Enhanced Morphine Preference Following Prolonged Abstinence: Association with Increased Fos Expression in the Extended Amygdala

Abstract

We previously found that chronically morphine-pretreated, abstinent rats show stronger preferences for morphine-associated environments than placebo-pretreated rats. Here we show that this increased preference persisted for at least 5 weeks after withdrawal of chronic morphine. To determine brain regions involved in this behavior, we examined neural activation (as indexed by Fos-like proteins) induced by a morphine-conditioned place preference test. Placebo-pretreated (P) morphine-conditioned rats showed significantly elevated Fos in the anterior cingulate cortex (Cg), nucleus accumbens core (Ac-C) and shell (Ac-S), ventral lateral and dorsal lateral bed nucleus of the stria terminialis (BNST-VL and -DL), and central and basolateral amygdala nuclei (ACE, ABL) when compared to nonconditioned P rats. Chronically morphine-pretreated (M) rats that exhibited enhanced morphine preference 5 weeks after morphine withdrawal showed significantly greater Fos in all the same areas except the BNST-DL relative to conditioned P or nonconditioned M rats. Place preference measures and Fos expression were positively correlated in the Cg and ABL, for conditioned P animals, and in the Cg, ABL and BNST-VL for conditioned M animals. These results indicate a relationship between place preference behavior and neural indices of activation in the forebrain in response to morphine-conditioned cues that may be chronically modulated by prior morphine exposure.

Activation in extended amygdala corresponds to altered hedonic processing during protracted morphine withdrawal

“…The finding that Fos expression in Cg and BLA showed significant positive correlations with preference scores in both abstinent and placebo-pretreated conditioned groups is consistent with what we previously reported for morphine place preference conditioning [23]. Thus, our current and previous results indicate that the Cg and BLA are associated with the expression of the positive reinforcing aspects of both food and drugs.…”

“…Previously we found that elevated Fos levels in the VL-BNST of morphine withdrawn animals were positively correlated with enhanced morphine preference [27], whereas in the present study elevated Fos levels in the VL-BNST were negatively correlated with food preference. Thus, the BNST may be a site where aversive responses to environmental stressors help to drive drug seeking behavior that can alleviate stress while decreasing the desire for natural rewards that are not effective in alleviating stress.…”

“…This enhanced preference correlated specifically in morphine-withdrawn animals with elevated Fos expression in the ventral lateral BNST (VL-BNST) [23]. We also reported that at this same withdrawal time-point, when morphine-abstinent animals show enhanced preferences for morphine-associated cues, they also exhibit significantly decreased preferences for food-associated cues [24].…”

“…This paradigm is thought to reflect a conditioned approach response to cues previously associated with reward. The brain areas examined included the anterior cingulate cortex (Cg) and BLA (regions that we previously identified as being correlated with the expression of conditioned place preference) [23], the dorsomedial hypothalamus (DMH) (an area involved in both homeostatic regulation and feeding behavior) [10,13], and the VL-BNST, CE and NTS (areas known to be associated with morphine withdrawal aversion) [12,55].…”

Alcohol Relapse Induced by Discrete Cues Activates Components of AP-1 Transcription Factor and ERK Pathway in the Rat Basolateral and Central Amygdala

“…The latter finding suggests that c-Fos expression was activated by the presentation of alcohol-paired stimuli and not by the performance of operant behavior. Our observation of increased c-Fos expression in the BLA after reexposure to the alcoholpaired discrete cues is in agreement with earlier studies which showed that reexposure to cocaine-, amphetamine-, morphine-, or beer-associated context and discrete cues activated c-Fos in this brain region (Topple et al, 1998;Baker et al, 1999;Mead et al, 1999;Neisewander et al, 2000;Ciccocioppo et al, 2001;Harris and Aston-Jones, 2003). Moreover, the BLA has been shown to be involved in context-and cue-induced relapse to drug-seeking, and to control the ability of environmental stimuli to form Pavlovian associations with reinforcing stimuli (Whitelaw et al, 1996;Meil and See, 1997;Kruzich and See, 2001;Shalev et al, 2003).…”