title: GABA(B) receptor-positive modulation decreases selective molecular and behavioral effects of cocaine.
abstract: 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 drug-induced 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'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-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 deltaFosB 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 deltaFosB 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.
authors.affiliation: Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Loic
authors.initials: L
authors.lastname: Lhuillier
authors.forename: Cedric
authors.initials: C
authors.lastname: Mombereau
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects / Q000037:antagonists & inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D003517:Cyclopentanes; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018755:GABA Agonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; C497929:Ppp1r1b protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; D018080:Receptors, GABA-B; D001418:Baclofen; D003042:Cocaine; D004298:Dopamine