ABSTRACT
BACKGROUND AND PURPOSE: An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied. EXPERIMENTAL APPROACH: The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed. KEY RESULTS: The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs. CONCLUSION AND IMPLICATIONS: These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis.
Subject(s)
Behavior, Animal/drug effects , Cyclopentanes/therapeutic use , GABA-B Receptor Agonists/therapeutic use , Phosphinic Acids/therapeutic use , Psychoses, Substance-Induced/drug therapy , Pyrimidines/therapeutic use , Receptors, GABA-B/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Catalepsy/chemically induced , Cyclopentanes/administration & dosage , Cyclopentanes/adverse effects , Disease Models, Animal , Dose-Response Relationship, Drug , Excitatory Postsynaptic Potentials/drug effects , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Frontal Lobe/physiopathology , GABA-B Receptor Agonists/administration & dosage , GABA-B Receptor Agonists/adverse effects , GABA-B Receptor Antagonists/pharmacology , Hyperkinesis/drug therapy , Hyperkinesis/metabolism , Hyperkinesis/psychology , Male , Mice , Motor Activity/drug effects , Phosphinic Acids/administration & dosage , Phosphinic Acids/adverse effects , Psychoses, Substance-Induced/metabolism , Psychoses, Substance-Induced/psychology , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Syndrome , gamma-Aminobutyric Acid/administration & dosage , gamma-Aminobutyric Acid/adverse effects , gamma-Aminobutyric Acid/therapeutic useABSTRACT
The effects of repeated administration of a tricyclic antidepressant, imipramine, lasting 14 days (10 mg/kg p.o., twice daily), were studied ex vivo in rat frontal cortex slices prepared 48 h after last dose of the drug. In slices prepared from imipramine-treated animals the mean frequency, and to a lesser degree the mean amplitude, of spontaneous excitatory postsynaptic currents recorded from layer II/III pyramidal neurons, were decreased. These effects were accompanied by a reduction of the initial slope ratio of pharmacologically isolated N-methyl-D-aspartate to AMPA/kainate receptor-mediated stimulation-evoked excitatory postsynaptic currents. Imipramine treatment also resulted in a decrease of extracellular field potentials evoked in layer II/III by stimulation of underlying sites in layer V. These results indicate that chronic treatment with imipramine results in an attenuation of the release of glutamate and an alteration in the postsynaptic reactivity of ionotropic glutamate receptors in rat cerebral cortex.
