Lloyd KG, Thuret F, Pilc A. Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock. J Pharmacol Exp Ther 235: 191-199
The action of different classes of clinically effective antidepressants and electroshock on gamma-aminobutyric acid (GABA) B recognition sites in the frontal cortex was compared to that of other psychotropic agents. After either prolonged (6-18 days) s.c. infusion via osmotic minipumps or repeated i.p. injections of different antidepressants, or a series of electroshocks, treatment was halted and 72 hr later the animals were sacrificed, the brain was dissected and frozen. All major antidepressants (desipramine, amitryptyline or maprotiline), several newer compounds with reported antidepressant activity (viloxazine, zimelidine, fluoxetine, citalopram, progabide, fengabine, sodium valproate, mianserin, trazodone or nomifensine) as well as pargyline and repeated electroshocks, up-regulated GABA B binding in the rat frontal cortex but not hippocampus. This appeared to be a maximum binding effect, but in some instance the kinetics were more complex. Reserpine, diphenylhydantoin and phenobarbital down-regulated GABA B binding in the frontal cortex, whereas this was unaltered by haloperidol, chlorpromazine or diazepam administration. Desipramine up-regulated GABA B binding in a dose- and time-dependent manner (minimum effective dose, 1.25 mg/kg/day s.c. for 18 days; onset of action, 6 days at 5 mg/kg/day s.c.). Together with the rather sparse data in the literature on GABA in depression and antidepressant drug action, these findings support a common GABAergic mechanism of action of antidepressant drugs and electroshock, mediated via GABA B synapses.
Available from: Andrzej Pilc
- "A role for the amino-acid neurotransmitter, g-aminobutyric acid (GABA), in mood disorders was first proposed over 20 years ago by Emrich et al. (1980), based on the clinical observation that valproic acid, a GABA agonist, was effective in the treatment of bipolar patients. The studies of Lloyd and colleagues showing an upregulation of GABA B receptors after prolonged antidepressant treatment in rats (Pilc and Lloyd, 1984; Lloyd et al., 1985) focused attention on this receptor type. GABA is the major inhibitory neurotransmitter in the central nervous system (Paredes and Agmo, 1992), acting via stimulation of GABA A , GABA B and GABA C receptors (Chebib and Johnston, 1999; Bormann, 2000; Rudolph et al., 2001). "
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ABSTRACT: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice.
Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated.
The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus.
These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.
British Journal of Pharmacology 12/2006; 149(5):581-90. DOI:10.1038/sj.bjp.0706845 · 4.84 Impact Factor
Available from: medicine.tums.ac.ir
- "Ž upregulated by administration of antidepressants Lloyd et . al., 1985 . GABA has been shown to play a role in Ž . depression Petty et al., 1995a,b . We had also shown that Ž . a GABA receptor mechanism s may modulate antidepres- Ž . sant-induced antinociception Sabetkasai et al., 1999 . Antidepressants are probably the most commonly prescribed Ž . drugs for the treatment of chronic pain Feinmann, 1985 . Ž"
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ABSTRACT: This study concerned the effects of GABA(B) receptor agents on imipramine-induced antinociception in ligated and non-ligated mice in hot-plate test. The data showed that different doses of morphine (3, 6 and 9 mg/kg) induced a dose-dependent antinociception in non-ligated or ligated mice. However, the opioid response was decreased in the ligated animals. Intracerebroventricular (i.c.v.) administration of imipramine (5, 10, 20 and 40 microg/mouse) did not induce antinociception in either non-ligated or ligated mice. However, the response induced in the ligated mice was less than that induced in the non-ligated animals. Intraperitoneal (i.p.) administration of imipramine (10, 20, 30 and 40 mg/kg) induced antinociception in both ligated and non-ligated animals. The responses to the drug were not significantly different in the two groups. Administration of baclofen either i.c.v. (0.125, 0.25 and 0. 5 microg/mouse) or i.p. (0.5, 1, 2 and 4 mg/kg) induced antinociception. The response to the drug was not significantly different in ligated and non-ligated mice. I.c.v. administration of a lower dose of baclofen (0.125 microg/mouse) with different doses of imipramine (2.5, 5 and 10 mg/kg) potentiates the response of imipramine. This effect was reduced by i.c.v. injection of GABA(B) receptor antagonist, CGP35348 [P-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid] (20 microg/mouse). The higher dose of antagonist (20 microg/mouse) also decreased the response induced by baclofen or imipramine. CGP35348 itself (2.5, 5, 10 and 20 microg/mouse) induced dose-dependent antinociception with no significant difference in the ligated and non-ligated mice. It is concluded that a GABA receptor mechanism(s) may modulate the antidepressant-induced antinociception.
European Journal of Pharmacology 11/2000; 407(1-2):65-72. DOI:10.1016/S0014-2999(00)00648-8 · 2.53 Impact Factor
Available from: nih.gov
- "Using clonidine as the pharmacological probe, studies on Cx2-receptor functioning have been conducted on rats and have indicated that TCP and PLZ both cause a down-regulation of cX2-adrenergic receptors after chronic administration (Greenshaw et al 1988; McKenna et al 1992a). Lloyd et al (1985) reported an up-regulation of GABAB receptors in the frontal cortex ofrats after chronic administration of the MAO inhibitor pargyline, but McManus and Greenshaw (199la; 199 lb) reported that PLZ did not affect GABAB receptor density or functioning, as measured in neurochemical and behavioral experiments, respectively. The chronic administration of both PLZ and TCP has been reported to cause a decrease in the density of 3H-tryptamine binding sites in the brains of rats (Mousseau et al, in press). "
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ABSTRACT: Although the non-selective monoamine oxidase inhibitors phenelzine and tranylcypromine have been used for many years, much still remains to be understood about their mechanisms of action. Other factors, in addition to the inhibition of monoamine oxidase and the subsequent elevation of brain levels of the catecholamines and 5-hydroxytryptamine, may contribute to the overall pharmacological profiles of these drugs. This review also considers the effects on brain levels of amino acids and trace amines, uptake and release of neurotransmitter amines at nerve terminals, receptors for amino acids and amines, and enzymes other than monoamine oxidase, including enzymes involved in metabolism of other drugs. The possible contributions of metabolism and stereochemistry to the actions of these monoamine oxidase inhibitors are discussed.
Journal of psychiatry & neuroscience: JPN 12/1992; 17(5):206-14. · 5.86 Impact Factor
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