Both GABAB receptor agonist and antagonists decreased brain stimulation reward in the rat

Froestl

et al. 2005

Neuropsychopharmacol

Self Cite

108

There is an increasing interest in the development of nondopaminergic pharmacotherapies for cocaine abuse. Emerging preclinical and clinical data with the metabotropic GABA B receptor agonist baclofen support a role for the modulation of GABA B receptors in the treatment of drug addiction. Nevertheless, the muscle relaxant, hypothermic, and sedative properties of baclofen somewhat limit its widespread potential therapeutic utility. Recently, positive modulators of the GABA B receptor such as GS39783 (N,N 0 -dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) have been identified. These positive modulators enhance the effects of GABA (g-aminobutyric acid) through actions at an allosteric site and are devoid of intrinsic agonistic efficacy. The aim of the present study was to assess the ability of the novel GABA B -positive modulator GS39873 or baclofen to modulate the behavioral effects of cocaine. Drugs of abuse such as cocaine lower brain reward thresholds obtained using intracranial self-stimulation (ICSS). We demonstrate here that GS39783 had no intrinsic effects on ICSS reward thresholds (10-100 mg/kg p.o.) in rats, whereas the full GABA B receptor agonist baclofen (2.5-5 mg/kg p.o.) dose dependently elevated thresholds. Moreover, both GS39783 and baclofen attenuated the threshold lowering effect of cocaine administration (10 mg/kg intraperitoneally) in a dose-related manner. These data strongly suggest that activation of GABA B receptors attenuates the rewarding effects of acute cocaine. Therefore, GABA B -positive modulation may represent a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse without the side effects of full GABA B receptor agonists.

Section: Discussionmentioning

confidence: 99%

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

Froestl

et al. 2005

Neuropsychopharmacol

Self Cite

108

“…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

2008

Phil. Trans. R. Soc. B

Self Cite

236

186

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.

“…g-Amino-butyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system (Sivilotti and Nistri, 1991), and has been implicated in the modulation of central reward processes (Willick and Kokkinidis, 1995;Macey et al, 2001;Panagis and Kastellakis, 2002). Mesolimbic dopaminergic neurons originating in the ventral tegmental area receive inhibitory GABA-ergic projections from the nucleus accumbens Rahman and McBride, 2002) and the ventral pallidum (Walaas and Fonnum, 1979;Sugita et al, 1992;Klitenick et al, 1992;Kalivas et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Repeated Administration of the GABAB Receptor Agonist CGP44532 Decreased Nicotine Self-Administration, and Acute Administration Decreased Cue-Induced Reinstatement of Nicotine-Seeking in Rats

Paterson

Froestl

2004

Neuropsychopharmacol

Self Cite

Acute administration of g-aminobutyric acid B (GABA B ) receptor agonists decreased nicotine, cocaine, ethanol, and heroin selfadministration. GABA B receptor agonists also decreased cue-induced cocaine craving or seeking in humans and animals, respectively. The present study investigated the effects of repeated subcutaneous administration of the GABA B receptor agonist CGP44532 on nicotineand food-maintained responding under a fixed ratio 5 schedule of reinforcement. The second part of the study determined whether contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior, and whether acute subcutaneous CGP44532 administration affected cue-induced reinstatement of extinguished nicotine-seeking behavior. The results indicated that repeated administration of 0.25 mg/kg CGP44532 selectively decreased nicotine self-administration compared to foodmaintained responding during the first 7 days of treatment. Repeated administration of 0.5 mg/kg/day CGP44532 nonselectively decreased both nicotine-and food-maintained responding. Contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior. Further, acute CGP44532 administration (0.125 and 0.25 mg/kg) decreased cue-induced reinstatement of nicotine-seeking behavior. In summary, the present results indicated that 0.25 mg/kg/day CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding, and acute administration of CGP44532 (0.125 and 0.25 mg/kg) dose-dependently decreased cue-induced reinstatement of nicotine-seeking behavior.