Faculty Bibliography

RATIONALE: Although it is well established that acute benzodiazepine administration impairs episodic memory encoding, little is known about the neuroanatomical substrates of this effect. OBJECTIVE: The objective was to examine the acute dose effects of the benzodiazepine hypnotic triazolam on brain activity during episodic memory encoding. METHODS: After oral capsule administration (placebo, 0.1, 0.2, and 0.4 mg/70 kg triazolam), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with 15O-H2O during performance of semantic categorization and orthographic categorization tasks in a double-blind, within-subject design in 12 healthy volunteers. The rCBF associated with episodic memory encoding was measured by subtracting the rCBF during orthographic categorization from that during semantic categorization and by examining correlations between brain activity during encoding and subsequent recognition memory performance. RESULTS: Results in the placebo condition replicated those of nonpharmacological encoding studies, including activation in left ventrolateral prefrontal cortex. Correlations between brain activity and subsequent memory performance additionally showed medial temporal activation. Triazolam produced dose-related impairment in memory performance and dose-related deactivation in encoding-associated areas including right prefrontal cortex, left parahippocampal gyrus, and left anterior cingulate cortex. CONCLUSIONS: Results are consistent with behavioral evidence that benzodiazepines impair prefrontal control processes as well as contextual memory and episodic binding processes thought to be controlled by the medial temporal lobe. In addition to elucidating the brain mechanisms underlying these benzodiazepine-induced behavioral deficits, results of this study also help validate hypotheses generated in nonpharmacological neuroimaging studies regarding the processes controlled by these brain regions.

BACKGROUND: The offspring of alcohol-dependent individuals are at increased risk for alcoholism. The present study was designed to determine whether mesolimbic dopamine binding potential (BP), dopamine release, stress hormones, and subjective responses to intravenous amphetamine are different in nonalcoholic offspring from families with a history of alcohol dependence [family history positive (FHP)] than in nonalcoholic offspring without a family history of alcohol dependence [family history negative (FHN)]. METHODS: Participants were 41 healthy men and women (11 FHP, 30 FHN; age range 18-29). After completing baseline psychiatric symptom and personality measures, striatal D2/D3 dopamine BP and dopamine release in response to an amphetamine challenge were measured with positron emission tomography (PET) using the D2/D3 dopamine (DA) receptor radioligand [11C]raclopride. Binding potential was defined as Bmax/KD, percent change in BP from baseline defined dopamine release. During the scans, subjects rated the degree to which they were experiencing each of 10 possible drug effects. Plasma cortisol and growth hormone (GH) were also measured at scheduled intervals during the scans. RESULTS: Neither baseline BP nor dopamine release differed by family history. Similarly, subjective responses to amphetamine did not differ by a family history of alcoholism. Although both cortisol and GH increased following administration of amphetamine, these increases did not differ between family history groups. CONCLUSIONS: Using amphetamine to provoke mesolimbic dopamine, we did not show significant differences in dopamine release, subjective responses, or stress hormone measures as a function of family history of alcoholism.