Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine

Abstract

Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis-an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the 'subthreshold' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 μg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.

Competitive Antagonism of Anesthetic Action at the γ-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy

“…They are also useful in scientific research as pharmacological tools to define the role that specific protein targets play in producing particular in vitro or in vivo drug effects. 7–10 Unfortunately, competitive antagonists for general anesthetic agents have not yet been developed and the long-held (but now widely discredited) view that general anesthetics act non-specifically via lipid membranes implied that such antagonists could never be created. 11–17 …”

Adderall-Induced Persistent Psychotic Disorder Managed With Long-Acting Injectable Haloperidol Decanoate

“…Besides the obvious predictors of amphetamine-induced psychosis that include the dosage and duration of amphetamine use, some studies have highlighted the additional role of gamma-aminobutyric acid (GABA) dysfunction resulting in a heightened risk of stimulant-induced psychosis. A study done by Ahn et al suggests that pre-existing GABA deficits increased vulnerability to stimulant-induced psychosis in healthy subjects [ 11 ].…”

Psychosis induced by amphetamines

“…Interestingly, a dysfunctional GABAergic system could play a role both in use of amphetamines and proneness to psychosis [27]. Use of a benzodiazepine antagonist increases the likelihood of positive psychotic symptoms after the use of amphetamines in healthy volunteers [28]. These findings are interesting because GABAergic cortical dysfunction seems to be related to schizophrenia [29 & ].…”