Antidepressant effects on GABA-stimulated super(36)Cl super(-) influx in rat cerebral cortex are altered after treatment with GABA sub(A) receptor antisense oligodeoxynucleotides

• Published in: Brain research 2000-06, Vol.869 (1-2), p.78-84
• Main Authors: Malatynska, E, Crites, G J, Harrawood, D, Goldenberg, R, Matheson, G K
• Format: Article
• Language: English
• Subjects: mianserin
• ISSN: 0006-8993
• DOI: 10.1016/S0006-8993(00)02354-4

Antidepressants act at the GABA sub(A) receptor to inhibit GABA-stimulated super(36)Cl super(-) influx and GABA reduction of [ super(35)S]TBPS binding. This study examined how selective knock-down (via antisense oligodeoxynucleotides, aODNs) of GABA sub(A) receptor subunits modified antidepressant activity. The specific aODNs used were for the alpha 1, beta 1, beta 2 or gamma 2 subunits of the GABA sub(A) receptor. The aODN microinjections reduced corresponding GABA sub(A) receptor subunit mRNA levels by 30-40% as assessed by RT-PCR. The inhibitory effect of the antidepressants amitriptyline and mianserin on GABA-stimulated super(36)Cl super(-) influx was decreased after microinjections of alpha 1, beta 1, or beta 2 subunit aODNs but potentiated after microinjections of gamma 2 subunit aODNs. This pattern of aODNs effect on amitriptyline and mianserin modulation of GABA-stimulated super(36)Cl super(-) influx was the same for both antidepressants and similar to GABA but different than that of diazepam and bicuculline. We conclude that multiple subunits of the GABA sub(A) receptor regulate the effect of amitriptyline and mianserin on the GABA sub(A) receptor chloride ionophore complex. However, the exact identity of the subunit mediating the direct or allosteric modulation of the antidepressant effect on GABA-stimulated super(36)Cl super(-) influx remains unclear.