Effects of chronic environmental and social stimuli during adolescence on mesolimbic dopaminergic circuitry markers

Abstract

Previously, we have shown that chronic exposure to environmental and social stimuli (ESS) during adolescence prevents the development of behavioral sensitization to amphetamine in adult rats. At the onset of the peripubertal-juvenile period (28-d) male rats were subjected to a 28-d long intermittent ESS protocol or handled as controls (NO-ESS). Twenty-four hours after the last session of ESS or NO-ESS, all rats started a regimen of behavioral sensitization to amphetamine (1mg/kg, i.p.), in which rats were injected every third day with amphetamine or saline on four occasions. Then following one week abstinence all rats were challenged with a lower dose of amphetamine (0.5mg/kg, i.p.) and their locomotor activity monitored for 2h. Our results showed that while NO-ESS rats developed behavioral sensitization to amphetamine, ESS rats did not develop this behavior. All rats were then sacrificed 3 days following the challenge to allow for amphetamine clearance. Since mesolimbic dopamine has been implicated in behavioral sensitization to amphetamine we compared messenger RNA (mRNA) expression of key dopamine-related molecules in the mesolimbic circuitry in ESS and NO-ESS rats. A decrease in dopaminergic D1 receptor (D1R) gene expression in the caudate-putamen (CPu) was associated with amphetamine sensitization in the controls, possibly as a result of a chronic increase in DA release. In contrast, amphetamine treatment did not modulate D1R mRNA levels in ESS rats. No change has been detected in any other dopaminergic markers [D2R, D3R, tyrosine hydroxylase (TH) or dopamine transporter (DAT) mRNAs]. Consequently, we conclude that ESS may inhibit the development of behavioral sensitization to amphetamine through preventing the decrease in CPu D1R mRNA levels.

Figure1

(A) modified figure from Kabbaj et al, 2002 showing that only control rats exhibit behavioral sensitization to amphetamine. ESS rats do not exhibit behavioral sensitization to the same drug. *=p<0.05 when compared to their respective saline pre-trained controls. (B) Control rats that exhibit behavioral sensitization to amphetamine show a decrease in D1 mRNA expression; ESS rats that do not exhibit sensitization to amphetamine do not show the decrease in D1 mRNA expression. *=p<0.05 when compared to their respective saline pre-trained controls.

Figure 2

Location of templates used to sample optical density measurements within specific brain regions in each animal. The CPu and Acb sections were sampled from bregma +1.2mm rostrally to bregma +1.0 mm caudally according to Paxinos and Watson rat brain Atlas. The VTA and SN sections were sampled from bregma −5.2 rostrally to bregma −6.04 caudally according to the same Atlas.

Figure 3

Color-enhanced pictures constructed from section images of x-ray films showing in situ hybridization with antisense cRNA probes against D1, D2, D3, DAT and TH mRNAs.