Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release

Rationale: Previous studies on the attentional effects of repeated psychost imulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulat e cortical acetylcholine (ACh) release. Furthermore, neurochemical data hav e raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebra in corticopetal cholinergic projections, thereby supporting speculations ab out relationships between the effects of repeated psychostimulant administr ation on NAC DA and cortical ACh release. Objectives. To determine whether repeated exposure to amphetamine would potentiate the stimulating effects o f the drug on cortical ACh and NAC DA efflux. Methods: Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the sh ell region of the ipsilateral NAG. Amphetamine (2.0 mg/kg i.p.) or saline ( 0.9%) was administered every other day for 10 days, for a total of five inj ections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. Air animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) gi ven 10 and 19 days after the last pretreatment injection. Results. The init ial injections of amphetamine stimulated ACh and DA efflux and locomotor be havior in both groups. The pretreatment with amphetamine potentiated the ab ility of the drug to stimulate cortical ACh efflux on day 19 of the withdra wal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphet amine did not result in a significant augmentation of the amphetamine-induc ed increase in DA efflux in the NAG. Conclusions. Pretreatment with ampheta mine sensitizes the ability of amphetamine to stimulate cortical ACh efflux . These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphet amine pretreated rats. Sensitized cortical ACh release following repeated e xposure to psychostimulants may mediate the overprocessing of addictive dru g-related stimuli, thus contributing to repeated compulsive addictive drug use.