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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    350—Cocaine: Neural Mechanisms of Addiction II

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    350.22: Hippocampal beta-adrenergic receptor blockade impairs retrieval but not reconsolidation of cocaine-associated memory and prevents subsequent reinstatement

    Location: Halls B-H

    *D. MUELLER, J. M. OTIS, M. K. FITZGERALD;
    Dept. of Psychology, Univ. of Wisconsin-Milwaukee, Milwaukee, WI

    Abstract Body: Retrieval of drug-associated memories is critical for addictive behaviors, as presentation of drug-associated cues induces drug seeking and relapse. Recent evidence from rat and human memory models reveals that beta-adrenergic receptor (beta-AR) blockade induces persistent retrieval impairments (Kroes et al, 2011; Otis et al, 2013) that protect against subsequent reinstatement (Kroes et al, 2012 SfN Abstracts; Otis et al, 2011). Despite this, the neural locus at which beta-ARs maintain retrieval and reinstatement is unclear. We investigated the involvement of beta-AR activation within the dorsal hippocampus (dHipp) for retrieval and subsequent reinstatement of a cocaine-associated memory. Using a conditioned place preference (CPP) procedure, rats were conditioned to associate one chamber, but not another, with cocaine. Memory retrieval was then tested by allowing free access to all chambers, during which rats expressed a CPP for the previously cocaine-paired chamber. Bilateral dHipp microinfusions of the beta-AR antagonist nadolol (2µg/µl/side) before the first CPP trial prevented retrieval and led to a persistent impairment in retrieval during subsequent microinfusion-free CPP trials. Moreover, the nadolol-induced retrieval impairment prevented cocaine-induced reinstatement of the CPP long after nadolol treatment. These effects were independent of reconsolidation blockade, as nadolol microinfusions immediately after retrieval had little effect on subsequent CPP expression and cocaine-induced reinstatement. Thus, beta-AR signaling within the dHipp is necessary for CPP memory retrieval. Furthermore, preventing retrieval by blocking these receptors induces a long-term deficit in retrieval that prevents reinstatement of drug seeking long after treatment.

    Lay Language Summary: Disruption of memory retrieval prevents cocaine seeking
    Researchers at the University of Wisconsin-Milwaukee (UWM) have identified primary players responsible for maintaining memories associated with drug use. Inhibition of these brain mechanisms, under the correct conditions, persistently impairs drug-related memories and prevents drug seeking in rats.
    Presentation of cues associated with drug use, such as drug paraphernalia, leads to drug cravings, withdrawal, and drug-seeking behavior in addicts. Preventing these associations from being retrieved from memory would therefore prevent cue-induced drug seeking.
    The researchers reveal that β-adrenergic receptors (β-ARs) within a memory-related structure known as the hippocampus are critical for maintaining drug-associated memory retrieval. Disruption of hippocampus β-ARs during cue presentation, but not in the absence of the cues, persistently impairs drug-associated memory retrieval.
    The memory impairment is long lasting, perhaps permanent, and provides protection against stimuli that normally induce relapse.
    In their investigation, researchers conditioned rats to associate one distinct chamber, but not another, with cocaine. Following conditioning, the rats were tested daily for a place preference by allowing drug-free access to both chambers. Rats demonstrating cocaine-seeking behavior spent significantly more time in the previously cocaine-associated chamber.
    To examine the neural mechanisms of memory retrieval, the researchers administered nadolol, which blocks β-ARs (also known as a β-blocker), into the hippocampus before a retrieval test. Control rats spent more time in the cocaine-associated chamber, whereas nadolol-treated rats did not. These effects were long-lasting, as rats treated with nadolol continued to display no place preference for the cocaine-associated chamber during nadolol-free tests even 2 weeks after nadolol treatment.
    The long-lasting effects of nadolol did not occur when the cues were not displayed to the rats during nadolol administration, indicating that a memory must be reactivated in order to be disrupted.
    These results demonstrate that β-blockers that reach the hippocampus in the brain could limit relapse susceptibility. In support of this, the researchers have also revealed that the commonly prescribed β-blocker propranolol, which reaches the brain when administered orally, is capable of preventing drug-associated memory retrieval in rats.
    Clinically, exposure therapy has been used to extinguish drug-associated memories with limited success. To date, pharmacological adjuncts have seldom been used to facilitate this learning or to disrupt the original drug-associated memories. The research described indicates that β-blockers, when coupled with exposure therapy, could block retrieval of memories associated with drug use.