Investigation of the neuroanatomical substrates of reward seeking following protracted abstinence in mice

Abstract

Key points• Persistent vulnerability to relapse represents a major challenge in the treatment of drug addiction. The brain circuitry that underlies relapse-like behaviour can be investigated using animal models.• This study compared the brains of mice that had relapsed to morphine with mice that had relapsed to sucrose following abstinence. We found that while some brain regions were implicated in both drug and food seeking, other specific parts of the brain were activated for either sucrose or morphine relapse.• Common regions included those with established involvement in reward and relapse-like behaviour. In addition we found some regions not previously linked to these behaviours.• Overall, while our findings support existing literature regarding relapse-like behaviour in rats, we have additionally identified brain regions outside this established circuitry which are worthy of further investigation.Abstract Persistent vulnerability to relapse represents a major challenge in the treatment of drug addiction. The brain circuitry that underlies relapse-like behaviour can be investigated using animal models of drug seeking. As yet there have been no comprehensive brain mapping studies that have specifically examined the neuroanatomical substrates of cue-induced opiate seeking following abstinence in a mouse operant paradigm. The aim of this study was to compare the brain regions involved in sucrose vs. morphine seeking following protracted abstinence in mice. Male CD1 mice were trained to respond for either sucrose (10% w/v) or intravenous morphine (0.1 mg kg −1 per infusion) in an operant paradigm in the presence of a discrete cue. Once stable responding was established, mice were subjected to abstinence in their home cages for 3 weeks and then perfused for tissue collection, or returned to the operant chambers to assess cue-induced reward seeking before being perfused for tissue collection. Brain tissue was processed for Fos immunohistochemistry and Fos expression was quantified in a range of brain nuclei. We identified unique patterns of neuronal activation for sucrose and morphine seeking mice as well as some overlap. Structures activated in both 'relapse' groups included the anterior cingulate and orbitofrontal cortex, nucleus accumbens shell, bed nucleus of the stria terminalis, substantia nigra pars compacta, ventral tegmental area, hippocampus, periaqueductal grey, locus coeruleus and lateral habenula. Structures that were more activated in morphine seeking mice included the nucleus accumbens core, basolateral amygdala, substantia nigra pars reticulata, and the central nucleus of the amygdala. The dorsal raphe was the only structure examined that was specifically activated in sucrose seeking mice. Overall our findings support a cortico-striatal limbic circuit driving opiate seeking, and we have identified some additional circuitry potentially relevant to reward seeking following abstinence. Abbreviations AC, anterior cingulate cortex; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; Ce...

Individual Variation in the Motivational and Neurobiological Effects of an Opioid Cue

“…This finding is consistent with a series of studies showing that, whereas lesions of the BLA attenuate ST behavior, lesions of the CeA do not affect acquisition or expression of sign-tracking behavior (Chang et al, 2012a,b). In addition, presentation of the food and remifentanil cue elicited robust Fos expression in the lateral habenula of STs, but not the medial habenula, which is consistent with the ability of an opioid cue to reinstate drug-seeking behavior and increase Fos expression in the lateral habenula (Madsen et al, 2012). Interestingly, Danna et al (2013) recently reported that modulation of lateral habenula outputs strongly influences sign-tracking, but not goal-tracking behavior, perhaps because of its influence on dopamine neurotransmission.…”

Amygdalostriatal projections in the neurocircuitry for motivation: a neuroanatomical thread through the career of Ann Kelley

“…Similarly, intra-BLA administration of the mGluR5 antagonist MTEP reduced cue-induced reinstatement of ethanol-seeking behavior (Sinclair et al, 2012), and intra-BLA blockade of opioid receptors reduced context-induced reinstatement of ethanol seeking (Marinelli et al, 2010). Consistent with these findings, cue-induced reinstatement of drug and ethanol seeking are associated with increased neuronal activation and glutamatergic synaptic transmission in the BLA (Gass et al, 2011; Jupp et al, 2011; Madsen et al, 2012). …”

Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice

“…With the exception of IVSA 21 NR mice, self-administering mice were subject to a 1 h cocaine-seeking (relapse) test in the absence of cocaine after either 1 (IVSA 1) or 21 days (IVSA 21) of forced abstinence (Brown et al , 2009, Madsen et al , 2012). All cocaine-paired cues were present and cocaine-seeking behavior was measured as the sum of all responses on the previously cocaine-paired lever.…”