RESUMEN
RATIONALE: Increasing clinical evidence suggests that menthol, a significant flavoring additive in tobacco products, may contribute to smoking and nicotine dependence. Relapse to smoking behavior presents a formidable challenge for the treatment of tobacco addiction. An unresolved issue is whether the mentholation of tobacco products precipitates relapse to tobacco use in abstinent smokers. OBJECTIVES: The present study examined the effects of menthol on the perseverance and relapse of nicotine-seeking behavior in rats. METHODS: Male Sprague-Dawley rats were trained to press a lever for intravenous nicotine self-administration (0.03 mg/kg/infusion) under a fixed-ratio five schedule of reinforcement. Each nicotine infusion was signaled by the presentation of a sensory stimulus that was established as a discrete nicotine-conditioned cue. Five minutes prior to the sessions, the rats received an intraperitoneal injection of menthol (0.1 mg/kg) or vehicle. In the subsequent extinction test sessions, nicotine was unavailable with or without menthol and/or the nicotine-conditioned cue. The reinstatement tests were performed the following day after the extinction criterion was met. Menthol was also tested on food-seeking responses. In a subset of nicotine-trained rats, a transient receptor potential melastatin 8 (TRPM8) antagonist RQ-00203078 was given prior to menthol administration. RESULTS: Continued administration of menthol sustained responses on the previously active and nicotine-reinforced lever in the extinction tests. The readministration of menthol after extinction reinstated active lever responses. In both the extinction and the reinstatement tests, a combination of pre-session menthol administration and cue representation during the session produced a more robust behavioral effect than either menthol or the cue alone. No such effects of menthol was observed in food trained rats. RQ-00203078 did not change menthol effect on nicotine seeking. CONCLUSION: These data demonstrated that menthol specifically sustained and reinstated nicotine-seeking behavior, and this effect was independent of TRPM8 activity. These findings suggest that menthol in most tobacco products, even not menthol labeled, may contribute to the perseverance of and relapse to tobacco-seeking behavior.
Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Señales (Psicología) , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Mentol/administración & dosificación , Nicotina/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Condicionamiento Psicológico/fisiología , Comportamiento de Búsqueda de Drogas/fisiología , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Autoadministración , Tabaquismo/psicologíaRESUMEN
RATIONALE: Tobacco smoking is a leading preventable cause of premature death in the USA. Menthol is a significant flavoring additive in tobacco products. Clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. However, it is unclear whether menthol enhances the reinforcing actions of nicotine and thus facilitates nicotine consumption. This study employed a rat model of nicotine self-administration to examine the effects of menthol on nicotine-taking behavior. METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to press a lever for intravenous nicotine self-administration under a fixed-ratio 5 schedule of reinforcement. In separate groups, rats self-administered nicotine at four different doses (0.0075, 0.015, 0.03, and 0.06 mg/kg/infusion). Five minutes prior to the two test sessions, menthol (5 mg/kg) or its vehicle was administered intraperitoneally in all rats in a counterbalanced design within each group. In separate rats that self-administered 0.015 mg/kg/infusion nicotine, menthol dose-response function was determined. Menthol was also tested on food self-administration. RESULTS: An inverted U-shaped nicotine dose-response curve was observed. Menthol pretreatment shifted the nicotine dose-response curve to the left. The facilitating effect of menthol on the self-administration of 0.015 mg/kg/infusion nicotine was dose-dependent, whereas it produced similar effects at doses above the threshold of 2.5 mg/kg. Menthol tended to suppress the self-administration of food pellets. CONCLUSIONS: These data demonstrate that menthol enhances the reinforcing effects of nicotine, and the effect of menthol was specific to nicotine. The findings suggest that menthol directly facilitates nicotine consumption, thereby contributing to tobacco smoking.
Asunto(s)
Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Mentol/farmacología , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Autoadministración , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Fumar Tabaco , TabaquismoRESUMEN
A 52-year-old African American male was admitted with acute kidney injury (AKI) four days after renal cryotherapy. He was started on continuous veno-venous hemodiafiltration (CVVHDF) immediately but his subsequent course was complicated by recurrent hypoglycemia, poorly responding to conventional therapy. To address the recalcitrant hypoglycemia, we changed the replacement fluid to 5% dextrose in water with 150 mEq/L of sodium bicarbonate, Y-connected with 0.9% sodium chloride at a global rate of 2000 mL/hr, with resolution of refractory hypoglycemia. A modified CVVHDF employing hyperglycemic solution can be a valuable addition in treatment of AKI complicated by severe refractory hypoglycemia.