RECONSOLIDATION OF MEMORY: A NEW APPROACH TO TREAT DRUG ADDICTION?
The Labile Nature of Consolidation Theory
Karim Nader, Ph.D.
Memory consolidation theory posits that new memories initially enter a labile or sensitive state, during which they can be disrupted, called short-term memory (STM). Over time, this STM is converted to a fixed long-term memory (LTM) state, which is resistant to being disrupted. For memories to enter the LTM, the neurons mediating the memory must produce new proteins that will be used for LTM storage. Recently, this study showed that when a consolidated LTM is remembered or reactivated, it returns to a labile state similar to STM, in that neurons must synthesize new proteins for the memory to persist. If protein synthesis is inhibited after the reactivation of a consolidated auditory fear memory, that memory could be erased from the brain. This phenomenon is called reconsolidation. The findings from these studies have significant clinical implications for disorders such as posttraumatic stress disorder and drug addiction. In the case of drug addiction, if drug-related memories could be reactivated and prevented from being restored, then drug seeking behavior could in principle be greatly reduced in one session. Theoretically, reconsolidation challenges the foundation on which memory consolidation theory rests.
Disrupting Memories Induced by Drugs of Abuse
Christina M. Alberini, Ph.D.
[Slides not available]
In human addicts, craving and relapse are frequently evoked by the recall of memories connected to a drug experience. Established memories can become labile if recalled or disrupted by several interfering events and pharmacological treatments, including the administration of protein synthesis inhibitors. Thus, the reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to pathological states. This study tested whether inhibiting consolidation-like processes could weaken or eliminate memories induced by drugs of abuse. Dr. Alberini found that, like conventional memories, both a new and an established morphine-conditioned place preference (mCPP) are persistently disrupted if protein synthesis is inhibited either during conditioning or following reactivation. Importantly, the disruption of an established mCPP requires that reactivation evokes a concomitant re-experience of both the conditioned context and the internal state induced by the drug. The established CPP can be abolished by selectively inhibiting protein synthesis in the hippocampus, basolateral amygdala, or nucleus accumbens, but not in the ventral tegmental area. The loss of mCPP appears to be permanent, as it does not return after further conditioning. Thus, memories induced by a drug of abuse can be persistently disrupted following reactivation.
Disrupting Reconsolidation of Drug Memories: Potential Treatment Target for Attenuating Drug-Seeking and Relapse Elicited by Drug-Associated Stimuli
Barry J. Everitt, Sc.D.
Drug-associated conditioned stimuli (CSs) elicit memories of prior drug experiences, induce craving, and precipitate relapse in abstinent drug addicts. In experimental animals, drug-associated conditioned CSs can similarly underpin drug seeking, reinstate previously extinguished drug seeking, and also support the learning of new instrumental drug seeking responses by acting as conditioned reinforcers. We investigated whether the impact of drug-associated conditioned stimuli on drug seeking could be reduced by knocking down the zif268 gene in the amygdala—a site known to be involved with conditioned reinforcing influences on drug seeking—thereby preventing the reconsolidation of a CS-cocaine association. Zif268 knockdown in the basolateral amygdala prevented relapse to drug seeking both early and late into a period of withdrawal, but the learning of a new drug seeking response could not be supported. The results of this study demonstrate that appetitive, drug-related, CS-US associations undergo reconsolidation; that this reconsolidation process depends on the expression of zif268 in the amygdala; and that it can be disrupted to reduce drug seeking behavior in the long term, even in animals that have undergone hundreds of pairings of a CS with self-administered cocaine. These results also suggest a novel approach to the prevention of addictive behavior, including relapse, especially as the neurochemical basis of reconsolidation is elucidated.
Reconsolidation, Cocaine, and Matrix Metalloproteinases
Barbara A. Sorg, Ph.D.
Repeated cocaine exposure induces neural plasticity, as implied by the development of behavioral sensitization and drug dependence. A critical aspect of cocaine-dependent plasticity is the impact of cocaine on proteins involved with synaptic remodeling during drug seeking and drug taking behaviors. This study focused on proteins that regulate the extracellular matrix (ECM), which are critical for the dynamic physical processes involved with synaptic reorganization during neural development, long-term potentiation, and learning. Dr. Sorg’s research team hypothesized that the formation of the original memory (consolidation) and reconsolidation processes require shifts in the expression of ECM proteins. One of the major regulators of the ECM is a family of proteins called matrix metalloproteinases (MMPs). MMPs are zinc metalloendopeptidases that are produced as zymogens and are secreted by cells. MMPs have been implicated in neural plasticity via degradation of the ECM, ultimately resulting in the restructuring of the ECM.
It has been proposed that drug addiction is a result of drug-induced learning and the formation of a long-term memory. With each drug use, the memory for the drug may be reactivated (retrieved) and reconsolidated to maintain the original memory. During reactivation, the memory is thought to be temporarily labile and susceptible to disruption so that reconsolidation of the memory may be prevented. Molecules involved with plasticity may therefore influence the process of reconsolidation. Dr. Sorg’s laboratory demonstrated through animal testing that intracerebroventricular (ICV) injection of an MMP inhibitor (FN-439) can attenuate the learning (consolidation) of cocaine-induced conditioned place preference (CPP) when FN-439 is administered prior to each training session. The researchers tested whether MMPs also play a critical role in memory reconsolidation. Their findings suggest that both the context (CPP chambers) and unconditioned stimulus (cocaine) were needed to reactivate the memory for cocaine and to disrupt the memory for the cocaine-paired chamber.