will complete 3 test days separated by a week during which they will receive intravenous ?9-THC (0, 0.018 and 0.036 mg/kg) over 20 minutes in randomized, counterbalanced fashion under double-blind conditions. Primary outcome variables include measures of euphoria, perceptual alterations and delayed recall. ? ? Preliminary Results: FHP individuals (n=4) showed blunted responses to the effects of ?9-THC on euphoria, perceptual alterations and delayed recall relative to FHN controls. These results may reflect indirect evidence of altered CB-1R function in FHP individuals. ? ? ?
| Ranganathan, Mohini; Sewell, R Andrew; Carbuto, Michelle et al. (2014) Effects of ?9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism. Psychopharmacology (Berl) 231:2385-93 |
| Sewell, R Andrew; Schnakenberg, Ashley; Elander, Jacqueline et al. (2013) Acute effects of THC on time perception in frequent and infrequent cannabis users. Psychopharmacology (Berl) 226:401-13 |
| D'Souza, Deepak Cyril; Pittman, Brian; Perry, Edward et al. (2009) Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology (Berl) 202:569-78 |
