TY - JOUR
T1 - Behavioral effects of γ-hydroxybutyrate, its precursor γ-butyrolactone, and GABAB receptor agonists
T2 - Time course and differential antagonism by the GABAB receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348)
AU - Koek, Wouter
AU - Mercer, Susan L.
AU - Coop, Andrew
AU - France, Charles P.
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009
Y1 - 2009
N2 - γ-Hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABAB receptors seem to play an important role. This role could be complex, because there are indications that different GABAB receptor mechanisms mediate the effects of GHB and the prototypical GABAB receptor agonist baclofen. To further explore possible differences in underlying GABAB receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABAB receptor antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor γ-butyrolactone (GBL), and the GABAB receptor agonists baclofen and 3-aminopropyl(methyl) phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose- and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the agonists. Schild analysis yielded a pA2 value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7- 4.2)] that was different (P = 0.0011) from the pA2 value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4-4.7)]. This finding is further evidence that the GABAB receptor mechanisms mediating the effects of GHB and prototypical GABAB receptor agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.
AB - γ-Hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABAB receptors seem to play an important role. This role could be complex, because there are indications that different GABAB receptor mechanisms mediate the effects of GHB and the prototypical GABAB receptor agonist baclofen. To further explore possible differences in underlying GABAB receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABAB receptor antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor γ-butyrolactone (GBL), and the GABAB receptor agonists baclofen and 3-aminopropyl(methyl) phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose- and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the agonists. Schild analysis yielded a pA2 value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7- 4.2)] that was different (P = 0.0011) from the pA2 value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4-4.7)]. This finding is further evidence that the GABAB receptor mechanisms mediating the effects of GHB and prototypical GABAB receptor agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.
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U2 - 10.1124/jpet.109.151845
DO - 10.1124/jpet.109.151845
M3 - Article
C2 - 19564487
AN - SCOPUS:70349091922
VL - 330
SP - 876
EP - 883
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -