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GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent.
J Pharmacol Exp Ther. 2005 Jan; 312(1):290-6.JP

Abstract

There is an emerging body of data purporting a role of gamma-aminobutyric acid (GABA) in the pathophysiology of mood disorders. However, the role of metabotropic GABA(B) receptors in depression is not well defined. The modified forced swim test has recently emerged as an excellent tool to assess behaviorally the role of monoamines in antidepressant action. To assess the role of GABA(B) receptors in antidepressant-related behavior, we examined a number of selective GABA(B) receptor ligands (novel positive modulators and antagonists) on behavior in the modified forced swim test. We demonstrate that the selective GABA(B) receptor antagonists CGP56433A [[3-{1-(S)-[{3-cyclohexylmethyl)hydroxy phosphinyl}-2-(S) hydroxy propyl]amino}ethyl]benzoic acid; 1-10 mg/kg] and [3-[[1-(S)-3-dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]phenylmethyl-phosphinic acid hydrochloride; 3-10 mg/kg] had a similar profile to the selective serotonin reuptake inhibitor fluoxetine; they decreased immobility and increased swimming behavior. The tricyclic antidepressant desipramine decreased immobility but increased climbing behavior. In contrast, the novel GABA(B) receptor-positive modulator GS39783 (10-40 mg/kg) did not display antidepressant-like activity in the modified forced swim test. To further assess the possible interaction between GABA(B) receptor antagonism and serotonin, rats were pretreated with the tryptophan hydroxylase inhibitor para-chlorophenylalanine. 5-Hydroxytryptamine depletion (>90%) abolished the antidepressant-like behavior of CGP56433A (10 mg/kg) by attenuating the increase in swimming. Together, these data demonstrate that GABA(B) receptor antagonists via an interaction with the serotonergic system display antidepressant-like properties and therefore represent a novel approach for the treatment of depression.

Authors+Show Affiliations

Neuroscience Research, Novartis Institutes for BioMedical Research WSJ 386.344, Novartis, Basel, CH-4002, Switzerland.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15333677

Citation

Slattery, David A., et al. "GABAB Receptor Antagonist-mediated Antidepressant-like Behavior Is Serotonin-dependent." The Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 1, 2005, pp. 290-6.
Slattery DA, Desrayaud S, Cryan JF. GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent. J Pharmacol Exp Ther. 2005;312(1):290-6.
Slattery, D. A., Desrayaud, S., & Cryan, J. F. (2005). GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent. The Journal of Pharmacology and Experimental Therapeutics, 312(1), 290-6.
Slattery DA, Desrayaud S, Cryan JF. GABAB Receptor Antagonist-mediated Antidepressant-like Behavior Is Serotonin-dependent. J Pharmacol Exp Ther. 2005;312(1):290-6. PubMed PMID: 15333677.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent. AU - Slattery,David A, AU - Desrayaud,Sandrine, AU - Cryan,John F, Y1 - 2004/08/27/ PY - 2004/8/31/pubmed PY - 2005/4/14/medline PY - 2004/8/31/entrez SP - 290 EP - 6 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 312 IS - 1 N2 - There is an emerging body of data purporting a role of gamma-aminobutyric acid (GABA) in the pathophysiology of mood disorders. However, the role of metabotropic GABA(B) receptors in depression is not well defined. The modified forced swim test has recently emerged as an excellent tool to assess behaviorally the role of monoamines in antidepressant action. To assess the role of GABA(B) receptors in antidepressant-related behavior, we examined a number of selective GABA(B) receptor ligands (novel positive modulators and antagonists) on behavior in the modified forced swim test. We demonstrate that the selective GABA(B) receptor antagonists CGP56433A [[3-{1-(S)-[{3-cyclohexylmethyl)hydroxy phosphinyl}-2-(S) hydroxy propyl]amino}ethyl]benzoic acid; 1-10 mg/kg] and [3-[[1-(S)-3-dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]phenylmethyl-phosphinic acid hydrochloride; 3-10 mg/kg] had a similar profile to the selective serotonin reuptake inhibitor fluoxetine; they decreased immobility and increased swimming behavior. The tricyclic antidepressant desipramine decreased immobility but increased climbing behavior. In contrast, the novel GABA(B) receptor-positive modulator GS39783 (10-40 mg/kg) did not display antidepressant-like activity in the modified forced swim test. To further assess the possible interaction between GABA(B) receptor antagonism and serotonin, rats were pretreated with the tryptophan hydroxylase inhibitor para-chlorophenylalanine. 5-Hydroxytryptamine depletion (>90%) abolished the antidepressant-like behavior of CGP56433A (10 mg/kg) by attenuating the increase in swimming. Together, these data demonstrate that GABA(B) receptor antagonists via an interaction with the serotonergic system display antidepressant-like properties and therefore represent a novel approach for the treatment of depression. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15333677/GABAB_receptor_antagonist_mediated_antidepressant_like_behavior_is_serotonin_dependent_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15333677 DB - PRIME DP - Unbound Medicine ER -