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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

    350.14: The paraventricular nucleus of the thalamus is differentially recruited by cocaine vs. natural reward: Correlation with cocaine seeking

    Location: Halls B-H

    *R. MARTIN-FARDON, A. MATZEU, G. CAUVI, F. WEISS;
    MCND, The Scripps Res. Inst., LA JOLLA, CA

    Abstract Body: The orexin/hypocretin (Orx/Hcrt) system was recently shown to regulate a range of physiological processes, including feeding, energy metabolism, and arousal, and has been shown to also be recruited by drugs of abuse. Orx/Hcrt neurons are mostly located in the lateral hypothalamus, and accumulating evidence indicates an important role for these neurons in drug addiction. Studies that explored the neurocircuitry of the reinstatement of drug seeking identified a core circuit that participates in the regulation of drug seeking, including the prefrontal cortex, amygdala, bed nucleus of the stria terminalis, ventral tegmental area, nucleus accumbens, and hippocampus. Additionally, the neural circuits implicated in drug conditioning, craving, and relapse overlap with those involved in natural reward. These Orx/Hcrt neurons project to the paraventricular nucleus of the thalamus (PVT). Although this thalamic region is not thought to be part of the “drug addiction circuitry,” recent evidence indicates that the PVT is involved in the modulation of reward function in general and drug-directed behavior in particular. The aim of this study was to establish the recruitment pattern of the PVT induced by presentation of a discriminative stimulus (SD) conditioned to cocaine (COC) or a highly palatable conventional reinforcer, sweetened condensed milk (SCM). Male Wistar rats were trained to associate the SD with the availability of COC or SCM (S+) versus saline or non-reward (S_). Following extinction of COC- and SCM-reinforced responding, the rats were presented with the respective S+ or S_ alone. Presentation of the COC S+ or SCM S+ after extinction stimuli elicited identical levels of reinstatement, whereas the non-reward S_ did not produce any reinstatement. The brains were labeled for Fos in the PVT, and Fos-positive neurons were counted following COC S+ or SCM S+ presentation and compared with counts obtained following the S_ presentation. Presentation of the COC S+ but not saline S_ activated c-fos. In contrast, presentation of both the SCM S+ and non-reward S_ produced identical neural activation. A correlation plot between the reinstatement responses and number of Fos-positive cells in the PVT revealed a significant correlation in the COC group but not in the SCM group. These data suggest that the PVT is specifically recruited during the conditioned reinstatement of cocaine seeking but not SCM seeking, further supporting the hypothesis that this thalamic structure is involved in “drug addiction circuitry.”
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    Lay Language Summary: Our present research indicates that a correlation exists between the reinstatement of cocaine-seeking behavior (an animal model of relapse) and the activation of the paraventricular nucleus of the thalamus, a brain region that plays a key role in energy homeostasis and metabolism, as well as in arousal, temperature modulation, endocrine regulation, reward, and feeding. Although this thalamic region is not thought to be part of the “drug addiction circuitry,” the present findings indicate that the dysregulation of neurotransmission within the paraventricular nucleus of the thalamus caused by cocaine exposure can be one of the underlying mechanisms for the long-lasting nature of drug relapse.
    Currently, the available therapeutic approaches have failed to completely address the compulsive nature of drug seeking and drug taking associated with addiction. The orexin/hypocretin system regulates a range of physiological processes, including feeding, energy metabolism, and arousal, and is recruited by drugs of abuse. Orexin/hypocretin neurons are predominantly located within the lateral hypothalamus, a brain region associated with reward and motivation, as well as the initiation of motivated behavior, and project to the paraventricular nucleus of the thalamus. Accumulating evidence indicates an important role for these neurons in reward seeking in general and drug seeking in particular.
    The aim of this study was to determine whether neurons in the paraventricular nucleus of the thalamus are recruited (using the Fos protein as a marker of neural activation) when a discriminative stimulus that is paired/conditioned to cocaine or a highly palatable conventional reinforcer (i.e., sweetened condensed milk) is presented.
    Two groups of male Wistar rats were trained to associate a discriminative stimulus with the self-administration of cocaine or sweetened condensed milk (S+) versus saline or non-reward (S-), respectively. Following extinction of cocaine and sweetened condensed milk self-administration, a period when rewards (cocaine and sweetened condensed milk) and discriminative stimuli (S+ and S-) were withheld, the rats were presented with the discriminative stimuli alone (conditioned reinstatement or relapse). Presentation of the cocaine or sweetened condensed milk S+ after extinction elicited identical levels of relapse. The brains were labeled for the Fos protein in the paraventricular nucleus of the thalamus, with Fos-positive neurons counted following the cocaine S+ or sweetened condensed milk S+ presentation, and then compared with counts obtained following the S- presentation. In the cocaine group, the presentation of the cocaine S+ but not saline S- increased Fos. In the sweetened condensed milk group, the presentation of both the sweetened condensed milk S+ and non-reward S- produced identical neural activation. A correlation plot between the reinstatement responses and the number of Fos-positive cells in the paraventricular nucleus of the thalamus revealed a significant relationship with cocaine seeking but not sweetened condensed milk seeking.
    These results suggest that the paraventricular nucleus of the thalamus is specifically recruited during the conditioned reinstatement of cocaine seeking but not during sweetened condensed milk seeking.
    The paraventricular nucleus of the thalamus may be a key brain region that contributes to the distinctly compulsive nature of cocaine seeking as opposed to behavior motivated by natural rewards that are essential for survival, well being, and healthy hedonic pursuits. Furthermore, the results may have detected a previously unrecognized mechanism in the etiology of cocaine dependence and may identify novel therapeutic targets for drug addiction.