A single link to the first track to allow the export script to build the search page
  • 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

    350.03: Stress or cocaine-induced metaplasticity of long term potentiation in the ventral hippocampus of rats

    Location: Halls B-H

    *M. MATHILAKATH KERALAPURATH1,2, J. J. WAGNER1,2;
    1Physiol. & Pharmacol., 2Interdisciplinary Toxicology Program, Univ. of Georgia, Athens, GA

    Abstract Body: Stress is found to potentiate the behavioral sensitization to psychostimulants such as cocaine, and is a major trigger for relapse to drug use. The ventral hippocampus (vH) is more sensitive to various types of stressors than is the dorsal hippocampus, and the vH is also implicated in reinstatement of drug-seeking. Here we investigate the effects of minor, intermittent stressors associated with locomotor sensitization experiments as well as the effects of repeated cocaine exposure on metaplasticity of LTP in the vH. After handling for 3 days, all the treatment groups received 5 daily i.p. injections of either saline (0.5ml/day) or cocaine (15mg/kg), and locomotor activity was monitored for 30 minutes pre- and 60 minutes post-injection in open-field activity chambers. 1 week following the fifth injection, animals were again challenged with either saline or cocaine in the locomotor activity environment. Rats were sacrificed 8-11 days after the challenge injection and LTP assessed using extracellular recording of fEPSPs evoked via stimulation in the stratum radiatum layer of the CA1 region of ventral hippocampal slices. A naïve group of rats remained undisturbed in the home cage until sacrificed for LTP assessment. First, we confirmed that the relatively minor stress associated with handling, i.p. injections and novelty exposure involved in the locomotor sensitization protocols causes persistent stress-like increases in ventral hippocampal LTP (LTP = 1.48±.04 vs. naïve LTP = 1.28±.05). This stress-like effect was blocked by i.p. injections of either a single dose of nor-binaltorphimine (nBNI, kappa-opioid receptor antagonists, @ 10mg/kg, LTP = 1.35 ± .04) or daily doses of SCH 23390 (DA D1R antagonist, @ 0.5mg/kg, LTP = 1.31 ± .06) or eticlopride (DA D2-like receptor antagonist, @0.1mg/kg, LTP = 1.32 ± .02). Injection of cocaine, where the rats are subjected to both stress & drug effects, also significantly altered the LTP in the vH (1.51 ± .05). Neither nBNI nor SCH 23390 injections in the cocaine-treated rats resulted in significant reversal of drug & stress effects. However, co-administration of eticlopride was able to block (1.33 ± .03) the increase in vH LTP in cocaine treated rats. These results indicate that DA D2-class of receptor antagonists can prevent stress- and cocaine-induced metaplasticity in the CA1 region of the ventral hippocampus.

    Lay Language Summary: One of the key characteristics of addiction is the relapse to drug seeking and usage even after long periods of abstinence. Stress has been considered to be one of the key contributors to relapse behaviors observed both in experimental animals as well as in humans. However, neither the cellular mechanism by which stress triggers relapse nor identification of the brain regions involved in this process has been fully determined. The results from our current study indicate that repeated exposure to either an aversive stimulus (stress) or rewarding stimulus (cocaine) induced a common change in hippocampal function which may contribute to the reinstatement of drug-seeking behaviors.
    The hippocampal formation is long known to be involved in learning, memory and spatial navigation, and these hippocampal dependent processes were shown to be impaired when animals were subjected to either acute or chronic stressors. Commonly employed behavioral protocols involving laboratory animals consist of several potential stress inducing procedures and the effects of these stressors on the animals are often ignored during the interpretation of results from these experiments. We found that minor stressors such as injection procedures or exposure to novel environment involved in a behavioral conditioning protocol in rats can cause persistent changes in hippocampal synaptic plasticity. These changes were measured in terms of magnitude of long-term potentiation (LTP), an index of strength of the synapses. Experiencing the behavioral protocol alone caused LTP in the ventral sector of the hippocampus to be significantly enhanced, while the LTP in the dorsal sector was significantly reduced. Both of these changes persisted up to 2 weeks of the last behavioral manipulation.
    The hippocampal formation is also known to be involved in the reinstatement of drug seeking behaviors triggered by either environmental context or cues which were previously associated with drug usage, or by the exposure to drug itself. In order to model the intermittent and repeated nature of psychostimulant drug use, cocaine was injected daily for 5 days in a novel environment during the behavioral conditioning protocol. In such cocaine conditioned rats, it was observed that LTP in the ventral sector of hippocampus was significantly enhanced, while that in the dorsal sector remained unchanged. Moreover, this cocaine conditioning induced enhancement of LTP in the ventral hippocampus persisted up to 2 weeks after the last cocaine dose.
    Our findings indicate that either intermittent, minor stressors (which may approximate daily life stressors) or cocaine exposure elicits a similar change in the synaptic plasticity in the ventral sector of the hippocampus. It is suggested that this persisting change (enhanced LTP) could in turn strengthen the connectivity of ventral hippocampus to the limbic system (regions that regulate reward, emotions etc.), whereas the connectivity of dorsal hippocampus to cortical regions is relatively weakened.
    In conclusion, this study suggests that the ventral sector of the hippocampus is well positioned at a key intersection of learning/memory and drug reward/reinstatement behavioral functions to mediate the memories of addiction involved with relapse to drug use.