Cl. Nelson et al., Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release, PSYCHOPHAR, 151(4), 2000, pp. 406-415
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.