The GABAB Receptor-Positive Modulator GS39783 and the GABAB Receptor Agonist Baclofen Attenuate the Reward-Facilitating Effects of Cocaine: Intracranial Self-Stimulation Studies in the Rat

Slattery, David A.; Markou, Athina; Froestl, Wolfgang; Cryan, John F.

doi:10.1038/sj.npp.1300734

Cited by 106 publications

(64 citation statements)

References 58 publications

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“…Nonetheless, GABA B receptor agonists have undesirable side effects, including disruption of performance on the rotarod test, a measure of locomotor impairment (Cryan et al 2004), and decreased responding for nondrug rewards, such as food and electrical brain stimulation (Macey et al 2001;Paterson et al 2005a;Slattery et al 2005). Interestingly, GABA B receptorpositive allosteric modulator compounds, such as GS39783 and the more recently synthesized BHF177, are likely to have more subtle effects than GABA B receptor agonists, due to their modulatory, rather than full agonist, properties at the receptors (Guery et al 2007).…”

Section: Neurosubstrates Of Nicotine Reward Dependence and Withdrawalmentioning

confidence: 99%

Neurobiology of nicotine dependence

Markou

2008

Phil. Trans. R. Soc. B

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229

182

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Nicotine is a psychoactive ingredient in tobacco that significantly contributes to the harmful tobacco smoking habit. Nicotine dependence is more prevalent than dependence on any other substance. Preclinical research in animal models of the various aspects of nicotine dependence suggests a critical role of glutamate, g-aminobutyric acid (GABA), cholinergic and dopamine neurotransmitter interactions in the ventral tegmental area and possibly other brain sites, such as the central nucleus of the amygdala and the prefrontal cortex, in the effects of nicotine. Specifically, decreasing glutamate transmission or increasing GABA transmission with pharmacological manipulations decreased the rewarding effects of nicotine and cue-induced reinstatement of nicotine seeking. Furthermore, early nicotine withdrawal is characterized by decreased function of presynaptic inhibitory metabotropic glutamate 2/3 receptors and increased expression of postsynaptic glutamate receptor subunits in limbic and frontal brain sites, while protracted abstinence may be associated with increased glutamate response to stimuli associated with nicotine administration. Finally, adaptations in nicotinic acetylcholine receptor function are also involved in nicotine dependence. These neuroadaptations probably develop to counteract the decreased glutamate and cholinergic transmission that is hypothesized to characterize early nicotine withdrawal. In conclusion, glutamate, GABA and cholinergic transmission in limbic and frontal brain sites are critically involved in nicotine dependence.

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Section: Neurosubstrates Of Nicotine Reward Dependence and Withdrawalmentioning

confidence: 99%

Neurobiology of nicotine dependence

Markou

2008

Phil. Trans. R. Soc. B

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229

182

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“…Positive GABA B receptor modulators such as GS39783 (N,N 0 -dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4, 6-diamine) are active only in the presence of GABA and are devoid of the sedative and muscle relaxant effects of full agonists (Urwyler et al, 2003;Cryan et al, 2004). GS39783 reduces the acute rewarding effects of cocaine self-administration in rodent models (Smith et al, 2004;Slattery et al, 2005). However, the effects of GS39783 on the long-term behavioral and molecular consequences of cocaine exposure are unknown.…”

Section: Introductionmentioning

confidence: 99%

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Lhuillier

Mombereau

Cryan

et al. 2006

Neuropsychopharmacol

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Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity, whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of druginduced neuroadaptive changes. Recent attention has been given to compounds activating GABA B receptors as potential antiaddictive therapies. In particular, the principle of allosteric positive GABA B receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABA B receptor agonists such as baclofen. Here, we investigated the effects of systemic application of the GABA B receptor-positive modulator GS39783 (N,N 0 -dicyclopentyl-2-methylsulfanyl-5-nitropyrimidine-4, 6-diamine) in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies, GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor DFosB and upregulates cAMP-response-element-binding protein (CREB) and dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited DFosB accumulation in the dorsal striatum. In summary, our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABA B receptor-positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted.

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“…However, baclofen did not have any protective effect on the KA-induced cochlear excitotoxicity, suggesting that the GABA B receptor did not have any effect on the cochlear excitotoxicity. It has been shown that the systemic administration of baclofen at the dosage of 1 to 2 mg/kg antagonizes glutamate excitotoxicity in the central nervous system (Slattery et al 2005, Diaz et al 2006and Wojnicki et al 2006. For this reason, we selected the administration dosage of baclofen in the present study.…”

Section: Discussionmentioning

confidence: 99%

Activation of the GABAA Receptor Ameliorates the Cochlear Excitotoxicity Caused by Kainic Acid in the Guinea Pig

Sakai

Tabuchi

Murashita

et al. 2008

Tohoku J. Exp. Med.

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Excitotoxicity is a major neurotoxic mechanism in cochlear disorders, including cochlear ischemic injury and acoustic injury. Kainic acid (KA), an excitatory amino acid, can damage glutamatergic neurons. The application of KA to the round window membrane, an opening of the cochlear bony labyrinth to the middle ear, induces excitotoxicity of cochlear afferent dendrites and significantly decreases the amplitude of compound action potential of the cochlea (CAP), a cochlear potential generated by activation of the auditory nerve fibers. On the other hand, muscimol, a gamma-aminobutyric acid (GABA) A receptor agonist, is neuroprotective in excitotoxicity in the central nervous system. Here we studied whether activation of GABA receptor decreased the excitotoxicity of the cochlea caused by KA. KA (10 mM) was applied to the round window membrane of guinea pigs for 30 minutes. Muscimol, bicuculline, a GABA A receptor antagonist, or baclofen, a GABA B receptor agonist, was given at the onset of KA application. The threshold shift of CAP was examined with chronically implanted electrodes. Application of KA significantly elevated the CAP threshold on day 1 and day 3 as compared with the pre-application level. Muscimol significantly decreased the KA-induced CAP threshold shifts. Furthermore, this protective effect of muscimol was inhibited by the application of bicuculline, a GABA A receptor antagonist. However, baclofen, a GABA B receptor agonist, did not affect the CAP threshold shifts caused by KA. These results suggest that activation of GABA A receptor could prevent cochlear excitotoxicity. GABA A rececptor activation may represent an effective treatment of cochlear ischemc injury and acoustic injury.

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The GABAB Receptor-Positive Modulator GS39783 and the GABAB Receptor Agonist Baclofen Attenuate the Reward-Facilitating Effects of Cocaine: Intracranial Self-Stimulation Studies in the Rat

Cited by 106 publications

References 58 publications

Neurobiology of nicotine dependence

Neurobiology of nicotine dependence

GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Activation of the GABAA Receptor Ameliorates the Cochlear Excitotoxicity Caused by Kainic Acid in the Guinea Pig

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