Modulation of ethanol reinforcement by conditioned hyperthermia

The present study was designed to determine whether a signal for availability of self-administered ethanol would acquire the ability to elicit a conditioned thermal response and to alter ethanol self-administration. Non-deprived male albino rats (n=8) were exposed to a differential conditioning procedure in which brief (30-min) periods of access to sweetened ethanol on a fixed-ratio operant schedule were either signalled (CS+ trials) or unsignalled (Blank + trials). A different stimulus signalled trials on which barpressing was not reinforced (CS– trials). Body temperature was recorded continuously from implanted telemetry devices. As in previous studies involving experimenter-administered ethanol injections, the stimulus paired with self-administered ethanol (CS+) acquired the ability to elicit a conditioned increase in body temperature. Moreover, barpressing for ethanol was greater on signalled trials (CS+) than on unsignalled trials (Blank +), indicating that ethanol's reinforcing efficacy was altered by CS+. Ethanol self-administration was significantly correlated with the anticipatory increase in body temperature on CS+ trials (Pearsonr=+0.77). When ethanol was removed, leaving sucrose alone as the reinforcer, the signal's effect on barpressing was eliminated. This finding suggests the signal's effect depended on ethanol's pharmacological properties. In general, these data are consistent with theories that attribute the signal's effect to conditioned changes in motivation to obtain ethanol or to an interaction between the conditioned response and ethanol's unconditioned effects. The specific pattern of results appears to support hypotheses linking ethanol's thermal and motivational effects. According to this view, conditioned hyperthermia produced tolerance to an aversive ethanol effect (hypothermia) that normally contributes to termination of an ethanol drinking bout, thereby allowing a longer period of self-administration on signalled trials.     

Role of hypothermia in ethanol-induced conditioned taste aversion

Two experiments examined the effect of ambient temperature during ethanol exposure on development of conditioned taste aversion to saccharin. In both studies, male albino rats receiving saccharin-ethanol (1.5 g/kg, IP) pairings followed by 6-h exposure to a 32° C environment developed a weaker saccharin aversion than did rats experiencing ethanol at room temperature. Exposure to the warm environment reduced ethanol-induced hypothermia, but enhanced ethanol's motor-impairing effect. The influence of ambient temperature on ethanol-induced taste aversion may be due to changes in body temperature, neural sensitivity, or elimination rate. Although alternative accounts cannot be entirely dismissed, this outcome suggests that ethanol-induced hypothermia plays a role in determining strength of conditioned taste aversion and thus may be involved in the regulation of oral ethanol intake in rats. Offprint requests to: C.L. Cunningham     

Schedule-controlled behavior as an index of the development and loss of ethanol tolerance in the rat

Twelve male Sprague-Dawley rats, following training on one of two food-motivated operant schedules (Fixed-Ratio 30 or Variable Interval 30 s), were exposed to an escalating regimen of daily ethanol (1.125–3.0 g/kg, IP) administration. This increasing dose regimen continued until the maximally tolerable dose for each subject was reached. Tolerance was then monitored for approximately 6 months by periodic ethanol challenge doses (1.5 g/kg). Dose-effect curves (DECs) were obtained prior to chronic ethanol (DEC1), immediately after ethanol tolerance development (DEC2), and 6 months (DEC3) following termination of ethanol exposure. At DEC1, ethanol produced dose-dependent decreases in rate on both schedules with no significant schedule differences in ED50 (the dose effective at reducing the maximal response rate by one-half) values. Maximal tolerance was achieved in means of 46 and 55 days on the VI and FR schedules, respectively. Differences in rate of tolerance acquisition on the initial dose of the chronic regimen (1.125 g/kg) account for most of the difference in the overall rate of acquisition. Comparison of the ED50 data from DECs 1 and 2 indicated that daily ethanol exposure resulted in a 2-fold decrease in ethanol sensitivity (i.e., tolerance) on both operant schedules. The ED50 data from DECs 1 and 3 demonstrated a 1.7-fold decrease in ethanol potency on DEC3. This duration of tolerance was considerably longer than that generally reported, and possibly related to the extended ethanol exposure and the sensitivity of operant schedules to drug effects.     

The role of associative factors in tolerance to the hypothermic effects of morphine in mice

Associative learning theories of drug tolerance emphasize the importance of stimuli which predict drug administration. One such model holds that drug tolerance is due to the development of a conditional response (CR) which is directionally opposed to the unconditional response (UCR) to the drug. By virtue of their opposing natures, the overlapping occurence of CR and UCR is seen as a diminished response, i.e., tolerance. The present experiments tested the predictions of this model using two doses of morphine, and included truly random controls to examine the role of excitatory and inhibitory conditioning in tolerance. Tolerance was greatest in mice administered morphine in the context of stimuli previously paired with drug administration, intermediate in random controls, and least or absent in mice administered the drug in the presence of cues paired with vehicle injections. No direct evidence of a compensatory CR which could offset morphine's hypothermic effect was obtained in placebo test sessions, nor was evidence for such a response obtained in cross-drug tests with amphetamine and apomorphine.     

Environmental context conditioning with ethanol reduces the aversive effects of ethanol in the acquisition of self-administration in rats

RATIONALE: Many recent theoretical approaches to drug-taking behavior feature a role for Pavlovian conditioning. Despite growing evidence for that role, the particular contributions of Pavlovian conditioning to self-administration are not clear. For example, few studies have addressed the effects of Pavlovian conditioning on the acquisition of self-administration. OBJECTIVES: The purpose of this study was to test the effect of Pavlovian conditioning with an environmental conditioned stimulus and an ethanol unconditioned stimulus on the acquisition of self-administration reinforced by ethanol. METHODS: Rats were either given ethanol by gastric gavage in a distinctive context or in their home cage. All animals were then trained to bar press on a variable interval schedule for a sweetened ethanol solution in the distinctive context. RESULTS: Animals that had received ethanol associated with the training context maintained a higher level of bar press behavior for ethanol as the reinforcing solution. This effect developed only after the first session and resulted from differences in response rates, but did not affect the rate of reinforcement. CONCLUSIONS: This study demonstrates that an environmental context signaling the effects of ethanol maintains a higher operant response rate when ethanol is used subsequently as a reinforcer. This finding replicates previous reports of Pavlovian conditioning effects on ethanol consumption. The specific pattern of results suggests that conditioned tolerance modifies the reinforcing impact of ethanol. Context conditioning with ethanol reduces the aversive impact of initial ethanol consumption and maintains the reinforcing value of the ethanol solution.     

Enhancement of pavlovian conditioned suppression by mild ethanol intoxication

Rats were trained to bar-press for food and then received aversive Pavlovian conditioning following low doses of ethanol (0–1600 mg/kg in different groups). They were tested for Pavlovian conditioned suppression of barpressing 48 h, 7 days, and 14 days later following no additional differential treatments. The results showed that very low doses of ethanol (approximately 200 mg/kg) during training enhanced later conditioned suppression, whereas more moderate doses (800–1600 mg/kg) disrupted Pavlovian conditioning. These results parallel earlier observations that very low ethanol doses enhance Pavlovian conditioned eyeblink and heart rate responses in rabbits, and suggest that facilitation of Pavlovian conditioning may be a general effect of mild ethanol intoxication.     

Assessment of ethanol's hedonic effects in mice selectively bred for sensitivity to ethanol-induced hypothermia

Mice selectively bred for sensitivity (COLD) or insensitivity (HOT) to the hypothermic effect of ethanol were tested in three tasks purported to assess ethanol's hedonic properties: place conditioning, taste conditioning, and ethanol drinking. In the place conditioning task, distinctive tactile (floor) stimuli were differentially paired with injection of ethanol (2.25 g/kg) or saline, and preference for the tactile stimuli was assessed during a choice test without ethanol. In the taste conditioning task, fluid-deprived mice were given repeated access to saccharin followed by injection of ethanol (2.25 g/kg). In the drinking task, mice were given access on alternate days to a single drinking tube containing water or ethanol in a concentration that gradually increased from 1 to 12% (v/v) over days. HOT mice showed greater conditioned preference for ethanol-paired tactile cues, greater aversion for ethanol-paired flavor cues, and drank less ethanol at concentrations above 5% than COLD mice. HOT mice also showed higher levels of ethanol-stimulated activity than COLD mice. Control experiments indicated that the lines did not differ in initial preference for the tactile and flavor stimuli used in the conditioning tasks. Because the same line differences were seen in mice selected from two genetically independent populations, these studies offer strong evidence of genetic correlations between ethanol's thermal effect and its effect on activity, place conditioning and taste conditioning. Evidence of a genetic correlation between ethanol's thermal effect and ethanol drinking, however, is weaker since it is based on a line difference observed in only one of the genetic replicates. In general, these findings suggest commonality in the biological mechanisms underlying ethanol's thermal effect and its effect in each behavioral task. This overall pattern of genetic correlations might indicate that these tasks measure the same motivational effect of ethanol.     

Effects of removing food on maintenance of drinking initiated by pairings of sipper and food

Two experiments evaluated the effects of removing food presentations on the maintenance of drinking induced by experience with sipper — food pairings. In Exp 1, ethanol drinking was induced in non-deprived Long-Evans rats by Pavlovian conditioning procedures employing an ethanol sipper as conditioned stimulus (CS) and food pellet as unconditioned stimulus (US). The Paired/Ethanol group received presentations of the ethanol sipper CS followed immediately by the response-independent presentation of the food pellet US. The Random/Ethanol group received the ethanol sipper CS and food US randomly with respect to one another. For both groups, the concentration of ethanol in the sipper CS [(3%, 4%, 6%, 8% (vol./vol.)] was increased across sessions, and, as in previous studies employing low concentrations of ethanol in non-deprived rats (i.e., maintained with free access to food in their home cages), the two procedures induced comparable levels of sipper CS-directed ethanol drinking. Removing food US presentations had no effect on sipper CS-directed ethanol drinking in either group. In Exp 2, groups of non-deprived Long-Evans rats were trained either with water or ethanol in the sipper CS paired with food US. Removing food US presentations had no effect on ethanol drinking in the Paired/Ethanol group, but water drinking in the Paired/Water group declined systematically across sessions. Results indicate that food US presentations contribute to the maintenance of water drinking but not to the maintenance of ethanol drinking. Implications for accounts of ethanol drinking based on Pavlovian sign-tracking, behavioral economics and intermittent sipper procedures are considered.     

Acquisition of behaviourally augmented tolerance to ethanol and its relationship to muscarinic receptors

Two groups of adult male rats were injected daily with ethanol (1.5 g/kg IP in 15% w/v solution) either before (the behaviourally augmented tolerant group) or after (the physiologically tolerant group) being placed in operant chambers. The control groups received daily isotonic saline injections either before or after the operant task. When challenged with ethanol (2.5 g/kg) on day 30 prior to the operant task, the control group was most impaired, while the behaviourally augmented tolerant group was significantly less impaired than the physiologically tolerant group. The two ethanol-treated groups were impaired to the same extent when challenged on day 60. Partial generalization of this behavioural tolerance to ethanol was observed, as the behaviourally augmented tolerant group was less impaired than the physiologically tolerant group for a tail flick response to painful stimuli after an ethanol challenge on day 30. However, the two ethanol-treated groups exhibited similar impairments of locomotor activity after an ethanol challenge on day 40. No differences in muscarinic receptor binding among the control and two ethanol-treated groups were found. These findings demonstrate that behaviourally augmented tolerance to ethanol may be partially generalizable but is unrelated to changes in muscarinic cholinergic receptors.     

Flavor preference conditioning by oral self-administration of ethanol

 Oral self-administration and operant tasks have been used successfully to confirm ethanol′s positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS–). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol’s efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS– in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol’s rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol’s nutrient and pharmacological effects both contributed to the development of conditioned flavor preference. Received: 15 February 1997 / Final version: 11 June 1997     

Effects of shock intensity on observed tolerance to decreased avoidance responding by clonidine

Interruption of a photobeam by rats was maintained under a Sidman avoidance schedule, and moderate response rates were maintained at low frequencies of electrical stimulation. After acute injections of clonidine, responding decreased, and frequency of electric stimulation increased, in a dose-dependent manner. At a lower intensity of electric stimulation, response-suppressive effects of clonidine did not diminish for up to 40 sessions with daily administration of clonidine. At a higher stimulus intensity, however, response-suppressive effects of clonidine diminished within 15 sessions, and stimulus frequency was at control level after 40 sessions with daily administration of clonidine. Behavioral consequences altered the effects of chronic clonidine so that tolerance was observed at a higher, but not a lower, intensity of electric stimulation.     

Stimulus and response factors affecting the development of behavioral sensitization to apomorphine

The present study was designed to assess the role of stimulus and response factors in the context-dependency of behavioral sensitization to the direct dopamine agonist apomorphine. In two experiments, male Wistar rats were given repeated injections of the direct dopamine agonist, apomorphine (5 mg/kg, SC), or vehicle at 24- to 72-h intervals and tested for locomotor activity for 30 min in either an openfield activity drum or a running wheel. In experiment 1, after eight activity sessions in either the activity drum or running wheel, one-half of the rats in each drug condition (apomorphine or vehicle) were tested in the alternate activity test environment. In both activity test environments, apomorphine produced progressively greater levels of locomotor activity with repeated treatment (i.e., sensitization). Moreover, sensitization to apomorphine transferred completely across test environments. That is, rats given apomorphine associated with one test environment (e.g., wheel) displayed equivalent sensitization when tested in the alternate environment (e.g., drum). Thus, changing external stimulus cues associated with repeated drug exposure did not affect the expression of sensitization. In experiment 2, rats were given either apomorphine or vehicle daily and tested for activity in a running wheel. For one-half the rats in each drug condition, the running wheel was free to move, but for the remainder the wheel was immobilized. After nine training sessions, all rats were given an apomorphine challenge injection and tested in a mobile wheel. After the challenge injection of apomorphine, rats previously treated with apomorphine and trained in the mobile wheel were significantly more active than rats previously treated with vehicle. In contrast, rats given equivalent apomorphine treatments and trained in the immobile wheel did not differ in activity from rats previously given only vehicle. Since the external stimulus cues associated with drug exposure for the mobile and immobile wheel groups were the same, this finding suggests that environmental factors affecting response expression are critical to the development of behavioral sensitization to apomorphine. Received: 20 March 1996/Final version: 4 October 1996     

Conditioned tolerance to the tachycardia effect of ethanol in humans

Human subjects were given a series of oral ethanol administrations in one environment and an equal number of placebo administrations in another distinct environment. Tolerance (a decreasing response with repeated administrations) to the tachycardia effect of ethanol was observed; no consistent changes in heart rate followed placebo administrations. Subsequently, tolerance to a test dose of ethanol administered in the environment normally associated with placebo was reduced relative to that in response to a dose administered in the usual ethanol environment. This demonstration of environment-specificity in a human drug tolerance experiment replicates previous reports from animal studies, and is interpreted according to a Pavlovian conditioning model of drug tolerance.     

Situational specificity of tolerance to decreased operant responding by morphine andl-nantradol

In one experiment, key pressing of rats was maintained under a fixed-ratio schedule of food presentation in a first daily session in one environmental situation, and interruption of a photobeam was maintained under a continuous shock avoidance schedule in a second daily session in another environmental situation. After receiving acute injections of the cannabinoidl-nantradol (0.01–0.3 mg/kg), rats received daily administration of a rate-decreasing dose of the drugafter the second session, thenbefore the second session, and thenbefore the first session. Tolerance that developed to decreased avoidance responding in the second daily session did not extend to decreased fixed-ratio responding in the first daily session, but was specific to circumstances coinciding with the pharmacological actions ofl-nantradol. In a second experiment, lever pressing of squirrel monkeys was maintained under an identical fixed-interval schedule of food delivery in two separate daily sessions in different experimental situations. After receiving once-weekly acute injections of morphine (0.3–3.0 mg/kg), monkeys received daily administration of a rate-decreasing dose of morphine in a counter-balanced orderbefore each session. Just as for experiment 1, tolerance that developed in the environment coinciding with the pharmacological actions of morphine did not immediately generalize to operants in the other environmental situation. Instead, tolerance depended on both pharmacologic action as well as concurrently operating behavioral processes.Animals used in this study were maintained in accordance with guidelines of the Animal Care Committee of the Worcester Foundation for Experimental Biology and of the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication Number (NIH)85-23, revised 1985     

Comparative effects of cathinone and amphetamine on fixed-interval operant responding: a rate-dependency analysis

The actions of dl-cathinone and d-amphetamine on operant responding were compared in rats. The effects of both drugs were predominantly suppressive on behaviour maintained by a Fixed Interval 2 minutes schedule of reward. Both drugs had equivalent durations of action in suppressing responding. The actions of the two compounds could be described as rate-dependent, although their rate-dependent actions could most parsimoniously be attributed to drug-induced rate constancy. Methysergide (10 mg/kg) had no significant differential effect on the response suppressant effects of the two compounds, even though in vitro studies have indicated that cathinone and amphetamine differ in their serotonin receptor affinity. The actions of cathinone were qualitatively similar to those of amphetamine in this behavioural test. Furthermore the observed potency ratio for dl-cathinone to d-amphetamine (1:3) was similar to that reported elsewhere in a range of other behavioural tests (anorexia, adipsia, drug-induced rotation, lethality) for this pair of isomers. The only major difference reported to date between the behavioural actions of cathinone and amphetamine relates to the unexpectedly weak potency of cathinone in the conditioned taste aversion procedure. Cathinone, the major active constituent of the Khat plant, is therefore a psychostimulant drug which may possess potent reinforcing properties by virtue of its amphetamine-like stimulant actions coupled with its very weak aversive properties.     

Effects of chronic phencyclidine on fixed-ratio responding: No relation to neurotransmitter receptor binding in rat cerebral cortex

The effects of chronic phencyclidine (3.2 mg/kg for 25 days) on responding maintained under a fixed-ratio 30 schedule of food presentation were studied in rats. Initially phencyclidine produced large decreases in the overall rate of responding. This decrease was due primarily to long pauses in responding and secondarily to a decrease in local rates of responding. Although tolerance developed to the rate-decreasing effects of phencyclidine in each subject, the extent and pattern of its development differed among the subjects. After the chronic drug regimen, the rats were sacrificed. Ligand binding to muscarinic cholinergic, opiate, adrenergic, and serotonergic receptors in cortex was then compared to that in rats which received saline with operant training, phencyclidine alone, or saline alone. Neither operant behavior alone, phencyclidine alone, nor the interaction of phencyclidine and operant behavior was found to alter binding to these receptors. The results indicate that behavioral tolerance develops to phencyclidine, but it is not accompanied by changes in binding to the receptors studied.     

Acquisition of behavioral tolerance to ethanol as a function of reinforced practice in rats

The roles of both reward and the amount of reinforced practice on the development of behavioral tolerance to ethanol were studied in 32 hooded rats in a Skinner-box situation. The effects of ethanol were evaluated on two aspects of the bar-press response (FR15): latency to complete 15 bar presses and proficiency to earn rewards. Results showed that the behavioral tolerance, as indicated by diminishing effects of ethanol on performances over repeated exposures, developed rapidly. The extent of the developed tolerance was greater and more stable in animals which had reinforced practice while under the influence of ethanol than in animals which had non-reinforced practice. Animals which were exposed to the same amount of ethanol but practiced the response in a nondrug state showed little sign of tolerance to ethanol. These findings give further support to a previous view that learning processes may be involved in acquisition of behavioral tolerance to ethanol.     

Effects of Pavlovian conditioning and MIF-I on the development of morphine tolerance in rats

Thirty male Sprague-Dawley-derived rats were given daily IP injections of morphine (5.0 mg/kg) in the presence of a specific set of environmental cues for eleven consecutive days. Twelve hours after each morphine session, a control injection was given in a different environment. On Day 12 through 14 the environmental cues associated with each session were reversed. On Day 15 environmental cues associated with each session were the same as on Days 1-11. Analgesia was assessed by the tail-flick method 30 minutes after each morphine and control injection. Four independent groups (n=6) received either a lower (0.1 mg/kg) or a higher (5.0 mg/kg) dose of MIF-I either 10 minutes before or immediately after each morphine and control session. A control group received an injection of a diluent vehicle both before and after each session. None of these peptide-treatments significantly affected either acute action of morphine or the development of tolerance across days. Tail-flick latencies from both morphine and control sessions significantly decreased across days. On Day 12, when morphine was administered in the presence of cues not previously associated with its administration, tail-flick latencies were significantly longer than on the previous day. Tail-flick latencies did not change from Day 11 to Day 15 during control sessions. Morphine-session latencies did not change from Day 14 to Day 15, although they did decrease from Day 12 to Day 14. The significant morphine-induced analgesia on Day 15 of the experiment increases a remarkable resistance to the development of tolerance to morphine. The results partially support the hypothesis proposed by Siegel [115-18] that principles of Pavlovian conditioning exert an important influence on the development of tolerance to morphine.     

Effects of delaying food availability contingent on ethanol-maintained lever pressing

The effects of delaying food availability 8 s contingent on every, every second, and every fourth lever press maintained by 4, 8, and 16% (v/v) ethanol solutions were examined when food was initially available to rats on a fixed-interval 26-s schedule. The delay contingency decreased ethanol-maintained responding at all ethanol concentrations, with the degree of decrease inversely related to the intermittency of the delay schedule and to the ethanol concentration. Such decreases were not evident in the performance of yoked-control animals which received food coincidentally with experimental animals. Temporal changes in food presentation alone therefore could not account for the decreases produced by the delay contingency.     

Pavlovian conditioning of morphine hyperthermia: assessment of interstimulus interval and CS-US overlap

The present study examined the effect of interstimulus interval on acquisition of conditioned thermal responses produced by trials in which a light/noise stimulus (CS) was repeatedly paired with infusion of morphine sulphate (US). Rats were implanted with a chronic intravenous catheter for drug delivery and a biotelemetry device for remote monitoring of core body temperature. In experiment 1, different groups received morphine either 0.5 (group P0.5) or 15 min (group P15) after onset of the 15-min CS. A third group was exposed to an identical number of CS and US presentations but in an explicitly unpaired manner (group UP). After repeated exposure to morphine, all groups showed a more rapid rise in body temperature in response to drug infusion. Test presentations of CS alone revealed conditioned hyperthermic responses to CS in groups P0.5 and P15. However, the response of the P15 group was smaller than that of the P0.5 group, suggesting weaker conditioning at the longer interstimulus interval. The contribution of CS-US overlap to the diminished associative strength observed in the P15 group was assessed in experiment 2. Groups P0.5/15 and P0.5/30 received infusions of morphine 0.5 min after onset of a 15- or 30-min CS, respectively. Group P15/30 received morphine 15 min after onset of a 30 min CS, whereas group UP/30 received explicitly unpaired presentations of the US and a 30-min CS. Enhancement of the hyperthermic effect of morphine was observed in all groups after ten conditioning trials. Test presentations of the CS without drug revealed that all paired groups had acquired conditioned hyperthermic responses. These results support the conclusion that drug-induced conditioning can occur at relatively long interstimulus intervals when there is sufficient temporal overlap between the CS and unconditioned response evoked by the drug US.