Rationale: Evidence indicates that drug-paired stimuli can evoke drug-craving leading to drug-seeking and repeated relapse periods can influence drug-seeking behaviors. Objectives: The present study examined (1) the effect of an interaction between repeated deprivation cycles and excitatory conditioning stimuli (CS+) on ethanol (EtOH)-seeking; (2) the effects of EtOH-paired cue-exposure in a non-drug-paired environment on subsequent conditioning in a drug-paired environment; and (3) the temporal effects of conditioned cues on subsequent EtOH-seeking. Methods: Adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS− associated with the absence of EtOH (extinction training), and a neutral stimulus (CS0) presented in a neutral non-drug-paired environment. The rats underwent four deprivation cycles or were non-deprived, following extinction they were maintained in a home cage for an EtOH-free period, and then exposed to no cue, CS+, CS−, or CS0 to assess the effect of the conditioned cues on EtOH-seeking behavior. Results: Repeated deprivations enhanced and prolonged the duration of CS+ effects on EtOH-seeking. Presentation of the CS− in a non-drug-paired environment blocked the ability of a CS+ to enhance EtOH-seeking in a drug-paired environment. Presentation of the CS+ or CS− in a non-drug-paired environment 2 or 4 h earlier significantly altered EtOH-seeking. Conclusion: Results indicated an interaction between repeated deprivation cycles and CS+ resulted in a potentiation of CS+ evoked EtOH-seeking. In addition, a CS− may have therapeutic potential by providing prophylactic protection against relapse behavior in the presence of cues in the drug-using environment.

Atrial Naturietic Peptide (ANP) is a neuropeptide that regulates function of the hypothalamic-pituitary-adrenal (HPA) axis, immune and neuroimmune system, and epigenetic factors. Research has indicated that ANP may mediate alcohol intake, withdrawal, and craving like behaviors. ANP receptors are present in the mesocorticolimbic (MCL) reward pathway of the brain, which includes the nucleus accumbens (Acb) and the ventral tegmental area (VTA). The objectives of the present study were to examine the effects of ANP microinjected into Acb subregions (Shell (Sh), Core (Co), ventral to AcbSh) on operant ethanol (EtOH) self-administration and into posterior VTA (pVTA) on EtOH-seeking behavior of female alcohol-preferring (P) rats. In the first experiment, ANP (0, 10 μg, or 100 μg) was microinjected into subregions of the Acb to determine its effects on EtOH self-administration. In the second experiment, ANP was microinjected into pVTA to determine its effects on Pavlovian Spontaneous Recovery (PSR) of responding, a measure of context-induced EtOH-seeking behavior. Administration of ANP directly into the AcbSh significantly reduced EtOH self-administration compared to vehicle, whereas ANP into the AcbCo or areas directly ventral to the AcbSh did not alter responding for EtOH. Microinjection of ANP into the pVTA significantly reduced responding on the EtOH-associated lever during the PSR test. The data indicate that activation of ANP systems in the (a) AcbSh can inhibit EtOH intake, and (b) in the pVTA can inhibit EtOH-seeking behavior. The results suggest that manipulations of the ANP system could be a potential target for pharmacotherapeutic intervention to treat alcohol use disorder. Supported in part by AA07462, AA07611, AA10717, AA10721, AA013522, AA019366, AA020908, AA022287, and AA024612.

No description available.

Co-users of alcohol and nicotine are the largest group of polysubstance users worldwide. Although pharmacotherapies are available for alcohol (EtOH) or tobacco use disorders individually, it may be possible to develop a single pharmacotherapy to treat heavy drinking tobacco smokers through capitalizing on the commonalities in their mechanisms of action. Towards this goal, several models of concurrent access to EtOH and nicotine were explored as potential preclinical models of co-use using female alcohol-preferring (P) rats. Additionally, potential pharmacotherapeutics for the treatment of EtOH and nicotine co-use disorder were tested using different variations of our model. Treatments tested included (1) varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist with high affinity for the α4β2* subtype; (2) r-bPiDI, a subtype-selective antagonist at α6β2* nAChRs; (3) (R)-modafinil, an atypical inhibitor of the dopamine transporter (DAT); and (4) naltrexone, a clinically available µ-opioid receptor antagonist used to treat alcohol use disorder (AUD). Results from the current dissertation show success in developing a translational animal model in female P rats for co-use of EtOH and nicotine under which pharmacologically relevant levels of both EtOH consumption and nicotine intake are achieved. Additionally, our model was successfully used in testing potential pharmacotherapeutics for the treatment of EtOH and nicotine co-use disorder. Although none of the drugs tested were effective as a monotherapy, results from testing the known smoking cessation agent varenicline and the known AUD treatment naltrexone indicate that our model is effective for selectively measuring changes in EtOH and nicotine intake separately, which suggests the beneficial utility of this model for future treatment research. Furthermore, by applying behavioral economic principles to our findings, we found that EtOH acts as an economic substitute for nicotine. Additionally, our behavioral economic analyses revealed that when the cost of nicotine is changed via response requirements vs dose per infusion, there are differences in the elasticity of demand for concurrently available EtOH and nicotine. Finally, the relatively flat consumption curve for EtOH following varenicline pretreatment suggests that pretreatment with varenicline acts to disrupt the relationship between EtOH and nicotine such that EtOH no longer acts as an economic substitute for nicotine.

Rationale: There is evidence for a common genetic link between alcohol and nicotine dependence. Rodents selectively bred for high alcohol consumption/responsivity are also more likely to self-administer nicotine than controls. Objectives: The experiments examined the response to systemic nicotine, the effects of nicotine within the drug reward pathway, and innate expression of nicotine-related genes in a brain region regulating drug reward/self-administration in multiple lines of rats selectively bred for high and low alcohol consumption. Methods: The experiments examined the effects of systemic administration of nicotine on locomotor activity, the effects of nicotine administered directly into the (posterior ventral tegmental area; pVTA) on dopamine (DA) release in the nucleus accumbens shell (AcbSh), and innate mRNA levels of acetylcholine receptor genes in the pVTA were determined in 6 selectively bred high/low alcohol consuming and Wistar rat lines. Results: The high alcohol-consuming rat lines had greater nicotine-induced locomotor activity compared to low alcohol-consuming rat lines. Microinjections of nicotine into the pVTA resulted in DA release in the AcbSh with the dose response curves for high alcohol-consuming rats shifted leftward and upward. Genetic analysis of the pVTA indicated P rats expressed higher levels of α2 and β4. Conclusion: Selective breeding for high alcohol preference resulted in a genetically divergent behavioral and neurobiological sensitivity to nicotine. The observed behavioral and neurochemical differences between the rat lines would predict an increased likelihood of nicotine reinforcement. The data support the hypothesis of a common genetic basis for drug addiction and identifies potential receptor targets.

No description available.

BACKGROUND: Alcohol use disorders (AUDs) affect 15 million people nationwide, 4% of which are adolescents (ages 12-17) and adolescents who binge drink significantly increase their likelihood of suffering from an AUD in adulthood. Research shows that cues (i.e. flavors) paired with alcohol (EtOH) produce significant cue-induced alcohol craving and contribute to relapse in adolescent and adult populations. However, there is a lack of research focused on how cues that accompany EtOH drinking during adolescence, affect EtOH craving later in life. The current study sought to examine the sex- and developmental-dependent effects of adolescent exposure to flavor cues associated with EtOH on operant-lick behavior and cue-induced dopamine (DA) levels within the nucleus accumbens shell (AcbSh; reward structure) in adulthood. METHODS: Adolescent alcohol-preferring (P) rats were randomly assigned to one of 4 groups and received 24 hr. access to three bottles on their home cage: Paired: 0.1% blueberry flavor extract (BB) + 15% v/v EtOH and 2 water bottles; Unpaired: 0.1% BB, 15% v/v EtOH, and water; 15% EtOH alone, and 2 water bottles; BB alone and 2 water bottles. Home cage fluid consumption was measured for 2-weeks. On the third week bottles were removed and all animals underwent 9 days of operant training using an operant sipper paradigm. This consisted of two sipper spouts connected to the computer by a lickometer, which registered tongue contacts with the sipper tube (Paired: BB+EtOH or water; Unpaired BB or EtOH; EtOH alone: EtOH or water; BB alone: BB or water). When the fixed ratio (FR) requirement for number of licks/tongue contacts was met, a liquid delivery solenoid dispensed 0.05 ml of fluid into the sipper tube. Following the final operant session all rats remained in their home-cage for approximately 40 days until adulthood at which point they were returned to the operant chambers and tested for appetitive and consummatory behavior in response to the flavor cue (all rats: BB or water; NO EtOH). Two weeks after the final operant session all rats underwent microdialysis testing to examine cue-induced DA levels in the AcbSh. RESULTS: Data indicated that animals in the paired group exhibited a significantly greater level of licking at the BB sipper and a significantly greater level of DA release in response to the flavor cue compared to the other groups. CONCLUSIONS: Overall, the data suggest that cues paired with EtOH during adolescence may produce persistent changes to the behavioral and neurobiological mechanisms that contribute to an increased risk of developing an AUD later in life.