Ketamine self-administration in the rat: evidence for a critical role of setting

Rationale

The abuse of ketamine has been reported to be on the rise over the past 15?years, but its abuse appears to be limited almost exclusively to the context of music and dance settings, indicating a major role of context in modulating its reinforcing effects. We have previously reported that amphetamine, cocaine, and heroin self-administration (SA) in the rat are differentially influenced by the setting in which testing takes place. The aim of the present study is to extend this pre-clinical model to ketamine.

Materials and methods

Independent groups of rats with intravenous catheters were given the possibility to self-administer different doses of ketamine (125, 250, and 500???g/kg per infusion) under two environmental conditions. Some animals were housed in the SA chambers (resident rats) whereas other rats were transported to the SA chambers only for the test sessions (non-resident rats). After training, within-subject dose effect curves (125, 250, 500, and 1,000???g/kg per infusion) and break-point (during a progressive ratio session) were calculated.

Results

Non-resident rats readily acquired ketamine self-administration. In contrast, resident rats self-administered only the highest dose of ketamine (500???g/kg), but still four times less than non-resident rats (11.0?±?6.0 vs 44.4?±?5.2 infusions during the last training session). No significant differences in break-point were found during the progressive ratio session.

Conclusions

The present study confirms at a preclinical level the importance of setting for ketamine SA and further validates a previously described animal model of drug?environment interaction.     

The role of dopamine in alcohol self-administration in humans: Individual differences

Objective: To clarify dopamine's role in alcohol self-administration in a heterogeneous sample of drinkers using acute phenylalanine/tyrosine depletion (APTD). Methods: Sixteen men with variable drinking histories were characterized on their ethanol-induced cardiac response, a marker previously proposed to index dopamine system reactivity and vulnerability to alcohol abuse. During separate sessions participants were administered (i) a nutritionally balanced (BAL) amino acid (AA) mixture, (ii) a mixture lacking the dopamine precursors, phenylalanine and tyrosine, and (iii) APTD followed by the dopamine precursor, l-DOPA. Five hours after AA administration, participants could earn units of alcohol using a progressive ratio breakpoint task. Results: Alcohol self-administration was reduced in the APTD and APTD + l-DOPA conditions relative to the BAL condition. In both cases the changes were predicted by ethanol-induced cardiac change. Conclusions: The motivation to drink is likely regulated by more than one neurobiological mechanism. Individual differences in cardiac responsivity to ethanol might provide a peripheral marker of responsiveness to pharmacological manipulations of dopamine.     

The influence of early postweaning ethanol exposure on oral self-administration behavior in the rat

The effects of three early ethanol home cage consumption procedures on the maintenance of operant lever responding reinforced by ethanol presentation were examined in the rat. Two groups of rats, 25 and 31 days of age, were exposed to 10% (v/v) ethanol as the only fluid in the home cage for 3 or 10 days. A third group, 31 days of age, were exposed to 10% ethanol or tap water for 24 h, with the fluid alternating daily for 18 days. All animals were subsequently trained to lever press using 10% ethanol reinforcement under a decreasing water restriction schedule. All three groups were found to have substantial ethanol consumption levels during the initial exposure in the home cage, ranging from 11.2 to 11.9 g/kg/day. The animals were all successfully trained to lever press in the operant chamber with ethanol as the reinforcer when limited to 15 ml/day of water in the home cage. The average number of reinforcements per day ranged from 29 to 43.5, yielding ethanol intakes from 1.06 to 1.97 g/kg in the 30-minute operant session. However, when 50 ml/day of water was available in the home cage, ethanol reinforcements were substantially reduced, with intakes which ranged from 0.14 to 0.18 g/kg/day. The data suggest that early exposure does not enhance ethanol's reinforcing properties later in the animal's life. These results were discussed in terms the effect of early ethanol exposure on later ethanol consumption and the role of ethanol initiation procedures in oral self-administration.     

Effects of oral ethanol self-administration on the EEG of alcohol preferring and -nonpreferring rats

EEG measures have been shown to differ in human subjects who are at genetically increased risk for the development of alcoholism. In the present study, EEG was recorded in rats that were selectively bred for alcohol-preferring (P) and nonpreferring (NP) behaviors during an ethanol self-administration paradigm. In this paradigm, rats initially learned to press a lever for a 0.2% saccharin solution. Ethanol was then added to the saccharin solution in increasing concentrations while saccharin was faded progressively. EEG recordings were analyzed under three different conditions: baseline, 0.2% saccharin and 10% ethanol. Statistical analyses were carried out within each group of rats for three 10-min intervals in each condition. NP rats showed increases in EEG power in the 6–32 Hz frequency ranges 20–30 min following ethanol availability. In contrast, no significant EEG effects were found for P rats in the 10% ethanol condition with respect to time. EEG power in the three time periods (0–10, 10–20, 20–30 min) was also compared between conditions (baseline, saccharin, 10% ethanol). For NP rats, a significant increase in EEG power during the 20–30 min time interval was found in the 10% ethanol session for the 16–32 Hz frequency range as compared to baseline and saccharin. In P rats, a significant increase in the power of the EEG was found during the first 10 min in the 10% ethanol session in the 8–16 Hz frequency range as compared to baseline and saccharin. The two rat lines also differed in their behavioral responses to the self-administration paradigm. In the ethanol condition, P rats appeared behaviorally aroused during the first 10 min of recording as compared to baseline and saccharin, whereas the NP rats were behaviorally quiescent during the 20–30 min period following ethanol availability. These experiments demonstrate that P and NP rats exhibit different electrophysiological and behavioral responses during exposure to ethanol self-administration paradigms. P rats appeared to be activated initially by ethanol availability whereas NP rats eventually reduced their behavioral activity. These findings may help to further characterize the brain substrates responsible for the difference in alcohol preference between the two rat lines.Presented in part at the 1991 Meetings of Society for Neuroscience and American College of Neuropsychopharmacology     

5-HT receptor ligands differentially affect operant oral self-administration of ethanol in the rat

The present study evaluated the effects of the selective serotonin (5-hydroxyhyptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT_1B receptor agonist, tetrahydro-4-pyridyl[3,2-b]pyridine, CP-94,253 the preferential 5-HT_2A receptor agonist, 1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane, DOI and the mixed 5-HT_2C/1B receptor agonist, 1-(3-chlorophenyl)piperazine, mCPP, on oral ethanol (10% v/v) self-administration in a two-lever, fixed-ratio:1, water vs. ethanol choice procedure in the rat. All compounds affected operant behavior, with varying degrees of specificity, that is, the extent to which a reduction of ethanol-reinforced lever pressing coincided with a reduction of ethanol preference, and selectivity, that is, the extent to which a reduction of ethanol-reinforced lever pressing could be dissociated from an effect on total responding on both levers. Fluoxetine (5–20 mg/kg, i.p.) and CP-94,253 (1–10 mg/kg, i.p.) induced a nonselective disruption of operant behavior; the profile being weakly specific for CP-94,253. DOI (0.1–0.3 mg/kg, i.p.) and mCPP (0.3–1 mg/kg, i.p.) induced a specific effect; the profile being more selective for DOI. These findings suggest that operant ethanol self-administration can be suppressed in a specific manner by activation of 5-HT_2A and, possibly, 5-HT_2C receptors, and in a nonselective manner by activation of 5-HT_1B receptors. As fluoxetine indirectly stimulates these receptors and its behavioral profile resembles more that of a 5-HT_1B receptor agonist, activation of 5-HT_1B receptors may underlie its effects on operant ethanol self-administration.     

Reduction in oral ethanol self-administration in the rat by the 5-HT uptake blocker fluoxetine

Long-Evans rats (N = 4) maintained on ad lib food and water were initiated to self-administer ethanol using the sucrose-substitution procedure. Following initiation, the rats received IP injections of fluoxetine HCl in sterile water 30 minutes before selected daily self-administration sessions. On other sessions, the rats were injected with sterile water only. Doses of 1, 2, 3, and 5 mg/kg were tested in a random order. Only one drug dose was given each week and each dose was tested at least twice except the 5 mg/kg dose. As dose increased, responding for ethanol decreased with significant reductions at both the 3 and 5 mg/kg dose. The nature of the decrease was such that the duration of continuous responding at the beginning of the session was reduced respective to control and noninjection performance. Overall, the findings of this study support prior work with fluoxetine and other 5-HT blockers which appear to affect satiety mechanisms and possibly reinforcement efficacy.     

Nicotine in alcohol deprivation increases alcohol operant self-administration during reinstatement

Tobacco and alcohol are highly co-abused by humans. Most experimental studies have evaluated ethanol consumption in animals exposed concomitantly to nicotine. However, little is known regarding the effects of nicotine administered during periods of alcohol deprivation. In the present study, adult male Wistar rats with an extended background of operant self-administration of ethanol were alcohol-deprived and treated with nicotine (0.1, 0.2, 0.4 and 0.8 mg/kg) or saline during five consecutive days in one chamber of a place conditioning apparatus. Nicotine-induced changes in locomotion were monitored daily, whereas the expression of place conditioning was studied the day after the last nicotine injection. Forty-eight hours after testing for conditioning, the animals resumed operant self-administration of ethanol and their alcohol intake was evaluated during the next 14 days. We observed that alcohol consumption was increased in animals treated with nicotine at doses of 0.2, 0.4 and 0.8 mg/kg but not in animals treated with the dose of 0.1 mg/kg or saline. Additionally, the dose of 0.8 mg/kg of nicotine not only induced persistent changes in alcohol self-administration but also produced conditioned place aversion and depressed locomotor activity. These results indicate that nicotine administration during the ethanol deprivation period can exacerbate the maintenance of alcohol consumption.     

Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats

Rationale and objective Alcohol and tobacco are often co-abused in humans and previous studies found that nicotine increases alcohol consumption in rats. Here, we studied whether nicotine would reinstate alcohol-taking behavior in drug-free rats and whether this effect would be enhanced by prior exposure to nicotine during alcohol self-administration training. Methods Rats were trained to press a lever for alcohol (12% w/v, 1 h/day), and following stable alcohol intake groups of rats (n=11–12) were given daily vehicle or nicotine (0.2, 0.4 or 0.8 mg/kg, SC) injections just prior to the self-administration sessions for 10 days. Rats were then given 6 days of alcohol self-administration in the absence of nicotine and an additional 5–10 drug-free days during which lever presses were not reinforced (extinction). Subsequently, rats were tested for reinstatement of alcohol seeking following exposure to priming injections of vehicle or nicotine (0.4 mg/kg, SC). Results Nicotine increased alcohol self-administration in a dose- and time-dependent manner over the 10-day period. Nicotine also reinstated alcohol seeking after extinction of the alcohol-reinforced behavior, and this effect was strongly enhanced by prior nicotine exposure. Conclusions The present data extend previous studies on the effect of nicotine on alcohol self-administration, and further indicate that nicotine is an effective stimulus for reinstatement of alcohol seeking during drug-free periods.     

Noradrenergic role in the self-administration of ethanol

Involvement of noradrenergic and/or dopaminergic processes of the brain in self-administration behavior toward ethanol was assessed in rats allowed to lever-press for 25 mg/kg intragastric doses on a CRF schedule. Initial access to infusions of saline for establishing an operant baseline was followed by one 10-hr session on acquisition contingencies for ethanol and then one extinction session on saline. Prior to a reacquisition session, rats were treated with either (a) saline, (b) alpha-methyl-p-tyrosine (AMT; 225 mg/kg), (c) 1-phenyl-3(2-thiazolyl)-2-thiourea (U-14,624; 600 mg/kg or 300 mg/kg), or (d) haloperidol (3.5 mg/kg). Only the saline- pretreated control group and the haloperidol-treated rats reacquired lever-press behavior. Groups treated in like fashion, but pressing for a sweet milk reinforcer, all showed reacquisition. Thus, the effects of AMT and U-14,624 are attributed to an interference with the reinforcing effects of ethanolinfusions. Brain levels of norepinephrine were depeleted by both compounds, dopamine was depleted only by AMT, and serotonin was elevated by 600 mg/kg of U-14,624 but unaffected by 300 mg/kg. These results suggest that a cerebral noradrenergic system plays an important role in the reinforcing effect of ethanol without an involvement of dopaminergic systems     

Effects of alcohol and lorazepam during extinction of alcohol self-administration in rats

Systemic injections of alcohol have previously been reported to 'prime' or to reinstate self-administration of alcohol in rats, and it has been suggested that the priming effects of drugs are related to their stimulus properties. We tested this hypothesis by investigating the effects of lorazepam, which cross-generalizes with alcohol in animal drug-discrimination studies, in rats trained to self-administer 7% alcohol in an operant paradigm. Once animals were trained, extinction tests were carried out twice weekly, before which rats were injected with either vehicle, alcohol (0.063-0.5 g/kg, i.p.) or lorazepam (0.03-0.25 mg/kg, i.p.). Alcohol did not increase responding for alcohol during extinction. Doses of 0.25 and 0.5 g/kg reduced alcohol-appropriate lever pressing (p < 0.05 versus 0 g/kg), with the largest dose also suppressing general activity (p < 0.02 versus 0 g/kg). Lorazepam also reduced alcohol-appropriate responding, in a behaviourally specific manner; doses of 0.03 mg/kg and above decreased lever pressing (p < 0.05 versus 0 mg/kg), whereas general activity was depressed at 0.06 mg/kg and larger doses (p < 0.05 versus 0 mg/kg). Although lorazepam mimicked the effect of alcohol at doses predicted to do so on the basis of their relative potency in drug discrimination studies, neither alcohol nor lorazepam primed rats to respond for alcohol. By contrast, the pattern of results suggested that, in this model, they 'satiated' or substituted for alcohol, resulting in a reduced motivation to respond.     

Cigarettes and alcohol: The influence of nicotine on operant alcohol self-administration and the mesolimbic dopamine system

Studies in human populations consistently demonstrate an interaction between nicotine and ethanol use, each drug influencing the use of the other. Here we present data and review evidence from animal studies that nicotine influences operant self-administration of ethanol. The operant reinforcement paradigm has proven to be a behaviorally relevant and quantitative model for studying ethanol-seeking behavior. Exposure to nicotine can modify the reinforcing properties of ethanol during different phases of ethanol self-administration, including acquisition, maintenance, and reinstatement. Our data suggest that non-daily intermittent nicotine exposure can trigger a long-lasting increase in ethanol self-administration. The biological basis for interactions between nicotine and ethanol is not well understood but may involve the stress hormone systems and adaptations in the mesolimbic dopamine system. Future studies that combine operant self-administration with techniques for monitoring or manipulating in vivo neurophysiology may provide new insights into the neuronal mechanisms that link nicotine and alcohol use.     

Dextromethorphan alters methamphetamine self-administration in the rat

Various lines of evidence indicate that methamphetamine (METH) self-administration in rats is under dopaminergic control, and NMDA receptors have been shown to control the release of dopamine at its synapse. Consequently, the aim of this study was to observe the effects of dextromethorphan (DM), a non-competitive NMDA antagonist, in rats self-administering METH. The hypothesis was that acute pretreatment of DM (25 mg/kg) would alter response to METH. DM significantly altered self-administration by reducing the number of correct responses for three METH self-administration doses (0.05, 0.1, 0.25 mg/kg). The same pretreatment did not affect responding for food reward. These findings show that the DM was able to selectively alter METH self-administration.     

Nicotine increases alcohol self-administration in non-dependent male smokers

BACKGROUND: Alcohol and tobacco are commonly co-administered, yet little is known about the effects of acute nicotine administration on alcohol consumption in humans. This study sought to determine how nicotine delivered by tobacco smoke influences alcohol intake in humans using a double-blind placebo controlled repeated measures design. METHODS: During two randomized 120 min sessions 15 male occasional smokers smoked four nicotine-containing or four de-nicotinized cigarettes at 30 min intervals. Throughout the session, subjects could earn units of their preferred alcoholic beverage and glasses of water using a progressive-ratio (PR) task. RESULTS: Wilcoxon signed-rank tests indicated that nicotine increased alcohol self-administration in a significant proportion of participants (Por=0.16). A two-way ANOVA supported this observation further, and, compared to de-nicotinized cigarettes, the nicotine-containing cigarettes increased PR breakpoints for alcohol but not water, as reflected by a Cigarettex Beverage interaction (P相似文献   

The role of human drug self-administration procedures in the development of medications

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest-that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.     

Effect of transdermal nicotine replacement on alcohol responses and alcohol self-administration

Rationale Nicotine replacement is commonly used to treat tobacco use in heavy-drinking smokers. However, few studies have examined the effect of nicotine replacement on subjective and physiological responses to alcohol and alcohol drinking behavior. Objective The primary aim of this within-subject, double-blind study was to examine whether transdermal nicotine replacement (0 mg vs 21 mg/day) altered response to a low-dose priming drink and subsequent ad libitum drinking behavior. Materials and methods Subjects (n = 19) were non-treatment-seeking, non-dependent heavy drinkers who were daily smokers. Six hours after transdermal patch application, subjective and physiological responses to a priming drink [designed to raise blood alcohol levels (BALs) to 0.03 g/dl] were assessed. This was followed by a 2-h self-administration period where subjects could choose to consume up to eight additional drinks (each designed to raise BALs by 0.015 g/dl) or to receive monetary reinforcement for drinks not consumed. Results We found that 6 h after patch application, tobacco craving associated with withdrawal relief was decreased, and systolic blood pressure and heart rate were increased in the active patch condition compared to the placebo patch condition. Subjective intoxication in response to the priming drink was attenuated in the active nicotine patch condition compared to 6 h of nicotine deprivation (i.e., placebo patch). During the self-administration period, subjects had longer latencies to start drinking and consequently appeared to consume fewer drinks when administered the active patch compared to the placebo patch. Conclusions In heavy drinkers, transdermal nicotine replacement compared to mild nicotine deprivation attenuated subjective and physiological alcohol responses and delayed the initiation of drinking.     

The induction of oral ethanol self-administration by contingent ethanol delivery

The necessity of delivering a highly reinforcing stimulus (20% sucrose) contingent upon ethanol consumption in order to induce ethanol self-administration in free-feeding rats was investigated. Rats water deprived for 12-16 h were placed in an environment in which ethanol drinking resulted in the presentation of ethanol. This procedure was successful in inducing and maintaining ethanol self-administration over concentrations of 5-20% (v/v). Compared to a group of rats initially reinforced for drinking ethanol with sucrose presentation, contingent ethanol delivery resulted in greater ethanol self-administration behavior. When 20% ethanol was available the group trained with ethanol had average intake of 0.91 g/kg, whereas the group trained with sucrose had a mean intake of 0.69 g/kg in a 30-min session. The results suggest that ethanol's reinforcing properties are sufficient to establish ethanol self-administration within the context of the inducing environment.     

Establishment and maintenance of oral ethanol self-administration in the baboon

A simple and reliable method was developed to study the self-administration of orally available ethanol by baboons. Two baboons were individually housed in a minimally controlled laboratory environment with visual and auditory access to other baboons and to laboratory technicians. The cages were equipped with standard drinking bottles and spouts. Each baboon was fed his entire daily ration of dry food at the same time each morning, at which time a fresh solution was added to the liquid reservoir. Three hours later, the amount of liquid consumed was measured. This procedure generated high rates of water drinking during the 3-h sessions (“food-induced drinking”). Next, the water available during the sessions was replaced by gradually increasing concentrations of aqueous ethanol (0.5–8%, w/v). When 8% ethanol was reached, the concentration was held constant across daily sessions as session feedings were gradually reduced and shifted to 30 min postsession. Eventually, daily test sessions consisted of simply 3 h access to ethanol, and water was continuously available during the 21-h intersession period. Over a range of ethanol concentrations of 8–32%, ethanol intake (g/kg) and blood ethanol levels remained fairly constant, while volumes (ml) of solution consumed were inversely related to the concentration. Finally, an additional liquid spout was added to each cage and the baboons were provided concurrent access to both ethanol (8%) and water during the sessions. The results indicated clearly that ethanol had come to serve as a positive reinforcer for both of these baboons. This simple preparation should be particularly useful in laboratories that are not equipped with the elaborate technology required in earlier described preparations, and might lend itself to the study of orally effective drugs other than ethanol.