Alpha-Noradrenergic Receptors Modulate the Development and Expression of Cocaine Sensitization

ABSTRACT

Abstract:  The increased activity and stereotyped behaviors that result from repeated administration of cocaine is called cocaine sensitization. This sensitized response has been postulated as one of the basic pathophysiological mechanisms in drug addiction. Recent evidence indicates that noradrenergic neurotransmission might be implicated in some of the behavioral effects of cocaine. The present article examined the role of alpha-adrenergic receptor agonists and antagonists in the development and expression of cocaine sensitization. Rats were injected once per day, for 7 consecutive days, with the alpha-1 receptor antagonist prazosin (0.5 mg/kg, i.p.) 15 min before cocaine administration (15 mg/kg, i.p.). After 8 days, animals received a cocaine challenge (15 mg/kg, i.p.) and were tested for locomotion. Following a 7-day withdrawal period rats received a second cocaine challenge. One day after the last challenge, rats were reinstated to the initial protocol for 1 day. In another set of experiments, rats were injected twice per day with the alpha-2 receptor antagonists yohimbine (5 mg/kg, i.p.), idazoxan (0.25 mg/kg, i.p.), or with the alpha-2 agonist clonidine (0.025 mg/kg, i.p.), followed by cocaine injections (15 mg/kg, i.p.), for 7 consecutive days. Thereafter, the protocol was similar to that following prazosin administration. The results demonstrated that the alpha-1 receptor antagonist prazosin blocked the development and expression of cocaine sensitization. On the other hand, both alpha-2 antagonists failed to inhibit the development or the expression of cocaine sensitization. Instead, they produced an increase in locomotor activity during the first day of experimentation. The alpha-2 agonist clonidine attenuated the acute response to cocaine on day 1 and retarded the increased locomotor activity on the following 2 days. There was a dramatic increase in the level of sensitization after the first cocaine challenge. However, it inhibited the expression of cocaine sensitization during the reinstatement protocol. These results suggest that alpha adrenoreceptors play an important role in modulating different stages of cocaine sensitization and probably cocaine addiction.