engleski

The effects of GABA and GABAergic drugs on the HPA axis activity

Various studies have shown that gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, regulates neuroendocrine functions and affects the activity of hypothalamic-pituitary-adrenal (HPA) axis. Although most data suggest that GABA, as well as benzodiazepines, inhibit HPA axis function through central mechanisms involving the hypothalamic control, the reports regarding possible involvement of GABAergic drugs in the control of HPA axis are still contradictory. Namely, diverse effects of these drugs on corticosterone and adrenocorticotropic hormone (ACTH) levels have been demonstrated both in experimental animals and in humans. Besides being dependent on the dose, the effects of GABAergic drugs on the HPA axis activity appear to be influenced by the gender of the animals. Moreover, the reasons for the observed discrepancies might be sought in the complexity of neural circuits and neuroendocrine relations, the lack of specificity of drugs used in the studies, but also in different levels (central or peripheral) at which drugs affecting GABAergic neurotransmission primarily act. Our results demonstrating the stimulatory effect of GABA antagonists picrotoxin and bicuculline, administered intraperitoneally (i.p.), on the plasma corticosterone levels in rats, suggest that blockade of GABAA receptors stimulates the activity of the HPA axis. The observed inhibitory effect of a low dose (1 mg/kg) of diazepam (i.p.), the GABAA receptor enhancer, as well as of baclofen (i.p.), the GABAB receptor agonist, and GABA administered intracerebroventriculary (i.c.v.), on plasma corticosterone and ACTH levels, respectively, is also in agreement with the hypothesis suggesting GABAergic inhibition of the HPA axis. In contrast, the i.p. administration of GABA, the GABA agonist progabide and aminooxyacetic acid (AOAA), the inhibitor of GABA degradation, increased corticosterone levels in plasma. While picrotoxin, bicuculline and progabide produced an increase of plasma corticosterone levels in both males and females (although more in female then in male rats), diazepam had a dual effect depending on the dose of the drug and on the sex of the animals. Namely, diazepam administered in lower dose (1 mg/kg) inhibited the activity of HPA axis only in female rats, while high dose of diazepam (10 mg/kg) stimulated the HPA axis activity of male and female rats. Hence, further studies are necessary to elucidate the complex mechanisms of GABAergic drugs on the activity of HPA axis and to consider the possible implications of these findings for the human therapy.

GABA ; GABAeric drugs ; HPA axis ; corticosterone ; ACTH ; sex differences ; rats

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