ABSTRACT
Indiplon [N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-alpha]pyrimidin-7-yl]phenyl]acetamide; NBI 34060] is a positive allosteric GABA(A) receptor modulator that is under development for the treatment of insomnia. This study compared the abuse potential of indiplon, a compound with preferential affinity for GABA(A) receptors containing an alpha(1) subunit, with triazolam in 21 volunteers with histories of drug abuse. Placebo, triazolam (0.25, 0.5, and 0.75 mg), and indiplon (30, 50, and 80 mg) were studied in counterbalanced order under double-blind conditions at two different residential research facilities. Both drugs impaired psychomotor and cognitive performance and produced similar dose-related increases in participant and observer ratings of drug strength. The onset of action of both drugs was rapid (30 min); however, the duration of action of indiplon (3-4 h) was shorter than that of triazolam (4-6 h). The profiles of subjective effects of triazolam and indiplon were similar; however, a maximum of 52% of participants identified indiplon as a benzodiazepine or barbiturate, compared with 81% of participants after 0.75 mg of triazolam. On participantrated subjective effects relevant to sedation, the slope of the triazolam dose-effect curve was significantly steeper than that of indiplon. Neither the largest doses of indiplon and triazolam nor the slope of the indiplon and triazolam dose-effect curves were significantly different from each other on any of the same-day or next-day measures of positive drug effects or next-day measures of reinforcing effects. Together, these data suggest that although the abuse potential of indiplon is not different from that of triazolam at these doses, psychomotor and cognitive impairment after large doses of indiplon might be less.
Subject(s)
Benzodiazepines/pharmacology , Cognition/drug effects , Psychomotor Performance/drug effects , Substance-Related Disorders/psychology , Thiophenes/pharmacology , Triazolam/pharmacology , Adult , Behavior/drug effects , Dose-Response Relationship, Drug , Female , Humans , Hypnotics and Sedatives/pharmacology , Male , Mental Recall/drug effects , Middle Aged , Reinforcement, Psychology , Single-Blind Method , Surveys and QuestionnairesABSTRACT
Posttraumatic stress disorder (PTSD) is characterized by anxiety symptoms and impulsivity and aggression, which are thought to represent examples of excessive behavioral inhibition and activation, respectively. PTSD and traumatized control subjects performed the Stop-Signal Task to assess behavioral activation and inhibition simultaneously. PTSD subjects showed no evidence of the generally increased behavioral inhibition expected to accompany anxiety, but exhibited progressively decreased behavioral activation during acquisition of the task. However, when behavior was facilitated using monetary rewards, both PTSD and traumatized control subjects showed increases in behavioral activation, whereas PTSD subjects also showed significant disinhibition. These findings argue against PTSD patients being chronically inhibited and unresponsive to rewards, and the presence of disinhibition accompanying behavioral activation in these subjects may explain the impulsivity and aggression associated with PTSD.
