RESUMO
Nicotine is the main active component of tobacco, and has both acute and chronic pharmacological effects that can contribute to its abuse potential in humans. The aim of the present study was to evaluate a possible role of GABA(B) receptors in acute and chronic responses to nicotine administration, by comparing GABA(B1) knockout mice and their wild-type littermates. In wild-type mice, acute nicotine administration (0.5, 1, 3 and 6 mg/kg, sc) dose-dependently decreased locomotor activity, and induced antinociceptive responses in the tail-immersion and hot-plate tests. In GABA(B1) knockout mice, the hypolocomotive effect was observed only with the highest dose of nicotine, and the antinociceptive responses in both tests were significantly reduced in GABA(B1) knockout mice compared to their wild-type littermate. Additionally, nicotine elicited anxiolytic- (0.05 mg/kg) and anxiogenic-like (0.8 mg/kg) responses in the elevated plus-maze test in wild-type mice, while selectively the anxiolytic-like effect was abolished in GABA(B1) knockout mice. We further investigated nicotine withdrawal in mice chronically treated with nicotine (25 mg/kg/day, sc). Mecamylamine (1 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type mice. However, signs of nicotine withdrawal were missing in GABA(B1) knockout mice. Finally, there was a decreased immunoreactivity of Fos-positive nuclei in the bed nucleus of the stria terminalis, basolateral amygdaloid nucleus and hippocampal dentate gyrus in abstinent wild-type but not in GABA(B1) knockout mice. These results reveal an interaction between the GABA(B) system and the neurochemical systems through which nicotine exerts its acute and long-term effects.
Assuntos
Estimulantes Ganglionares/toxicidade , Atividade Motora/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Receptores de GABA-B/metabolismo , Tabagismo/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/toxicidade , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/toxicidade , Ansiedade/induzido quimicamente , Comportamento Animal , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Relação Dose-Resposta a Droga , Bloqueadores Ganglionares/administração & dosagem , Bloqueadores Ganglionares/farmacologia , Estimulantes Ganglionares/administração & dosagem , Estimulantes Ganglionares/antagonistas & inibidores , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Nicotina/administração & dosagem , Nicotina/antagonistas & inibidores , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Limiar da Dor/efeitos dos fármacos , Receptores de GABA-B/genética , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Núcleos Septais/patologia , Tabagismo/metabolismoRESUMO
1. The present study reevaluates the effect of atropine on the rate of recovery from tetanic fade caused by intraarterial administration of neostigmine or antinicotinic agents in cat anterior tibial muscle preparations submitted to a train-of-four (TOF) pattern of nerve stimulation. The study also compares the sensitivity of the TOF and tetanic responses as indices of residual nondepolarizing block. 2. Neostigmine, hexamethonium and d-tubocurarine all produced short-lived TOF fade. Both single and TOF twitches were increased by neostigmine and depressed by the antinicotinic agents. 3. Prior administration of atropine reduced the TOF fade induced by the antinicotinic drugs but potentiated that caused by anticholinesterase drugs. 4. These results indicate that TOF fade is not the most sensitive index for studying neuromuscular blockade when drugs other than neuromuscular blockers are also present.