Browsing by Subject "relapse"

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    A medium throughput rodent model of relapse from addiction with behavioral and pharmacological specificity
    (Elsevier, 2019-08) Eiler, William J. A., II; Gleason, Scott D.; Smith, Jodi L.; Witkin, Jeffrey M.; Neurological Surgery, School of Medicine
    One of most formidable problems in the treatment of addiction is the high rate of relapse. The discovery of medicines to help mitigate relapse are aided by animal models that currently involve weeks of training and require surgical preparations and drug delivery devices. The present set of experiments was initiated to investigate a rapid 8-day screening method that utilizes food instead of intravenous drug administration. Male Sprague-Dawley rats were trained in a reinstatement paradigm in which every lever press produced a 45 mg food pellet concurrently paired with a light and tone. Behavior was subsequently extinguished with lever responses producing neither food nor food-associated stimuli. Reinstatement of responding was evaluated under conditions in which the first three responses of every 5 min time bin produced a food pellet along with food-associated stimuli. The mGlu5 receptor antagonists MPEP and MTEP produced a significant reduction in reinstatement while failing to alter responding where every response produced food. The cannabinoid CB1 receptor antagonist rimonabant and the mGlu2/3 receptor agonist LY379268 also selectively reduced reinstatement. Other compounds including clozapine, d-amphetamine, chlordiazepoxide, ABT-431, naltrexone and citalopram were without effect. The results suggest that relapse-like behavioral effects can be extended to non-pharmacological reinforcers. Drug effects demonstrated both behavioral and pharmacological specificity. The present experimental design thus allows for efficient and rapid assessment of the effects of drugs that might be useful in the treatment of addiction-associated relapse.
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    Therapeutic challenges for concurrent ethanol and nicotine consumption: naltrexone and varenicline fail to alter simultaneous ethanol and nicotine intake by female alcohol-preferring (P) rats
    (Springer, 2019-02-13) Waeiss, Robert A.; Knight, Christopher P.; Hauser, Sheketha R.; Pratt, Lauren A.; McBride, William J.; Rodd, Zachary A.; Psychiatry, School of Medicine
    Rationale and Objectives: Simultaneous alcohol and nicotine consumption occurs in the majority of individuals with alcohol use disorder (AUD) and nicotine dependence. Varenicline (Var) is used to assist in the cessation of nicotine use, while naltrexone (Nal) is the standard treatment for AUD. Despite evidence that ethanol (EtOH) and nicotine (NIC) co-use produces unique neuroadaptations, preclinical research has focused on the effects of pharmacotherapeutics on a single reinforcer. The current experiments examined the effects of Var and Nal on EtOH, NIC, or EtOH+NIC intake. Methods: Animals were randomly assigned to 1 of 4 drinking conditions of 24-hour access to a 3-bottle choice paradigm, one of which always contained water. Drinking conditions were water only, 0.07 and 0.14 mg/mL NIC (NIC only), 15% and 30% EtOH (EtOH only), or 15% and 30% EtOH with 0.14 mg/mL NIC (EtOH+NIC). The effects of Var (0, 1, or 2 mg/kg) or Nal (0, 1, or 10 mg/kg) injections on maintenance and relapse consumption were determined during 4 consecutive days. Results: Var reduced maintenance and relapse NIC intake but had no effect on EtOH or EtOH+NIC drinking. Conversely, Nal reduced EtOH maintenance and relapse drinking, but had no effect on NIC or EtOH+NIC drinking. Discussion: The results indicate the standard pharmacological treatments for nicotine dependence and AUD were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC couse/abuse. These findings suggest that co-abuse may promote unique neuroadaptations that require models of polysubstance abuse to develop pharmacotherapeutics to treat AUD and nicotine dependence.
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    WHEN A FIRE LEADS TO A DRINK: ENHANCEMENT OF ALCOHOL-SEEKING BY MICROINJECTIONS OF NICOTINE DIRECTLY INTO THE REWARD NEUROCIRCUITRY
    (Office of the Vice Chancellor for Research, 2012-04-13) Popoola, Daniel O.; Hauser, Sheketha R.; Rodd, Zachary A.
    Alcohol addiction is a cyclical disorder that is characterized by periods of alcohol consumption and abstinence. The periods of abstinence are frequently brief, and the rate of relapse to alcohol consumption is typically higher than 95% within a year. Most alcoholics are not just alcoholics. The vast majority (80-95%) of alcoholics also concurrently use, or are dependent on, nicotine. During periods of alcohol abstinence, nicotine use dramatically increases. The use of nicotine can potentiate self-reported craving for alcohol and the amount of alcohol used following a relapse episode. The goal of the present project was to determine the biological basis of nicotine’s ability to stimulate alcohol (EtOH)-seeking in a rodent model of alcoholism (alcohol-preferring [P] rat). Specifically, the current project examined the effect of nicotine on EtOH-seeking when administered directly into the brain reward neurocircuit (posterior Ventral Tegmental Area – pVTA). In order to determine the neurotransmitter systems regulating nicotine’s ability to enhance EtOH-seeking when administered into the pVTA, two subsequent studies examined the effect of co-administration of nicotine with a acetylcholine nicotine receptor (AchN) antagonist (mecamylamine (MEC)) or with a serotonin-3 (5HT3) receptor antagonist (zacopride (Zac)). Nicotine binds with high affinity to both the AchN and 5HT3 receptors. The data collected indicated that at very low concentrations nicotine microinjected into the pVTA increased EtOH-seeking in P rats. Co-administration of mecamylamine or zacopride blocked nicotine’s ability to potentiate EtOH-seeking. Overall, the results show that nicotine can enhance alcohol-seeking behaviors through activation of the AchN and 5-HT3 receptors in pVTA. The clinical implication of the data set would be that to reduce the amount of alcohol-craving, which could lead to relapse, nicotine use should also be terminated.