Involvement of GABAB receptors in biochemical alterations induced by anxiety-related responses to nicotine in mice: genetic and pharmacological approaches.
Previous studies from our laboratory showed that anxiety-related responses induced by nicotine (NIC), measured by the elevated plus maze, were abolished by 2-OH-saclofen (GABAB receptor antagonist) (1 mg/kg; ip) or the lack of GABAB receptors (GABAB1 knockout mice). Based on these behavioral data, the aims of the present study were: 1) to evaluate the possible neurochemical changes (dopamine, DA, serotonin, 5-HT, 3,4-dihydroxyphenylacetic acid, DOPAC, 5-hydroxyindoleacetic acid, 5-HIAA and noradrenaline, NA) and the c-Fos expression induced by the anxiolytic (0.05 mg/kg) or anxiogenic (0.8 mg/kg) doses of NIC in the dorsal raphe (DRN) and lateral septal (LSN) nucleus; 2) to study the possible involvement of GABAB receptors on the neurochemical alterations and c-Fos expression induced by NIC (0.05 and 0.8 mg/kg), using both pharmacological (2-OH-saclofen) and genetic (mice GABAB1 knockout) approaches. The results revealed that in wild-type mice, NIC (0.05 mg/kg) increased the concentration of 5-HT and 5-HIAA (p < 0.05) in the DRN, and NIC (0.8 mg/kg) increased the levels of 5-HT (p < 0.01) and NA (p < 0.05) in the LSN. Additionally, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors abolished these neurochemical changes induced by NIC (p < 0.01, p < 0.05, respectively). On the other hand, NIC 0.05 and 0.8 mg/kg increased (p < 0.01) the c-Fos expression in the DRN and LSN respectively, in wild-type mice. In addition, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors prevented the c-Fos alterations induced by NIC (p < 0.01). In summary, both approaches show that GABAB receptors would participate in the modulation of anxiolytic- and anxiogenic-like responses induced by NIC, suggesting the potential therapeutic target of these receptors for the tobacco addiction treatment.
Instituto de Investigaciones Farmacológicas (CONICET), Junín 956, 5° Piso, Buenos Aires C1113AAD, Argentina.
Andrés P
AP
Varani
Instituto de Investigaciones Farmacológicas (CONICET), Junín 956, 5° Piso, Buenos Aires C1113AAD, Argentina.
Valeria T
VT
Pedrón
Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
Bernhard
B
Bettler
Instituto de Investigaciones Farmacológicas (CONICET), Junín 956, 5° Piso, Buenos Aires C1113AAD, Argentina; Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 5° Piso, Buenos Aires C1113AAD, Argentina. Electronic address: gbalerio@ffyb.uba.ar.
Graciela N
GN
Balerio
D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D001418:Baclofen / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D058788:GABA-B Receptor Antagonists / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009538:Nicotine / Q000633:toxicity; D018722:Nicotinic Agonists / Q000633:toxicity; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics* / Q000378:metabolism*; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism
D058788:GABA-B Receptor Antagonists; D018377:Neurotransmitter Agents; D018722:Nicotinic Agonists; D016760:Proto-Oncogene Proteins c-fos; D018080:Receptors, GABA-B; D009538:Nicotine; D001418:Baclofen; C057491:2-hydroxysaclofen
2-OH-saclofen; Anxiety; Catecholamine; GABA(B) receptor; Nicotine; c-Fos