RESUMEN
RATIONALE: Nicotine is a major active ingredient in tobacco and plays a major role in tobacco addiction. In rodents, repeated nicotine administration produces behavioral responses related to its addictive properties, such as reinforcing effects and physical dependence. OBJECTIVES: The aim of the present study was to evaluate the possible role of GABAB receptor in responses induced by repeated nicotine administration in Swiss Webster mice. RESULTS: Nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.) administration induced rewarding properties in the conditioning place preference test. The GABAB receptor agonist, baclofen (3 mg/kg, i.p.) abolished the rewarding properties induced by nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.). In addition, naloxone-precipitated nicotine withdrawal induced somatic manifestations, anxiety-like effects in the elevated plus maze test and dysphoric manifestations in the conditioned place aversion paradigm. Baclofen (2 and 3 mg/kg, i.p.) prevented the somatic manifestations and the anxiety-like effects associated with naloxone-precipitated nicotine withdrawal but not the dysphoric manifestations. CONCLUSIONS: These results showed that nicotine rewarding properties and negative aspects of nicotine withdrawal, such as anxiety-like effects and somatic manifestations, can be modulated by the GABAB receptor activity. This study now reveals a novel possible application of baclofen to develop new therapeutic strategies to achieve smoking cessation.
Asunto(s)
Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Recompensa , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Masculino , Ratones , Movimiento/efectos de los fármacos , Movimiento/fisiología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Receptores de GABA-B/metabolismo , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiología , Síndrome de Abstinencia a Sustancias/fisiopatología , Tabaquismo/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Estimulantes Ganglionares/toxicidad , Actividad Motora/efectos de los fármacos , Nicotina/toxicidad , Agonistas Nicotínicos/toxicidad , Receptores de GABA-B/metabolismo , Tabaquismo/fisiopatología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/patología , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/toxicidad , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/toxicidad , Ansiedad/inducido químicamente , Conducta Animal , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Giro Dentado/patología , Relación Dosis-Respuesta a Droga , Bloqueadores Ganglionares/administración & dosificación , Bloqueadores Ganglionares/farmacología , Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/antagonistas & inhibidores , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Nicotina/administración & dosificación , Nicotina/antagonistas & inhibidores , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/administración & dosificación , Antagonistas Nicotínicos/farmacología , Umbral del Dolor/efectos de los fármacos , Receptores de GABA-B/genética , Núcleos Septales/efectos de los fármacos , Núcleos Septales/metabolismo , Núcleos Septales/patología , Tabaquismo/metabolismoRESUMEN
BACKGROUND: Nicotine (NIC), the major active component of tobacco, is critical in the maintenance of the smoking habit. The aims of the present study were to analyze the behavioural and neurochemical variations during NIC withdrawal syndrome in mice, and whether they are prevented with baclofen (BAC, GABA(B) receptor agonist). METHODS: Swiss-Webster albino mice received NIC (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. On day 8 (the day of the experiment), NIC-treated mice received the nicotine antagonist mecamylamine (MEC, 2 mg/kg, i.p.) 1h after the last dose of NIC. A second group of dependent mice received BAC (2mg/kg, i.p.) before MEC-precipitated abstinence. The somatic signs were measured for 30 min. Dopamine (DA), serotonin (5-hydroxytryptamine; 5-HT) and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. RESULTS: The global score was greater in the abstinent group compared to the control group. Moreover, the global score time course showed a higher increase at 10 min compared to the global score at 5 min or 30 min after MEC-precipitated NIC withdrawal. In addition, the global score was attenuated by BAC. The DA and dihydroxyphenyl acetic acid (DOPAC) cortical levels decreased in the abstinent group, while BAC reestablished these levels 10 min after NIC withdrawal. Furthermore, DA and 5-HT striatal levels decreased during NIC withdrawal, and BAC reverted this decrease. CONCLUSION: In conclusion, the prevention of NIC withdrawal signs by BAC could be related to changes in dopaminergic and serotonergic activity.