SAL produces reinforcing effects in the posterior VTA of Wistar rats, and these effects are mediated by activation of DA neurons and local 5-HT3 receptors.

Rats reared in an IC show greater proclivity to respond operantly for 10% ethanol compared with rats raised in either SC or EC (which did not differ from each other). These findings agree with a number of studies that have shown isolate reared animals to consume greater amounts of ethanol compared with their socially reared counterparts yet contrast some studies showing EC animals consume greater amounts of ethanol than IC rats. The current findings illustrate that rearing environment also plays an important role in an animal's proclivity to respond for ethanol.

The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH) -seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n = 11–14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration.

Rationale Ethanol and nicotine are frequently co-abused. The biological basis for the high co-morbidity rate is not known. Alcohol-preferring (P) rats will self-administer EtOH or nicotine directly into the posterior ventral tegmental area (pVTA). Objective The current experiments examined whether sub-threshold concentrations of EtOH and nicotine would support the development of self-administration behaviors if the drugs were combined. Methods Rats were implanted with a guide cannula aimed at the pVTA. Rats were randomly assigned to groups that self-administered sub-threshold concentrations of EtOH (50 mg%) or nicotine (1 μM) or combinations of ethanol (25 or 50 mg%) and nicotine (0.5 or 1.0 μM). Alterations in gene expression downstream projections areas (nucleus accumbens shell, AcbSh) were assessed following a single, acute exposure to EtOH (50 mg%), nicotine (1 μM) or ethanol and nicotine (50 mg% + 1 μM) directly into the pVTA. Results The results indicated that P rats would co-administer EtOH and nicotine directly into the pVTA at concentrations that did not support individual self-administration. EtOH and nicotine directly administered into the pVTA resulted in alterations in gene expression in the AcbSh (50.8-fold increase in BDNF, 2.4-fold decrease in GDNF, 10.3-fold increase in Vglut1) that were not observed following microinjections of equivalent concentrations/doses of ethanol or nicotine. Conclusion The data indicate that ethanol and nicotine act synergistically to produce reinforcement and alter gene expression within the mesolimbic dopamine system. The high rate of co-morbidity of alcoholism and nicotine dependence could the result of the interactions of EtOH and nicotine within the mesolimbic dopamine system.

Exposing rats to differential rearing conditions during early postweaning development has been shown to produce changes in a number of behaviors displayed during adulthood. The purpose of the present studies was to investigate whether rearing alcohol-preferring (P) and nonpreferring (NP) rats in an environmental enrichment condition (EC), a social condition (SC), or an impoverished condition (IC) would differentially affect self-administration of 10% ethanol. In Experiment 1, rats were tested for consumption of 10% ethanol in limited- and free-access tests. For Experiment 2, rats were trained to respond in an operant chamber for ethanol and then provided concurrent access to 10% ethanol and water. Each solution was presented in a separate liquid dipper after meeting the schedule of reinforcement on distinct levers. After concurrent access tests, the water lever/dipper was inactivated and a progressive ratio (PR) schedule was initiated. Three successive solutions (10% ethanol, 15% ethanol, and 10% sucrose) were tested under the PR. For P rats, rearing in an EC reduced ethanol consumption, preference, and motivation to obtain ethanol, relative to P rats reared in an IC. Thus, exposure to a novel environment immediately after weaning acted to decrease the reinforcing properties of ethanol in an animal model for alcoholism.

Background Published findings indicate that acetaldehyde (ACD; the first metabolite of EtOH) and salsolinol (SAL; formed through the non-enzymatic condensation of ACD and dopamine) can be formed following ethanol (EtOH) consumption. Both ACD and SAL exhibit reinforcing properties within the posterior ventral tegmental area (pVTA) and both exhibit an inverted “U-shaped” dose-response curve. The current study was undertaken to examine the dose-response effects of microinjections of ACD or SAL into the pVTA on DA efflux in the nucleus accumbens shell (AcbSh). Methods For the first experiment, separate groups of male Wistar rats received pulse microinjections of aCSF or 12, 23 or 90 µM ACD into the pVTA while extracellular DA levels were concurrently measured in the AcbSh. The second experiment was similarly conducted, except rats were given microinjections of aCSF or 0.03, 0.3, 1.0 or 3.0 µM SAL, while extracellular levels of DA were measured in the AcbSh. Results Both ACD and SAL produced a dose-dependent inverted “U-shaped” response on DA release in the AcbSh, with 23 µM ACD (200% baseline) and 0.3 µM SAL (300% baseline) producing maximal peak responses with higher concentrations of ACD (90 µM) and SAL (3.0 µM) producing significantly lower DA efflux. Conclusions The findings from the current study indicate that local application of intermediate concentrations of ACD and SAL stimulated DA neurons in the pVTA, whereas higher concentrations may be having secondary effects within the pVTA that inhibit DA neuronal activity. The present results parallel studies on the reinforcing effects of ACD and SAL in the pVTA and support the idea that the reinforcing effects of ACD and SAL within the pVTA are mediated by activating DA neurons.

The rate of co-dependency for alcohol and nicotine is extremely high. Numerous studies have indicated that there is a common genetic association for alcoholism and nicotine dependency. The current experiments examined whether selective breeding for high alcohol preference in rats may be associated with increased sensitivity of the posterior ventral tegmental area (pVTA) to the reinforcing properties of nicotine. In addition, nicotine can directly bind to the serotonin-3 (5-HT3) receptor, which has been shown to mediate the reinforcing properties of other drugs of abuse within the pVTA Wistar rats were assigned to groups that were allowed to self-infuse 0, 10, 50, 100, 200, 400 or 800 μM nicotine in 2-lever (active and inactive) operant chambers. P rats were allowed to self-infuse 0, 1, 10, 50 or 100 μM nicotine. Co-infusion of 5-HT3 receptor antagonists with nicotine into the pVTA was also determined. P rats self-infused nicotine at lower concentrations than required to support self-administration in Wistar rats. In addition, P rats received more self-infusions of 50 and 100 μM nicotine than Wistar rats. Including a 5HT3 receptor antagonist (LY-278,584, or zacopride) with nicotine reduced responding on the active lever. Overall, the data support an association between selective breeding for high alcohol preference and increased sensitivity of the pVTA to the reinforcing properties of nicotine. In addition, the data suggest that activation of 5HT3 receptors may be required to maintain the local reinforcing actions of nicotine within the pVTA.

Background Alcohol abuse is frequently associated with nicotine use. The current experiments were conducted to establish an oral operant ethanol + nicotine (EtOH + Nic) co-use model, and to characterize some aspects of EtOH + Nic co-use. Methods: Rats were allowed to choose between EtOH alone or EtOH + Nic solutions. Additionally, P rats were allowed to concurrently self-administer 3 distinct EtOH solutions (10, 20, and 30%) with varying amounts of nicotine (0.07, 0.14, or 0.21 mg/ml) under operant conditions. P rats were also allowed to concurrently self-administer 2 distinct amounts of nicotine (0.07 and 0.14 mg/ml) added to saccharin (0.025%) solutions. Results During acquisition, P rats responded for the EtOH + Nic solutions at the same level as for EtOH alone, and responding for EtOH + Nic solutions was present throughout all drinking conditions. P rats also readily maintained stable self-administration behaviors for Nic + Sacc solutions. The results demonstrated that P rats readily acquired and maintained stable self-administration behaviors for EtOH + 0.07 and EtOH + 0.14 mg/ml Nic solutions. Self-administration of EtOH+ 0.21 mg/ml Nic was established in only 50% of the subjects. P rats readily expressed seeking behaviors for the EtOH + Nic solutions, and reacquired EtOH + Nic self-administration during relapse testing. In addition, tailblood samples indicated that EtOH + Nic co-use resulted in pharmacologically relevant levels of both EtOH and Nic in the blood. Discussion Overall, the results indicate that P rats readily consume EtOH + Nic solutions concurrently in the presence of EtOH alone, express drug-seeking behaviors, and will concurrently consume physiologically relevant levels of both drugs. These results support the idea that this oral operant EtOH + Nic co-use model would be suitable for studying the development of co-abuse and the consequences of long-term chronic co-abuse.