From the street to the brain: neurobiology of the recreational drug γ-hydroxybutyric acid

Wong, C. Guin Ting; Gibson, K. Michael; Snead, O. Carter

doi:10.1016/j.tips.2003.11.001

Cited by 174 publications

(135 citation statements)

References 50 publications

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“…At present, there appears to be little evidence for a role for GHB receptors in the in vivo effects of GHB (Wong et al 2004). Instead, many studies suggest that GABA B receptors are particularly important for various behavioral effects of GHB, including discriminative stimulus effects (e.g., Winter 1981, Colombo et al 1998, Carter et al 2003, decreased operant responding (Goodwin et al 2005), and directly observable effects such as hypolocomotion (Kaupmann et al 2003), catalepsy (Carter et al 2005), ataxia (Goodwin et al 2005), and loss of righting (Carai et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

Koek

2008

Psychopharmacology

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Rationale-Gamma-hydroxybutyrate (GHB) is a gamma-aminobutyric acid (GABA) analog that is used to treat narcolepsy but that is also abused. GHB has many actions in common with the GABA B receptor agonist baclofen, but their underlying GABA B receptor mechanisms may be different.Objective-The aim of this study is to further investigate a possible differential role of glutamate in GABA B receptor-mediated effects of GHB and baclofen. Materials and methods-The experiments examined the effects of non-competitive antagonists at the N-methyl-d-asparate (NMDA) subtype of glutamate receptors on GHB-induced catalepsy and compared these effects with those on baclofen-induced catalepsy.Results-In C57BL/6J mice, ketamine, phencyclidine (PCP), and dizocilpine (MK-801) all enhanced GHB-induced catalepsy. They did so with a potency order (i.e., MK-801 > PCP > ketamine) consistent with their relative potencies as NMDA antagonists but not as inhibitors of dopamine or organic cation transporters. Ketamine, PCP, and MK-801 enhanced catalepsy along inverted U-shaped dose-response curves likely because higher doses affected motor coordination, which limited their catalepsy-enhancing effects. Doses that were maximally effective to enhance GHB-induced catalepsy did not affect the cataleptic effects of baclofen.Conclusions-The finding that NMDA receptor antagonists enhance the cataleptic effects of GHB but not those of baclofen is further evidence that the GABA B receptor mechanisms mediating the effects of GHB and GABA B agonists are not identical. Differential interactions of glutamate with the GABA B receptor mechanisms mediating the effects of GHB and baclofen may explain why GHB is effective for treating narcolepsy and is abused, whereas baclofen is not.

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Section: Introductionmentioning

confidence: 99%

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

Koek

2008

Psychopharmacology

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“…There was no difference in the resting membrane potential [Ϫ60.24 Ϯ 5.63 mV (n ϭ 17) vs. Our previous study showed that mice lacking ␣1G T-type Ca 2ϩ channels were specifically resistant to GABA B R agonist-induced absence seizures (17). To investigate the sensitivity of PLC␤4 Ϫ/Ϫ mice to GABA B R agonist, we used ␥-butyrolactone (GBL) known to induce absence seizures primarily by acting on GABA B receptors (32,33) and RS(ϩ/Ϫ) baclofen, a selective GABA B receptor agonist (34).…”

mentioning

confidence: 99%

Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures

Cheong

Zheng

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Absence seizures are characterized by cortical spike-wave discharges (SWDs) on electroencephalography, often accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing driven by T-type Ca 2؉ currents. We recently demonstrated that the phospholipase C ␤4 (PLC␤4) pathway tunes the firing mode of TC neurons via the simultaneous regulation of T-and L-type Ca 2؉ currents, which prompted us to investigate the contribution of TC firing modes to absence seizures. PLC␤4-deficient TC neurons were readily shifted to the oscillatory burst firing mode after a slight hyperpolarization of membrane potential. TC-limited knockdown as well as whole-animal knockout of PLC␤4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLC␤4 leads to the genesis of absence seizures. The SWDs were effectively suppressed by thalamic infusion of a T-type, but not an L-type, Ca 2؉ channel blocker. These results reveal a primary role of TC neurons in the genesis of absence seizures and provide strong evidence that an alteration of the firing property of TC neurons is sufficient to generate absence seizures. Our study presents PLC␤4-deficient mice as a potential animal model for absence seizures.epilepsy ͉ gene knockdown ͉ knockout mice ͉ thalamus A bsence seizures are generalized nonconvulsive seizures characterized by a brief and sudden impairment of consciousness, concomitant with bilaterally synchronized spike-and-wave discharges (SWDs) in the electroencephalogram (EEG) over wide cortical areas (1-4). Abnormal hypersynchronized oscillatory activities in the thalamocortical network, consisting of feedforward and feedback connections between the cortex and the thalamus, have been implicated as an underlying mechanism for the generation of SWDs (5-9). Some studies using rat models of absence seizures have suggested that the cortex plays a leading role in the generation of SWDs (10-13). Other studies support the hypothesis that massive thalamocortical synchronization is driven from recurrent oscillatory activities in the network between reticular thalamic nucleus (nRT) and thalamocortical (TC) relay nucleus (3,8,9,14,15). A majority of these studies proposed a leading role for nRT neurons in the genesis of absence seizures. Relatively less attention has been directed on the role of TC neurons in the generation of SWDs. Thalamocortical network oscillations are often observed to be accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing (16). Low-threshold burst firing driven by T-type Ca 2ϩ currents in TC neurons has long been proposed to be a critical component in sustaining the oscillations during the SWDs (3,8,17), although a controversy still remains (4, 18).Many studies have described spontaneous appearance of SWDs in the cortical EEG from rodent models for absence epilepsy (19)(20)(21)(22)(23)(24). Some showed that T-type Ca 2ϩ currents were incre...

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“…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.…”

Section: Discussionmentioning

confidence: 75%

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

2008

Pharmacology Biochemistry and Behavior

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It has been observed that agents with agonist activity at 5-HT 2A receptors prevent neurotoxicity induced by the non-competitive NMDA antagonist, dizocilpine (MK-801). Subsequent behavioral studies reported complete antagonism by LSD and DOM of the stimulus effects of the related NMDA antagonist, phencyclidine [PCP]. The present study sought to extend those observations to include other psychoactive drugs. Male F-344 rats were trained in a 2-lever, fixed ratio 10, food-reinforced task with PCP (3.0 mg/kg; IP; 30 min pretreatment) as a discriminative stimulus. Tests of generalization were then conducted using the training dose of PCP in combination with a range of doses of DOM, LSD, d-amphetamine, MDMA, psilocybin, buspirone, and GHB. All of the drugs tested in combination with PCP produced a statistically significant diminution of PCP-appropriate responding but for none was antagonism complete. These data, obtained using a stimulus control model of the hallucinogenic effects of PCP, fail to support the hypothesis that LSD and DOM completely antagonize stimulus control by PCP. Instead, the data suggest complex interactions between PCP-induced stimulus control and a variety of psychoactive drugs including GHB, an agent with no known affinity for serotonergic receptors.

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From the street to the brain: neurobiology of the recreational drug γ-hydroxybutyric acid

Cited by 174 publications

References 50 publications

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures

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

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