RESUMEN
Zoletil® is an equal amount combination of the NMDA receptor antagonist, tiletamine, and the benzodiazepine, zolazepam, usually used as a veterinary anesthetic. Previous studies have shown that pre-exposure to Zoletil® and other psychoactive drugs (e.g. ketamine, diazepam) plays a significant role in the abuse liability of the compound. However, these studies were only focused on illicit psychoactive drugs and not on the more widely used licit psychoactive substances. Thus, the goal of the present work is to investigate whether pre-exposure to the three most commonly used licit psychoactive substances (caffeine, nicotine, and ethanol) affects the rewarding and reinforcing effects of Zoletil®. Rats were pretreated with caffeine (1.25 or 2.5 mg/kg), nicotine (125 or 250 µg/kg), ethanol (0.5, 2, or 4 g/kg), or saline (1 ml/kg) for 14 days, and evaluated for subsequent Zoletil® place preference (2.5 mg/kg) and self-administration (250 µg/kg). Zoletil® produced neither place preference nor self-administration in saline-pretreated rats. Pre-exposure to caffeine or nicotine does not have significant effects on Zoletil®'s abuse potential. However, pretreatment of ethanol significantly produced Zoletil® place preference and self-administration. These results suggest that individuals who are exposed to ethanol may have a high propensity to use/abuse Zoletil®. More importantly, the present result advocates the careful monitoring on the use and dispensation of Zoletil® or related substances.
Asunto(s)
Anestésicos/farmacología , Condicionamiento Operante , Etanol/farmacología , Tiletamina/farmacología , Zolazepam/farmacología , Anestésicos/administración & dosificación , Animales , Benzodiazepinas/farmacología , Cafeína/farmacología , Combinación de Medicamentos , Antagonistas de Aminoácidos Excitadores/farmacología , Locomoción/efectos de los fármacos , Nicotina/farmacología , Ratas , Ratas Sprague-Dawley , Autoadministración , Tiletamina/administración & dosificación , Zolazepam/administración & dosificaciónRESUMEN
Several questions remain unanswered concerning the effects of long-term methylphenidate treatment in individuals with attention-deficit/hyperactivity disorder (ADHD). It has been speculated that repeated methylphenidate treatment may facilitate abuse of the drug or psychological dependence. In the present study, we conducted conditioned place preference (CPP) tests to investigate whether the repeated treatment of methylphenidate results to greater "liking" of the drug. We compared the effect of methylphenidate with that of methamphetamine, a drug with high abuse and dependence liability; also used as a treatment of ADHD. Prior to CPP tests, adolescent spontaneously hypertensive rats (SHR) (putative rodent model of ADHD) and Wistar rats (strain used to represent the "normal" heterogeneous population) were administered intraperitoneally with methylphenidate (1.25, 5 and 20 mg/kg) or methamphetamine (1.25 and 5 mg/kg) for 14 days in their home cages. CPP tests were commenced and rats were conditioned with the two stimulants at the doses stated. We found that (1) repeated administration of methylphenidate and methamphetamine was rewarding in Wistar rats (2) stimulant-treated SHR showed CPP only to methamphetamine but not to methylphenidate. The observation that Wistar rats, but not SHR showed CPP to methylphenidate indicates vulnerability of "normal" individuals to methylphenidate abuse and dependence following repeated exposure or administration of the drug. The findings in SHR suggest the safety of methylphenidate as an ADHD intervention insofar as its behavioral effects are compared with those of methamphetamine, and to the extent that the SHR appropriately models ADHD in humans.
Asunto(s)
Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Metanfetamina/farmacología , Metilfenidato/farmacología , Animales , Trastorno por Déficit de Atención con Hiperactividad/psicología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Modelos Animales de Enfermedad , Masculino , Metanfetamina/administración & dosificación , Metilfenidato/administración & dosificación , Ratas , Ratas Endogámicas SHR , Ratas Wistar , RecompensaRESUMEN
RATIONALE: Methylphenidate is a psychostimulant given for extended periods of time as a treatment of attention-deficit/hyperactivity disorder (ADHD). The long-term effects of the drug are not yet known, and it is speculated that repeated exposure may produce drug dependence. OBJECTIVE: To investigate the effects of repeated methylphenidate treatment on methylphenidate self-administration and reinstatement in the most validated animal model of ADHD, the spontaneously hypertensive rat (SHR), and Wistar rat, strain representing the "normal" heterogeneous population. METHODS: Rats were administered intraperitoneally with saline or methylphenidate (2 mg/kg) for 14 days, prior to experiments. Thereafter, responses for intravenous methylphenidate under the fixed ratio (FR1 and FR3) and progressive ratio (PR) schedules were assessed. Extinction experiments followed, as well as tests to determine the ability of intraperitoneal administration of methylphenidate (2 and 5 mg/kg) to reinstate extinguished drug-seeking behaviors in rats. RESULTS: Previous exposure to methylphenidate enhanced methylphenidate self-administration in Wistar rats but not in SHR (FR3). Methylphenidate pretreatment reduced responding for methylphenidate in SHR but did not affect self-administration behaviors of Wistar rats (PR). Methylphenidate pre-exposure robustly reinstated drug-seeking behaviors in Wistar rats, but not in SHR. CONCLUSION: The contrasting effects of repeated methylphenidate treatment in methylphenidate self-administration and reinstatement in Wistar and SHR, and the increased susceptibility of the Wistar rat strain to the reinforcing effects of methylphenidate indicate that "normal" individuals are more likely to develop psychological dependence to the drug and experience relapse. Meanwhile, the clinical use of methylphenidate may not produce drug dependence or relapse in ADHD patients.