Exposure to amphetamine in rats during periadolescence establishes behavioural and extrastriatal neural sensitization in adulthood

Abstract

Drug abuse during adolescence may predispose towards later adult substance abuse and major depressive disorders (Brook et al., 2002). The purpose of the present study was to characterize whether behavioural sensitization to amphetamine occurred in adult rats following adolescent exposure to amphetamine [low (2 mg/kg.d) or high (10 mg/kg.d) i.p. for 10 d] and the pattern of neural activation associated with sensitized behaviour, in male Sprague-Dawley rats. Following initial treatment (post-natal days 33-41) and a subsequent 4-wk period of abstinence, rats initially treated with either amphetamine regime showed a similar sensitized locomotor activity upon re-challenge with amphetamine (1.5 mg/kg i.p.) compared to rats acutely challenged with this dose of amphetamine. Fos-IR expression in the "high" sensitized group was significantly greater than acutely challenged rats in all quadrants of the CPu. Both "low" and "high" sensitized groups demonstrated heightened Fos expression relative to acutely challenged rats in the medial and central amygdala, as well as rostroventrolateral medulla, whereas Fos-IR in the locus coeruleus and substantia nigra pars reticulata was significantly increased only in the "high" sensitized group compared to acute. Double-labelling for tyrosine hydroxylase confirmed an absence of Fos-IR in A9 and A10 regions. The present study has shown a robust and persistent sensitization in adulthood to amphetamine re-challenge following initial adolescent exposure in rats. This manifestation of sensitization apparently results in widespread neural activation in limbic and autonomic structures.

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

“…Sensitization to the locomotor responses induced by chronic morphine treatment was performed as previously described (McPherson and Lawrence, 2006). Briefly, locomotor activity responses induced by morphine (10 mg/kg, i.p.)…”

Quantification of Phosphorylated cAMP-Response Element-Binding Protein Expression throughout the Brain of Amphetamine-Sensitized Rats: Activation of Hypothalamic Orexin A-Containing Neurons

“…The model of amphetamine sensitization has been described previously (McPherson and Lawrence, 2006). Briefly, rats were randomized into three equal groups (n ϭ 16 per group) and allowed to acclimatize to the holding room for 5 days.…”

“…The rats were immediately decapitated, and brains were quickly removed and postfixed overnight in fixative containing 10% sucrose. Brains were subsequently sectioned on a freezing microtome at 50 m in the coronal plane and floated in 48-well tissue culture microplates containing cryoprotectant solution, and stored at Ϫ20°C until use (McPherson and Lawrence, 2006). Every fourth section (200-m interval) was slide-mounted with 0.5% gelatin, counterstained with neutral red (0.5%), and then differentiated, cleared, and coverslipped with Gurr DePex mounting medium (BDH, Poole, Dorset, UK).…”

“…Immunohistochemical procedures were performed essentially as described previously (McDougall et al, 2004;McPherson and Lawrence, 2006). Brain sections from each treatment group were processed simultaneously for each discrete brain region (n ϭ 4 sections per brain region of interest per rat from n ϭ 6 rats per treatment group).…”

“…Regions quantified included the caudate putamen, nucleus accumbens, amygdaloid complex, substantia nigra pars compacta, ventral tegmental area, lateral septum, habenula, and the BNST. pCREB-IR quantification was conducted with a stereology L-RGB video capture device analysis system as described previously (McPherson and Lawrence, 2006). Quantification of c-Fos and orexin A immunoreactivity was conducted using a 20ϫ objective using the same stereological apparatus.…”