Long-Term Gene Expression in the Nucleus Accumbens Following Heroin Administration is Subregion-Specific and Depends on the Nature of Drug Administration

Abstract

Repeated exposure to addictive drugs results in long-lasting neuroadaptations in the brain, especially in the mesocorticolimbic system. Within this system, the nucleus accumbens (NAc) plays a major integrative role. As such, the NAc has been shown to be a target of short- and long-lasting drug-induced neuroadaptations at the levels of neurotransmission and cellular morphology. The long-lasting neuroadaptations might depend critically on alterations in gene expression. Recently, we obtained a set of transcripts by means of subtractive hybridization, of which the expression was decreased in the rat NAc shell after long-term extinction of intravenous heroin self-administration. Interestingly, the majority of these transcripts were also down-regulated upon long-term extinction of cocaine self-administration. Using the yoked-control operant paradigm, it was shown that non-contingent administration of these drugs resulted in a totally different gene expression profile. However, in the rat NAc core, both self-administration and non-contingent heroin administration induced a qualitatively similar expression profile. Hence, cognitive processes associated with drug self-administration seem to direct the long-term genomic responses in the NAc shell, whereas the NAc core might primarily mediate the persistent pharmacological effects of addictive drugs (including Pavlovian conditioning).

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

“…These results are in line with previous studies demonstrating differential neuroadaptations in rats receiving heroin in a response-contingent vs -non-contingent manner (Kuntz et al, 2008;Jacobs et al, 2004;Jacobs et al, 2005), and these data may have particular importance for addiction and pain management fields, respectively. Interestingly, we also found that increases in NAc TacR1 mRNA following repeated (moderate dose) heroin was reduced following non-contingent, escalated-dose heroin exposure, possibly reflecting tolerance-associated changes in the NK1 receptor system.…”

NMDA Receptors Regulate Nicotine-Enhanced Brain Reward Function and Intravenous Nicotine Self-Administration: Role of the Ventral Tegmental Area and Central Nucleus of the Amygdala

“…Indeed, neurobiological correlates of reward (eg neurotransmitter release in the basal ganglia) are increased after response-contingent drug infusions by a far greater magnitude than by response non-contingent drug infusions (Wilson et al, 1994;Mark et al, 1999;Kimmel et al, 2005;Lecca et al, 2007). In addition, different gene expression, neurochemical, stress system, and behavioral adaptations occur in response to volitional vs nonvolitional drug consumption (Stefanski et al, 1999;Jacobs et al, 2005). Therefore, in addition to effects on experimenter-administered nicotine injections, we also assessed the effects of LY235959 on the threshold lowering induced by intravenously self-administered nicotine infusions.…”

The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

“…Substantial evidence demonstrates that volitional (actively intended) drug intake produces distinct physiological, biochemical, and behavioral effects when compared with forced drug administration. For example, the response contingency of drug exposure robustly influences gene expression (Jacobs et al, 2002(Jacobs et al, , 2003(Jacobs et al, , 2005, neural activation (Chang et al, 1994;Peoples and West, 1996;Stuber et al, 2005), and resultant extracellular neurochemistry (Di Ciano et al, 1996;Hemby et al, 1997;Jacobs et al, 2003;Lecca et al, 2007;Orejarena et al, 2009;You et al, 2007). With specific regard to nicotine, differential effects of volitional SA vs forced drug administration have been observed on a 4 b 2 nAChR expression (Metaxas et al, 2010), cortical glutamatergic projection activity and plasticity mechanisms in the ventral tegmental area (VTA) (McFarland et al, 2003;You et al, 2007), and plasma corticosterone levels (Donny et al, 2000).…”