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Link to original content: https://pubmed.ncbi.nlm.nih.gov/19564487
Behavioral effects of gamma-hydroxybutyrate, its precursor gamma-butyrolactone, and GABA(B) receptor agonists: time course and differential antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348) - PubMed Skip to main page content
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. 2009 Sep;330(3):876-83.
doi: 10.1124/jpet.109.151845. Epub 2009 Jun 29.

Behavioral effects of gamma-hydroxybutyrate, its precursor gamma-butyrolactone, and GABA(B) receptor agonists: time course and differential antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348)

Wouter Koek  1 , Susan L Mercer, Andrew Coop, Charles P France
Affiliations

Behavioral effects of gamma-hydroxybutyrate, its precursor gamma-butyrolactone, and GABA(B) receptor agonists: time course and differential antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348)

Wouter Koek et al. J Pharmacol Exp Ther. 2009 Sep.

Abstract

Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABA(B) receptors seem to play an important role. This role could be complex, because there are indications that different GABA(B) receptor mechanisms mediate the effects of GHB and the prototypical GABA(B) receptor agonist baclofen. To further explore possible differences in underlying GABA(B) receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABA(B) 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 gamma-butyrolactone (GBL), and the GABA(B) 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 pA(2) value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7-4.2)] that was different (P = 0.0011) from the pA(2) value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4-4.7)]. This finding is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and prototypical GABA(B) 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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Figures

Fig. 1.
Fig. 1.
Effects of baclofen, administered intramuscularly immediately before the session, on fixed ratio 20 responding in a one-key, food-reinforced procedure (n = 5–9). Each 12-h session consisted of 10 5-min response periods starting at different times after the beginning of the session. For each of these response periods, the rate of key peck responding is plotted as a function of dose. Symbols represent mean ± S.E.M.; S.E.M. values are contained by the symbol.
Fig. 2.
Fig. 2.
Effects of baclofen, SKF97541, GHB, and GBL, administered intramuscularly immediately before the session, on fixed ratio 20 responding in a one-key, food-reinforced procedure in pigeons (n = 4–9). The potency to decrease the rate of key peck responding is plotted as a function of time from the beginning of the session. Circles represent ED50 and 95% confidence limits. For each drug, open circles indicate ED50 values that differed significantly from the lowest observed value, and closed circles indicate ED50 values that did not. Squares represent interval estimates of ED50 values.
Fig. 3.
Fig. 3.
Top and middle, attenuation by CGP35348 of response rate-decreasing effects of baclofen, SKF97541, GHB, and GBL in pigeons (n = 5–6). CGP35348 or saline was injected 10 min before each agonist, and 30 min after the agonist was injected, key peck responding was measured. For each agonist, the rate of key peck responding, expressed as a percentage of saline control, is plotted as a function of dose after pretreatment with saline (•) or different doses of CGP35348 [○, ▵, ▿, data comprising the linear portion of the dose-response curves, and fitted with log-linear regression lines; gray-filled symbols, data obtained with the same doses of CGP35348 as the corresponding open symbols, but not part of the linear portion of the dose-response curves, and not used in the regression calculations (see “Data Analysis”)]. Symbols represent mean ± S.E.M.; if not shown, S.E.M. values are contained by the symbol. Bottom, Schild regression plots for antagonism by CGP35348 of the response rate-decreasing effects of baclofen, SKF97541, GHB, and GBL. Dose ratios are the ED50 values of SKF97541 in the presence of CGP35348 (3.2–32 mg/kg) divided by the ED50 value after pretreatment with saline. ED50 values were calculated from the regression lines shown in the top and middle. Data obtained with each agonist could be fitted with a regression line with a slope of -1. Calculated from these regression lines, the pA2 value of CGP35348 ranged from 3.91 (95% confidence limits, 2.98–4.85) for GBL to 4.63 (4.17–5.09) for SKF97541.
Fig. 4.
Fig. 4.
Time-dependent attenuation by CGP35348 of the response rate-decreasing effects of SKF97541 in pigeons (n = 5–6) (left, top to bottom, and right, top and middle). CGP35348 or saline was injected 10 min before SKF97541, and key peck responding was measured at different times after the agonist was injected (range, 15–240 min). For each time interval, the rate of key peck responding, expressed as a percentage of saline control, is plotted as a function of dose after pretreatment with saline (•) or different doses of CGP35348 [○, ▵, ▿, data comprising the linear portion of the dose-response curves, and fitted with log-linear regression lines; gray-filled symbols, data obtained with the same doses of CGP35348 as the corresponding open symbols, but not part of the linear portion of the dose-response curves, and not used in the regression calculations (see “Data Analysis”)]. Symbols represent mean ± S.E.M.; if not shown, S.E.M. values are contained by the symbol. Bottom right, Schild regression plots for the ability of CGP35348 to antagonize, at different times after its administration (in minutes), the response rate-decreasing effects of SKF97541. Dose ratios are the ED50 values of each agonist in the presence of CGP35348 (3.2–32 mg/kg) divided by the ED50 value of the agonist after pretreatment with saline. Data obtained at each time interval could be fitted with a regression line with a slope of -1. Calculated from these regression lines, the pA2 value of CGP35348 to antagonize SKF97541 at the different intervals ranged from 4.18 (95% confidence limits, 3.92–4.43) at 240 min after SKF97541 to 4.63 (4.17–5.09) at 30 min after SKF97541 (i.e., 250 and 40 min after CGP35348, respectively).
Fig. 5.
Fig. 5.
Antagonism by CGP35348 of the rate-decreasing effects of different agonists at different times after their administration. pA2 values are plotted for each agonist at the times it had rate-decreasing effects. CGP35348 was approximately 4-fold less potent to antagonize the effects of GHB and GBL than to antagonize the effects of baclofen and SKF97541. CGP35348 was approximately 2-fold less potent to antagonize SKF97541 at 240 min after its administration than at shorter intervals. a, P < 0.05 compared with baclofen and SKF; b, P < 0.05 and <0.10 compared with SKF97541 and baclofen, respectively; c, P < 0.05 compared with SKF97541 at all shorter intervals.
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