Administration of GABA(B) receptor positive allosteric modulators inhibit the expression of previously established methamphetamine-induced conditioned place preference

Abstract

Little is known about the role of GABA(B) receptors (GABA(B)Rs) in the maintenance of memories associated with using abused substances. We have embarked on a series of studies designed to determine if enhancing the efficacy of GABA-occupied GABA(B)Rs with positive allosteric modulators (PAMs) can negate previously established conditioned place preference (CPP) induced by methamphetamine. In the current study, we evaluated the effects of acute administration of GABA(B)R PAMs, GS39783 and CGP7930. We determined that post-conditioning treatments with these PAMs, administered in the home cage, blocked the subsequent expression of methamphetamine-induced CPP. These data indicate that selectively augmenting GABA-occupied GABA(B)R signaling is sufficient to reduce memory maintenance and/or the salience of contextual cues previously associated with methamphetamine.

Fig. 1

Meth-induced CPP is inhibited by post-conditioning administration of the PAMs GS39783 and CGP7930. (A) Illustration of treatment protocol. A drug-free Pre-Test was conducted and rats were assigned to receive Meth (1 mg/kg, i.p.) in the initially non-preferred chamber. Conditioning occurred on days 1–6. A drug-free CPP Test was conducted on day 9 to verify the development of CPP (CPP Test 1). Vehicle, baclofen, or a PAM was administered in the home cage on days 10 and 11. A final drug-free CPP Test (CPP Test 2) was conducted on day 14 to determine the capacity of GABAergic ligands to influence the expression of Meth-induced CPP. (B) Rats assigned to the PAM vehicle (10% propylene glycol) group (n = 14) expressed CPP on both Test days (CPP Tests 1 and 2). Rats administered (C) GS39783 (n = 11) or (D) CGP7930 (n = 9) as an intervening treatment did not express a preference for the Meth-paired chamber on CPP Test 2. Post hoc Newman–Keuls test was used to determine between chamber differences (center chamber not included for statistical analysis), **p < 0.01. Solid line, time spent in the Meth-paired chamber; dashed line, time spent in the saline-paired chamber; grey line, time spent in the center chamber. M, methamphetamine (1 mg/kg); S, saline (1 mg/kg); Veh, vehicle (1 ml/kg); Bac, baclofen (2 mg/kg); PAM, positive allosteric modulator: GS39783 (30 mg/kg), CGP7930 (30 mg/kg).