Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.
The present study examined delta 9-tetrahydrocannabinol (THC)-induced alterations in monoamine transmission in the rat forebrain as well as the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on the monoamine response to THC. Activation of dopamine (DA) and norepinephrine (NE) but not serotonin (5-HT) turnover in the prefrontal cortex (PFC) was observed after THC (5 mg/kg i.p.) administration. Both enantiomers of HA966 completely prevented the effects of THC on PFC DA turnover and partially blocked the THC-induced rise in NE metabolism. The cognitive consequences of THC exposure were also examined. THC significantly impaired spatial working, but not reference, memory in rats, and this effect was ameliorated by HA966. Thus, HA966 prevents the THC-induced increases in PFC DA turnover and impairments of prefrontal cortical working memory function. Furthermore, these data suggest that cognitive impairments displayed by marijuana self-administering humans may be related to PFC DA hyperactivity and that HA966 may prevent this effect.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.