The effects of varenicline on alcohol seeking and self-administration in baboons.

BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) may play a critical role in alcohol reinforcement and consumption. The effects of varenicline, an nAChR partial agonist, on alcohol seeking and self-administration responses were evaluated in 2 groups of baboons trained under a 3-component chained schedule of reinforcement (CSR). METHODS: Alcohol (4% w/v; n = 4; alcohol group) or a preferred nonalcoholic beverage (n = 4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2, required to gain access to alcohol, provided indices of seeking behavior. Varenicline (0.032 to 0.32 mg/kg; 0.32 mg/kg twice daily [BID]) and vehicle were administered before CSR sessions subchronically (5 consecutive days). Higher doses (0.56, 1.0 mg/kg) were attempted, but discontinued due to adverse effects. RESULTS: Subchronic varenicline administration significantly (p < 0.05) decreased the seeking response rate and increased the time to complete the response requirement to gain access to the daily supply of alcohol at the higher doses (0.32 mg/kg, 0.32 mg/kg BID dosing) in the alcohol group compared with the control group. Mean number of drinks was significantly decreased (p < 0.05), but effects did not differ between groups. The pattern of drinking was characterized by a high rate during an initial bout. Number of drinks during and duration of the initial bout were significantly decreased in the alcohol group, compared with the control group, at 0.32 mg/kg (p < 0.05). CONCLUSIONS: Varenicline may be clinically useful for reducing alcohol-seeking behaviors prior to alcohol exposure. Given the modest effects on drinking itself, varenicline may be better suited as a treatment in combination with a pharmacotherapy that significantly reduces alcohol consumption.

Differences in extinction of cue-maintained conditioned responses associated with self-administration: alcohol versus a nonalcoholic reinforcer.

BACKGROUND: Stimuli paired with alcohol may evoke conditioned responses that influence consumption and relapse. Understanding extinction of conditioned responses for both alcohol and nonalcoholic reinforcers, and their relation to subsequent consumption, may be useful in identifying methods to maintain abstinence. METHODS: Nine baboons self-administered alcohol (n = 4) or a nonalcoholic reinforcer (orange-flavored Tang(®) , n = 5) under a 3-component chained schedule of reinforcement (CSR). Each component was associated with distinct stimuli and response requirements, which modeled periods of anticipation (Component 1), seeking (Component 2), and consumption (Component 3). No behavioral contingencies were in effect during Component 1. Responses in Component 2, required to gain access to Component 3, provided indices of seeking behavior. Alcohol or Tang® was available only in Component 3. Initial conditions parametrically manipulated the concentration of alcohol (2 to 6% w/v) or Tang (25 to 100%) that was available for self-administration. The breaking point (BP) of alcohol- and Tang-seeking responses at each of the concentrations was determined by adding a progressive ratio schedule to Component 2. Extinction of responding under stimulus conditions identical to those during baseline, but with no access to alcohol or Tang, was examined using across- and within-session extinction procedures. RESULTS: The BP for 2% w/v alcohol was lower than that for 4 and 6%, which were closely similar. For Tang, BPs increased as the concentration increased. When concentrations of alcohol and Tang were adjusted to produce comparable BPs, self-administration of Tang was higher when compared to alcohol; however, alcohol-related cues maintained higher BPs than Tang-related cues when only water was available for self-administration. Alcohol seeking and self-administration responses were more resistant to extinction than those for Tang. CONCLUSIONS: Stimuli paired with alcohol or nonalcoholic reinforcers will gain different motivational properties. Alcohol-related stimuli produced persistent responding that was highly resistant to change, highlighting the role of environmental stimuli in compulsive drinking and relapse.

Baclofen effects on alcohol seeking, self-administration and extinction of seeking responses in a within-session design in baboons.

Baclofen, a gamma-aminobutyric acidB receptor agonist, is currently under investigation as a potential treatment to prevent relapse to drinking in alcohol-dependent persons. In the current study, two groups of baboons were trained under a chained schedule of reinforcement (CSR), with three linked components, which were each correlated with different response requirements and cues. Fulfilling the requirement in the second link initiated the third link where either alcohol (n = 4) or a preferred non-alcoholic beverage (Tang, n = 5) was available for self-administration; failure to complete the response requirement in Link 2 ended the session (no access to alcohol or Tang). Seeking responses in Link 2 were used as indices of the motivational processes thought to be involved in relapse. The effects of baclofen (0.1-2.4 mg/kg) were examined under conditions with alcohol or Tang access and under extinction. Under the CSR, baclofen (1.8 and 2.4 mg/kg) significantly decreased (P < 0.05) alcohol self-administration responses and total g/kg alcohol intake. In contrast, only the highest dose of baclofen (2.4 mg/kg) reduced Tang self-administration and consumption. Under within-session extinction conditions, baclofen (1.8 and 2.4 mg/kg) facilitated extinction of responding for both alcohol and Tang, particularly during the first 10 minutes of extinction. Baclofen may be effective in reducing craving and alcohol drinking, although the facilitation of extinction and suppression of both alcohol and Tang self-administration by baclofen suggests these effects may be related to a more general suppression of consummatory and conditioned behaviors.

Dissociation of alcohol-seeking and consumption under a chained schedule of oral alcohol reinforcement in baboons.

BACKGROUND: Initiation and maintenance of compulsive alcohol drinking involves a sequence of behaviors which occur in the presence of environmental cues. Animal models using chained schedules of alcohol reinforcement may be useful for examining the complex interactions between cues and alcohol-seeking and -consumption. METHODS: Four baboons self-administered alcohol under a 3-component chained schedule of reinforcement; distinct cues were presented in the context of different behavioral contingencies associated with gaining access to 4% w/v alcohol (alcohol-seeking) and concluding with alcohol self-administration. First, the response strength of alcohol-related seeking responses was evaluated using a between-sessions progressive ratio (PR) procedure in which the response requirement to initiate the final contingency and gain access to the daily supply of alcohol was increased each session. The highest response requirement completed that resulted in alcohol access was defined as the breaking point (BP). Second, water was substituted for alcohol and PR procedures were repeated. The effects of increasing the "seeking" response requirement on subsequent alcohol or water consumption were also determined. RESULTS: When alcohol was available, operant responses to gain access to and self-administer alcohol were maintained. When water was substituted for alcohol, alcohol-related cues continued to maintain alcohol-seeking responses. However, higher BPs, higher rates of self-administration and higher volumes of intake occurred when alcohol was available compared with water. Increasing the response requirement to gain access to alcohol did not reduce alcohol consumption (total alcohol intake). CONCLUSIONS: These results show that alcohol-related cues maintained alcohol-seeking even after a prolonged period of only water availability. Cue-maintained alcohol-seeking behavior can be dissociated from subsequent alcohol consumption.

Attenuation of cocaine-seeking by GABA B receptor agonists baclofen and CGP44532 but not the GABA reuptake inhibitor tiagabine in baboons.

The current study evaluated the effects of drugs that increase GABA levels by activation of GABA(B) receptors (baclofen and CGP44532) or by inhibition of GABA reuptake (tiagabine) on the reinstatement of extinguished lever responding produced by priming doses of cocaine in baboons (i.e., cocaine-seeking). Cocaine self-injection was established and maintained under a fixed ratio (FR10) schedule of reinforcement during daily 2h sessions. Lever responding was extinguished by substituting vehicle (saline) for cocaine until the number of self-injections decreased to 10 or less per session for two consecutive sessions (defined as extinction). Once extinction occurred, priming doses of cocaine (0.1-3.2mg/kg, i.v.) were administered during extinction conditions. Administration of priming doses of cocaine significantly increased cocaine-seeking in a dose-dependent manner. Cocaine-seeking produced by priming doses of cocaine were attenuated by pretreatment with baclofen (N=5) or CGP44532 (N=5) but not tiagabine (N=3). The doses of baclofen (0.32 mg/kg), and CGP445532 (0.32 mg/kg) that reduced cocaine-seeking produced by cocaine priming doses did not reinstate cocaine-seeking and did not produce overt effects when administered alone. These data indicate that GABA(B) agonists may reduce relapse to cocaine taking.

Baclofen and naltrexone effects on alcohol self-administration: Comparison of treatment initiated during abstinence or ongoing alcohol access in baboons.

BACKGROUND: Baclofen, a GABAB receptor agonist, is under investigation as a pharmacotherapy for alcohol use disorder. Treatment with a pharmacotherapeutic can be initiated during alcohol abstinence or active drinking, which may influence treatment outcomes. This study examined whether baclofen treatment initiated and maintained during alcohol abstinence would reduce alcohol seeking and self-administration upon return to alcohol access, and whether effects differed from treatment initiated and maintained during ongoing alcohol access. Naltrexone was tested under similar conditions for comparison. METHODS: Five baboons self-administered alcohol under a three-component chained schedule of reinforcement that modeled periods of anticipation (Component 1), seeking (Component 2), and consumption (Component 3). Alcohol was only available in Component 3. In Experiment 1, baclofen (0.1-1.8mg/kg) or naltrexone (1.0-5.6mg/kg) was administered daily beginning on the first day of a 5-day abstinence period and treatment was continued for 5days of alcohol access. In Experiment 2, selected doses of both drugs were administered during ongoing alcohol access. RESULTS: When treatment was initiated during alcohol abstinence, baclofen and naltrexone did not significantly reduce total alcohol intake (g/kg) or alcohol seeking. In comparison, when treatment was initiated during ongoing alcohol access, both baclofen (1.8mg/kg) and naltrexone (3.2 and 5.6mg/kg) significantly reduced total alcohol intake (g/kg). Naltrexone (5.6mg/kg), but not baclofen, significantly reduced alcohol seeking. CONCLUSIONS: Initiation of baclofen treatment (or other alcohol use disorder treatments) during abstinence or active drinking may be an important factor in influencing efficacy and appropriate dose selection.

Comparison of the behavioral effects of bretazenil and flumazenil in triazolam-dependent and non-dependent baboons.

Behavioral effects of the benzodiazepine receptor partial agonist bretazenil were compared with those of the benzodiazepine receptor antagonist flumazenil under conditions in which three baboons received continuous intragastric (i.g.) infusion of vehicle and then continuous i.g. infusion of triazolam (1.0 mg/kg/day). In each condition, acute doses of flumazenil (0.01-3.2 mg/kg) and bretazenil (0.01-10.0 mg/kg) were administered every 2 weeks (beginning after 30 days of treatment in the triazolam-dependent condition). Food pellets were available during daily 20-h sessions. Following test injections, 60-min behavioral observations were conducted followed by a fine motor assessment. During chronic vehicle administration, neither drug produced changes in observed behaviors. Bretazenil increased pellets earned and time to complete the fine-motor task (10.0 mg/kg dose). During chronic triazolam dosing, both bretazenil and flumazenil precipitated benzodiazepine withdrawal syndromes, characterized by vomiting, tremors/jerks, and a decrease in pellets earned. Thus, bretazenil can function as an antagonist under conditions of benzodiazepine physical dependence.

Self-administration of gamma-hydroxybutyric acid (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons.

RATIONALE: Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are gamma-hydroxybutyrate (GHB) pro-drugs and drugs of abuse. OBJECTIVE: Given the reports of abuse, and the ease at which GBL and 1,4-BD may be obtained, we investigated the reinforcing effects of GBL (n = 5) and 1,4-BD (n = 4) in baboons using IV self-administration procedures. METHODS: Sessions ran 24 h/day. Each injection was contingent upon completion of a fixed number (120 or 160) of lever responses. A 3-h timeout period followed each injection, limiting the total number of injections to eight per day. Self-administration was first established with cocaine (0.32 mg/kg/injection). GBL (10-130.0 mg/kg/injection), 1,4-BD (10-100 mg/kg/injection), or vehicle was substituted for cocaine for at least 15 days. Food pellets were available ad libitum 24 h/day and were contingent upon completion of ten lever responses. RESULTS: GBL (32-100 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in four of five baboons, and the mean rates of injection were high (more than six per day) in three baboons and moderate in the fourth baboon (four to six per day). 1,4-BD (78-130 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in only two out of four baboons, and mean rates were moderate to high in both baboons. Self-injection of these doses of GBL and 1,4-BD generally inhibited food-maintained responding. CONCLUSIONS: GBL and 1,4-BD have abuse liability. Given that GBL and 1,4-BD are self-administered, are easier to obtain than GHB, and are detected in seized samples, additional legal control measures of these GHB pro-drugs may be needed.

Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-ß-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons.

RATIONALE: The various α subtypes of GABAA receptors have been strongly implicated in alcohol reinforcement and consumption. OBJECTIVES: The effects of the GABAA α1-preferring ligand, 3-propoxy-ß-carboline hydrochloride (3-PBC), on seeking and self-administration responses were evaluated in two groups of baboons trained under a 3-component chained schedule of reinforcement (CSR). METHODS: Alcohol (4 % w/v; n = 5; alcohol group) or a preferred nonalcoholic beverage (n = 4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2 provided indices of motivation to drink (seeking). 3-PBC (1.0-30.0 mg/kg) and saline were administered before drinking sessions under both acute and 5-day dosing conditions. RESULTS: Repeated, and not acute, doses of 3-PBC significantly decreased total self-administration responses (p < 0.05), volume consumed (p < 0.05), and gram per kilogram of alcohol (p < 0.05) in the alcohol group. In the control group, 5-day administration of 3-PBC significantly decreased total self-administration responses (p < 0.05) but produced nonsignificant decreases in volume consumed. Within-session pattern of drinking was characterized by a high level of drinking in the first 20 min of the session for both groups, which was significantly (p < 0.05) decreased by all doses of 3-PBC (1.0-18.0 mg/kg) only in the alcohol group. In contrast, the first drinking bout in the control group was only reduced at the highest doses of 3-PBC (10.0 and 18.0 mg/kg). CONCLUSIONS: The results support the involvement of the GABAA α1 subtype receptor in alcohol reinforcement and consumption.

Effects of naltrexone on alcohol drinking patterns and extinction of alcohol seeking in baboons.

RATIONALE: Understanding naltrexone's effect on motivation to drink and pattern of drinking is important for better treatment outcomes and for comparison with novel medications. OBJECTIVES: Naltrexone's effects on number and pattern of seeking, self-administration, and extinction responses were evaluated in two groups of baboons trained under a three-component chained schedule of reinforcement (CSR). METHODS: Alcohol (4 % w/v; n = 4; alcohol group) or a preferred nonalcoholic beverage (n = 4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2 provided indices of motivation to drink (seeking). Naltrexone (0.32-3.2 mg/kg) and saline were administered before drinking and component 2 extinction sessions. RESULTS: Acute doses of naltrexone significantly decreased total self-administration responses (p < 0.01), intake volume (p < 0.001), and grams per kilogram of alcohol (p < 0.01) in the alcohol group only. Pattern of drinking did not change, but the number of drinks during the initial drinking bout was decreased significantly by naltrexone for both groups (p < 0.05). During within-session extinction tests, acute naltrexone significantly decreased time to reach extinction (p < 0.01) and number of seeking responses (p < 0.05), particularly early in the extinction period in the alcohol group only. When administered chronically, naltrexone did not decrease progressive ratio breaking points to gain access to alcohol, but dose dependently reduced alcohol self-administration (p < 0.05) by decreasing the magnitude of the initial drinking bout. CONCLUSIONS: The results support clinical observations that naltrexone may be most effective at reducing self-administration in the context of ongoing alcohol availability and may reduce motivation to drink in the presence of alcohol-related cues.

A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT2A/C and 5-HT1A receptor agonists.

RATIONALE: Existing animal models of impulsivity frequently use food restriction to increase subjects' motivation. In addition, behavioral tasks that assess impulsive choice typically involve the use of reinforcers with dissimilar caloric content. These factors represent energy-homeostasis limitations, which may confound the interpretation of results and limit the applicability of these models. OBJECTIVES: This study was aimed at validating face and convergent validities of a modified adjusting delay task, which assesses impulsive choice between isocaloric reinforcers in ad libitum fed rats. METHODS: Male Wistar rats (n = 18) were used to assess the preferredness and reinforcing efficacy of a "supersaccharin" solution (1.5% glucose/0.4% saccharin) over a 1.5% glucose solution. A separate group of rats (n = 24) was trained in a modified adjusting delay task, which involved repeated choice between the glucose solution delivered immediately and the supersaccharin solution delivered after a variable delay. To pharmacologically validate the task, the effects of the 5-HT(2A/C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)-DOI] and the 5-HT(1A) receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide [(±)-8-OH-DPAT] on impulsive choice were then evaluated. RESULTS: Supersaccharin was highly reinforcing and uniformly preferred over the glucose solution by all subjects. Rats quickly learned the task, and impulsivity was a very stable and consistent trait. DOI and 8-OH-DPAT significantly and dose dependently increased impulsive choice in this modified adjusting delay task. CONCLUSIONS: We validated a rodent task of impulsive choice, which eliminates typical energy-homeostasis limitations and, therefore, opens new avenues in the study of impulsivity in preclinical feeding and obesity research.

Intravenous self-administration of γ-hydroxybutyrate (GHB) in baboons.

BACKGROUND: Abuse of gamma-hydroxybutyrate (GHB) poses a public health concern. In previous studies, intravenous (IV) self-administration of GHB doses up to 10 mg/kg was not maintained in non-human primates under limited-access conditions, which was inconsistent with the usual good correspondence between drugs abused by humans and those self-injected by laboratory animals. METHODS: Self-administration of GHB was studied in 10 baboons using procedures standard for our laboratory to assess drug abuse liability. Each self-injection depended on completion of 120 or 160 lever responses. Sessions ran continuously; a 3-h timeout limited the number of injections per 24h to 8. Self-injection was established at 6-8 injections/day with cocaine (0.32 mg/kg/injection) prior to substitution of each GHB dose (3.2-178 mg/kg/injection) or vehicle for 15 days. Food pellets were available 24h/day. RESULTS: GHB maintained significantly greater numbers of injections when compared to vehicle in 6 of the 9 baboons that completed GHB evaluations that included 32 mg/kg/injection or higher. The baboons that self-administered GHB at high rates were ones for which GHB was the first drug each had tested under the 24-h/day cocaine baseline procedure. Self-injection of the highest doses of GHB decreased food-maintained responding. CONCLUSIONS: High-dose GHB can function as a reinforcer in non-human primates under 24-h access, but self-administration history may be important. The findings are consistent with the demonstrated abuse liability of GHB in humans, and remove GHB as an exception to the typical good correspondence between those drugs abused by humans and those self-administered by nonhuman primates.

Environmental cues, alcohol seeking, and consumption in baboons: effects of response requirement and duration of alcohol abstinence.

BACKGROUND: Environmental stimuli (cues) that have been paired with alcohol drinking may evoke classically conditioned states that in turn influence alcohol consumption and relapse to heavy drinking. Animal models using chained schedules of alcohol reinforcement may be useful for examining such complex interactions. METHODS: Alcohol drinking was established in 4 baboons. A sequence of lights and tones was presented during daily 3-hour sessions. First, cues were presented alone and no programmed contingencies were in effect. Second, cues were paired with 3 linked components consisting of different behavioral contingencies leading to and concluding with access to alcohol for self-administration in the last component (i.e., a chained schedule of alcohol reinforcement). Third, the effects of withholding alcohol access (i.e., forced abstinence) and increasing the number of lever responses required per drink were evaluated. RESULTS: Cues paired with a chained schedule of alcohol reinforcement engendered behaviors that brought baboons into contact with alcohol-related cues and occasioned operant responding that facilitated access to alcohol (alcohol seeking) during components that preceded alcohol access. Increasing the response requirement for each drink decreased the number of drinks and volume of alcohol consumed, but did not alter alcohol seeking. On the first session after 14 days of alcohol abstinence, latency to complete the operant requirement that produced alcohol access was decreased while both alcohol self-administration and volume of alcohol consumed were increased. CONCLUSIONS: Alcohol self-administration and consumption were sensitive to increases in response requirement and duration of alcohol abstinence, while seeking was only enhanced by duration of alcohol abstinence. This animal model may be useful to further examine the interactions between environmental cues and behaviors associated with seeking and consumption of alcohol and to evaluate the efficacy of potential alcohol treatment drugs on these behaviors.