A Specific Limbic Circuit Underlies Opiate Withdrawal Memories

Abstract

Compulsive drug-seeking behavior and its renewal in former drug addicts is promoted by several situations, among which reactivation of drug withdrawal memories plays a crucial role. A neural hypothesis is that such memories reactivate the circuits involved in withdrawal itself and promote a motivational state leading to drug seeking or taking. To test this hypothesis, we have analyzed the neural circuits and cell populations recruited when opiate-dependent rats are reexposed to stimuli previously paired with withdrawal (memory retrieval) and compared them with those underlying acute withdrawal during conditioning (memory formation). Using in situ hybridization for c-fos expression, we report here that reexposure to a withdrawal-paired environment induced conditioned c-fos responses in a specific limbic circuit, which can be partially dissociated from the structures involved in acute withdrawal. At the amygdala level, c-fos responses were doubly dissociated between the central and basolateral (BLA) nuclei, when comparing the two situations. Detailed phenotypical analyses in the amygdala and ventral tegmental area (VTA) show that specific subpopulations in the BLA are differentially involved in the formation and retrieval of withdrawal memories, and strikingly that a population of VTA dopamine neurons is activated in both situations. Together, this indicates that withdrawal memories can drive activity changes in specific neuronal populations of interconnected limbic areas known to be involved in aversive motivational processes. This first study on the neural substrates of withdrawal memories strongly supports an incentive-motivational view of withdrawal in opiate addiction that could be crucial in compulsive drug seeking and relapse.

Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

“…This latter finding extends the data in previous reports not only by confirming that Zif268 ASO attenuates Zif268 upregulation in the BLA (Lee et al, 2005) and whole amygdala (Malkani et al, 2004) but also providing the novel finding that the effect is selective to the BLA, because there is no reduction of Zif268 protein in the CeN. The amygdalar nuclei form part of an interconnected circuit that has been suggested to underlie the aversive aspects of opiate withdrawal (Frenois et al, 2002(Frenois et al, , 2005. A wealth of evidence suggests that, whereas the CeN is activated during primary withdrawal, the BLA appears to be selectively involved in mediating the formation and expression of conditioned opiate withdrawal.…”

“…The neural mechanisms underlying the formation and expression of conditioned opiate withdrawal involve the amygdala (Schulteis et al, 2000;Frenois et al, 2005). One way to assess whether amygdala-dependent conditioned stimulus (CS)-drug withdrawal associations are similar to other CS-unconditioned stimulus (US) memories is to investigate the propensity of CSwithdrawal memories to undergo reconsolidation in the basolateral amygdala (BLA).…”

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

“…For instance, a predator (dog) stress elevates extracellular GABA content in the sheep amygdala (Cook, 2004). Moreover, naloxone-precipitated opiate withdrawal increases the number of c-fos-positive GABA neurons in the CeA of rats or mice (Bagley et al, 2011;Frenois et al, 2005). However, to our knowledge, studies assessing amygdala GABA biosynthesis in long-term drug-withdrawn animals are lacking.…”

“…In situ hybridization is performed as previously described (Ingallinesi et al, 2012) with antisense 35 S-labeled complementary RNA probes designed to recognize GAD 67 (Frenois et al, 2005), TH, and CRF (Ingallinesi et al, 2012) mRNAs. GAD 67 gene expression is assessed in the BLA, the CeA, the nucleus accumbens shell (NaccSh) and the cingulate cortex (CinCtx).…”

Brain Regional Fos Expression Elicited by the Activation of μ- but not δ-Opioid Receptors of the Ventral Tegmental Area: Evidence for an Implication of the Ventral Thalamus in Opiate Reward

“…In self-administering DORÀ/À mice, however, BLA Fos induction was decreased as compared to vehicleinjected mice, suggesting an indirect effect of DORs in modulating BLA activity. Naloxone-precipitated withdrawal induces an opposite pattern of c-fos mRNA expression within two subpopulations of BLA neurons (Frenois et al, 2002(Frenois et al, , 2005). Involvement of CeA in self-administering subjects could reveal a feedback control of VTA activation by CeA GABAergic output neurons (See et al, 2003).…”