The Discriminative Stimulus Effects of γ-Hydroxybutyrate and Related Compounds in Rats Discriminating Baclofen or Diazepam: The Role of GABA_B and GABA_A Receptors

Abstract

The discriminative stimulus effects of ␥-hydroxybutyrate (GHB) can be mimicked by GABA A receptor-positive modulators (e.g., diazepam) and GABA B receptor agonists (e.g., baclofen). The purposes of this study were to see whether stimulus control could be established with baclofen and to further characterize the role of GABAergic mechanisms in the behavioral actions of GHB by evaluating GHB and related compounds in rats discriminating either diazepam or baclofen. Training criteria were satisfied with baclofen and diazepam after 69 and 44 sessions, respectively. GHB and its precursors ␥-butyrolactone and 1,4-butanediol occasioned Ͼ80% responding on the drug-associated lever in rats discriminating baclofen and Ͻ11% in rats discriminating diazepam. Diazepam and other GABA A receptor-positive modulators occasioned intermediate levels of responding on the baclofen lever, whereas baclofen occasioned less than 4% responding on the diazepam lever. The GABA B receptor antagonist CGP 35348 [(3-aminopropyl)(diethoxymethyl) phosphinic acid] partially antagonized the effects of baclofen as well as the baclofen-like effects of GHB, and flumazenil partially antagonized the effects of diazepam. This study established stimulus control with baclofen, and substitution data provided direct evidence for a role of GABAergic, especially GABA B , mechanisms in the discriminative stimulus effects of GHB. The lack of substitution by GHB or its metabolic precursors for diazepam indicates a comparatively smaller role of GABA A mechanisms in these effects of GHB. The inability of CGP 35348 to completely attenuate the effects of baclofen and GHB suggests that multiple receptors could be involved in the discriminative stimulus effects of GHB.

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABABReceptor Agonists

“…Specific GHB receptors have been hypothesized (Benavides et al, 1982;Snead and Liu, 1984;Hechler et al, 1987;Castelli et al, 2000;Mehta et al, 2001) and recently cloned (Andriamampandry et al, 2003). However, behavioral studies suggest an important role for GABA B receptors (Colombo et al, 1998;Lobina et al, 1999;Carai et al, 2001Carai et al, , 2002aCarter et al, 2003Carter et al, , 2004aRen and Mody, 2003), consistent with the finding that GHB binds to these receptors (Bernasconi et al, 1992;Xie and Smart, 1992;Mathivet et al, 1997;Lingenhoehl et al, 1999).…”

“…Increasing evidence (e.g., cross-substitution between GHB and baclofen) in rats and pigeons suggests that GABAergic activity is a major component of the discriminative stimulus effects of GHB (Colombo et al, 1998;Lobina et al, 1999;Carter et al, 2003Carter et al, , 2004aBaker et al, 2004;Koek et al, 2004). Thus, compounds that do not bind to GABA receptors might not be expected to produce or attenuate GHB-like discriminative stimulus effects, which is consistent with the relatively small amount of GHB-appropriate responding observed after administration of selective GHB receptor ligands current study) and the failure of UMB86, UMB72, or 3-HPA to fully antagonize the discriminative stimulus effects of the training dose in either rats or pigeons.…”

“…As the dose of GHB is increased, additional mechanisms of action are likely to contribute to its behavioral profile. Thus, GHB or dopamine receptor-mediated mechanisms that do not seem to play a prominent role in the discriminative stimulus effects of GHB in rats (Winter, 1981;Wu et al, 2003;Carter et al, 2004a) could play a more predominant role in mediating the effects of GHB that are observed at larger doses.…”

Antagonism of phencyclidine-induced stimulus control in the rat by other psychoactive drugs

“…While there is little doubt that the stimulus effects of PCP were antagonized by each of the agents tested, all effects were intermediate in nature and, for all but GHB, the combinations were accompanied by decreased rates of responding. Given the complex nature of GHB's effects [Wong et al 2004;Carter et al 2004;Snead and Gibson 2005], extensive speculation is not warranted at this time but the present findings suggest the possibility that GABA A , GABA B , and, indirectly, dopaminergic receptors may play a role in the interaction of GHB with PCP. Whether the observed diminution of PCP-appropriate responding by each of the psychoactive drugs examined represents either direct or indirect interactions with NMDA receptors remains to be established.…”

“…Subsequent experiments tested the interactions between PCP and the serotonergic agents, LSD, DOM, psilocybin, and buspirone. In addition, interactions with PCP were tested with the dopaminergic/serotonergic drugs, d-amphetamine and MDMA, as well as with GHB, a drug thought to act via non-serotonergic mechanisms (Bernasconi et al 1999;Carter et al 2004;Winter, 1981).…”