The role of gamma-aminobutyric acid (GABA)-benzodiazepine neurotransmission in an animal model of methamphetamine-induced psychosis.
Repeated administration of amphetamine or methamphetamine (MA) results in an augmentation of its locomotor-activating effects, which is a phenomenon known as behavioral sensitization. In humans, chronic use of the drug elicits a progressive augmentation in paranoid symptoms that closely resemble schizophrenia. Behavioral sensitization has some common properties with other forms of neural plasticity such as kindling, learning and long-term potentiation (LTP). The author examined in the present study whether behavioral sensitization could be blocked by GABA-benzodiazepine agonists, known to inhibit kindling, learning as well as LTP. Rats (Male Wistar-King rats) treated with MA (1 mg/kg, s.c.) for 10 days displayed significantly enhanced motor activity when tested with MA (1 mg/kg) after a 7-8 day withdrawal period indicating the acquisition of behavioral sensitization. Treatment with clonazepam (CZP) (0.5 and 2.0 mg/kg), a GABA-benzodiazepine agonist, prior to MA administration prevented the acquisition of sensitization. In contrast, treatment with flumazenil (Flu) (10 mg/kg), a GABA-benzodiazepine antagonist, prior to MA administration did not affect the acquisition of sensitization. And treatment with Flu prior to CZP administration suppressed the inhibitory effect of CZP. CZP had no effect on the expression of sensitization in the sensitized rats, when given prior to the MA readministration. These results suggest that stimulation of GABA-benzodiazepine receptors plays a role in the acquisition but not in the expression of behavioral sensitization.
Ito
K
K
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D002998:Clonazepam / Q000494:pharmacology / Q000627:therapeutic use; D003864:Depression, Chemical; D004195:Disease Models, Animal; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D011605:Psychoses, Substance-Induced / Q000188:drug therapy / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
D000697:Central Nervous System Stimulants; D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil; D008694:Methamphetamine; D002998:Clonazepam