Modification in gamma-aminobutyric acid-B (GABA(B)) receptors may contribute to the symptoms of some neurological and psychiatric disorders and to the clinical response to psychotherapeutics. The present study was undertaken to determine whether chronic administration of tranylcypromine (TCP), an antidepressant, and chronic stress influence GABA(B) receptor function in rat brain. The results indicate that TCP treatment, but not stress, increases GABA(B) receptor activity in the cerebral cortex, as measured by baclofen-stimulated GTPgammaS binding. In addition, chronic administration of TCP enhances significantly the locomotor response to a single dose of amphetamine, an effect that is abolished by restraint stress. These results indicate that although TCP administration modifies brain GABA(B) receptor activity, which may contribute to the antidepressant response to this agent, this effect is unrelated to the interaction of stress and TCP treatment on the locomotor response to amphetamine.

Experiments were undertaken to examine whether once daily i.p. administration of either of two antidepressants used for the treatment of neuropathic pain, amitriptyline (10 mg/kg) and fluoxetine (5 mg/kg), to rats for 7 days modifies GABA(B) receptor function and subunit expression in the lumbar spinal cord. The results indicate that, as previously reported for desipramine, both amitriptyline and fluoxetine increase the pain threshold to a thermal stimulus, the expression of GABA(B(1)) subunits, and baclofen-stimulated [35S]GTPgammaS binding, a measure of GABA(B) receptor function. The effects of antidepressant administration on GABA(B(1b)) and GABA(B(2)) subunit expression in spinal cord are more variable than for GABA(B(1a)). It was also discovered that repeated daily exposure to a thermal stimulus or immobilization stress increases GABA(B(1a)) expression in the lumbar spinal cord, with no commensurate change in thermal pain threshold or GABA(B) receptor sensitivity. These results support a relationship between GABA(B) receptors and the action of antidepressants. The findings demonstrate that drug-induced increases in GABA(B) receptor function can occur independently of any change in GABA(B) receptor subunit expression and are consistent with the notion that GABA(B) receptor subunits have multiple functions, only one of which is dimerization to form GABA(B) receptors. The data also suggest that GABA(B) subunit gene expression may serve as a preclinical marker of antidepressant efficacy and of drug- or stress-induced modifications in central nervous system activity.

Little is known about the chronology of expression, cellular localization and function of GABA(B) subunits in the developing rat spinal cord. In the present study, in situ hybridization, immunohistochemistry and quantitative RT-PCR analysis were used to examine this issue. At embryonic day 18, in situ hybridization reveals that all three transcripts, GABA(B(1a)), GABA(B(1b)), and GABA(B(2)), are present throughout the gray matter. At postnatal day (PN) 2, while overall expression appears to decrease, it becomes more highly concentrated in motoneurons of the ventral horn. By PN 7, distinct subpopulations of cells expressing the transcripts become heavily expressed in motoneurons. Immunohistochemical analysis revealed that, unlike mRNA, GABA(B(1)) protein is more highly concentrated in the dorsal horn as compared to the motoneurons. Analysis using RT-PCR demonstrates that in spinal cord GABA(B(1a)) mRNA expression remains constant throughout development, GABA(B(1b)) increases from PN 2 to adult, and GABA(B(2)) decreases from PN 2 to adult. The distribution of functional GABA(B) receptors, as measured by baclofen-stimulated [35S]GTPgammaS binding, in the spinal cord during development generally follows the distribution of subunit expression, being widely distributed throughout the gray matter in embryonic spinal cord slices and becoming more concentrated in the dorsal horn during postnatal development, similar to the distribution of subunit proteins as measured by immunohistochemistry. These findings suggest that spinal cord GABA(B(1a)), GABA(B(1b)), and GABA(B(2)) transcripts are differentially regulated during development with the chronology of this expression suggesting that GABA(B) receptor subunits, in addition to forming functional GABA(B) receptors, may have a trophic function or participate in synaptogenesis.