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Repeated treatment with psychostimulant drugs causes long-lasting behavioral sensitization and associated neuroadaptations. Although sensitization induced by a single psychostimulant exposure has also been reported, information on the behavioral and neurochemical consequences of a single psychostimulant exposure is sparse. Therefore, to evaluate whether behavioral sensitization evoked by single and repeated psychostimulant pretreatment regimens represent the same neurobiological phenomenon, the time-dependent expression of behavioral, neurochemical, and neuroendocrine sensitization after a single exposure to amphetamine was investigated in rats. A single exposure to amphetamine (5 mg/kg, i.p.) caused context-independent sensitization of the locomotor effects of amphetamine, which intensified over time. Thus, sensitization to amphetamine was marginal at 3 d after treatment and more evident after 1 week, whereas 3 weeks after treatment, profound sensitization, as well as cross-sensitization, to cocaine was observed. Amphetamine pretreatment caused an increase in the electrically evoked release of [(3)H]dopamine from nucleus accumbens, caudate putamen, and medial prefrontal cortex slices and of [(14)C]acetylcholine from accumbens and caudate slices. The hyperreactivity of dopaminergic nerve terminals appeared to parallel the development of locomotor sensitization, i.e., whereas hyperreactivity of accumbens dopaminergic terminals increased between 3 d and 3 weeks after treatment, the hyperreactivity of medial prefrontal dopaminergic terminals decreased. Pre-exposure to amphetamine also sensitized the hypothalamus-pituitary-adrenal axis response to amphetamine at 1 and 3 weeks, but not at 3 d after treatment. Because these data closely resemble those reported previously for repeated amphetamine pretreatment, it is concluded that a single exposure to amphetamine is sufficient to induce long-term behavioral, neurochemical, and neuroendocrine sensitization in rats.

Animal studies have shown that nicotine and psychostimulant drugs (amphetamine and cocaine) share the property of inducing long-lasting behavioral and neurochemical sensitization, which is thought to contribute to their addictive properties. Neuroplasticity subserving learning and memory mechanisms is considered to be involved in psychostimulant-induced sensitization and addiction behavior. Because nicotinic receptors in the brain play a role in the storage of drug-related information underlying reinforcement learning, we evaluated the possibility that activation of central nicotinic receptors may underlie psychostimulant-induced sensitization. Repeated exposure of rats to nicotine profoundly enhanced the psychomotor effects of nicotine and amphetamine 3 weeks after nicotine pretreatment. Moreover, the nicotinic receptor antagonist mecamylamine completely blocked the induction, but not the long-term expression, of behavioral sensitization to amphetamine in amphetamine-pretreated rats. Mecamylamine also prevented the development of cocaine-induced behavioral sensitization. Behavioral sensitization induced by nicotine, amphetamine, or cocaine was associated with an increase in the electrically evoked release of [(3)H]dopamine from nucleus accumbens slices. Coadministration of mecamylamine during pretreatment with nicotine, amphetamine, or cocaine prevented the development of this long-term hyperreactivity of nucleus accumbens dopamine neurons. Similarly, the high-affinity non-alpha7 subtype nicotinic receptor antagonist dihydro-beta-erythroidine prevented the development of amphetamine-induced behavioral and neurochemical sensitization. These data indicate that nicotinic receptor activation (by endogenously released acetylcholine) is a common denominator initiating neuroplasticity involved in the development of amphetamine, as well as cocaine-induced sensitization.

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RationaleTreatment of the most widely abused drugs, nicotine and alcohol, is hampered by high rates of relapse. Varenicline tartrate, an α4β2 nicotinic receptor partial agonist, is currently prescribed as a smoking cessation aid. However, there is emerging evidence that it may also modulate alcohol seeking and cognitive functioning in rats.ObjectivesAs preclinical data on alcohol taking and relapse are limited, we used a self-administration–reinstatement model to evaluate the effects of varenicline on operant responding for alcohol (12%, v/v), intravenous nicotine (40 μg/kg/inf.), sucrose (10%, w/v) and on cue-induced relapse to alcohol and nicotine seeking in rats. At the cognitive level, we assed varenicline's effects on 5-choice serial reaction time task (5-CSRTT) performance with a focus on correct responses (attention) and premature responding (impulsivity), modalities that have previously been associated with addictive behaviour.ResultsVarenicline, at doses of 1.5 and 2.5 mg/kg, reduced alcohol and nicotine self-administration and enhanced operant responding for sucrose. At these doses, varenicline reduced cue-induced relapse to alcohol, but not nicotine seeking. In contrast, at 0.5 mg/kg, varenicline facilitated cue-induced nicotine seeking. Similar to nicotine, varenicline increased premature responding at low doses, but had no effect on any of the other behavioural parameters in the 5-CSRTT.ConclusionsOur data indicate that varenicline specifically reduced responding for nicotine and alcohol, but not for natural reinforcers such as sucrose. Interestingly, varenicline strongly attenuated cue-induced relapse to alcohol seeking, but not nicotine seeking. Varenicline may therefore be a promising aid in the treatment of alcohol addiction.