Unmixing Memory and Desire

Abstract

Abstinent drug addicts often relapse following exposure to environmental cues associated with drug taking. The ability of some forms of previously acquired memory to influence future behavior may depend upon reconsolidation of retrieved memories (see Hernandez and Kelley), leading two groups to see if disrupting such reconsolidation also disrupts the association of addictive drugs with contextual cues. The acquisition of cocaine-conditioned place preference (COC-CPP) in rats depends on activation of the extracellular signaling-regulated kinase (ERK) signaling pathway; it is blocked by inhibiting mitogen-activated protein kinase kinase (MEK), which phosphorylates and thereby activates ERK. Miller and Marshall used immunocytochemistry and Western analysis to show increased phosphorylation of ERK and of the downstream transcription factors Elk-1 and CREB in the nucleus accumbens core (AcbC, a midbrain region associated with cue-elicited drug seeking) in rats that had acquired COC-CPP. Infusion of a MEK inhibitor into the AcbC shortly before testing for COC-CCP blocked COC-CCP-related behavior and an associated increase in ERK, CREB, and Elk-1 phosphorylation and Fos abundance in the AcbC of rats that had already undergone pairing of cocaine with a particular environment. When administered independently of behavioral testing, MEK inhibition did not affect COC-CCP tested 24 hours later. However, rats in which exhibition of COC-CPP was blocked by preadministration of a MEK inhibitor, or that received a MEK inhibitor right after testing (who exhibited COC-CCP during the test), failed to show COC-CCP when retested 24 hours or 14 days later. These rats also showed decreased activation of the AcbC ERK pathway. Thus, the authors concluded that disruption of AcbC ERK signaling during memory reconsolidation blocked the subsequent expression of COC-CCP. Expression of the transcription factor Zif268 in the basolateral amygdala increases following reexposure to stimuli associated with self-administration of cocaine. In the second study, by Lee et al. , rats learned to nosepoke for a cocaine infusion, which was accompanied by a light. When paired with a memory reactivation session, Zif268 antisense oligodeoxynucleotides (Zif268 ASO) infused into the basolateral amygdala eliminated the ability of light to promote acquisition of a new drug-seeking behavior, whereas missense oligodeoxynucleotides, administered with the reactivation session, or Zif268 ASO, administered without it, did not. C. A. Miller, J. F. Marshall, Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47 , 873-884 (2005). [PubMed] J. L. C. Lee, P. Di Ciano, K. L. Thomas, B. J. Everitt, Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior. Neuron 47 , 795-801 (2005). [PubMed] P. J. Hernandez, A. E. Kelley, Cracking addiction the second time around: Reconsolidation of drug-related memories. Neuron 47 , 772-775 (2005). [PubMed]