Methamphetamine-induced conditioned place preference or aversion depending on dose and presence of drug.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
C L Cunningham
Publications and source records attributed to C L Cunningham.
Ethanol produces rapid biphasic hedonic effects.
Explore the source record for details and available documents.
Analysis of Variance↗
Genetic differences in the rewarding and activating effects of morphine and ethanol.
The influence of genotype on the rewarding and locomotor activating effects of morphine and ethanol was examined in the place conditioning paradigm. Two inbred mouse strains (C57BL/6J and DBA/2J) were exposed to a differential conditioning procedure in which each mouse received four pairings of a distinctive floor stimulus with IP injection of morphine (0, 2.5, 5 or 10 mg/kg) or ethanol (0, 1, 2, 3 or 4 g/kg). A different floor stimulus was paired with saline. Conditioning trials lasted 30 min and each experiment concluded with a floor preference test in the absence of drug. In accord with previous studies, morphine evoked a dose-dependent increase in activity during conditioning that was greater in C57BL/6J mice than in DBA/2J mice. In contrast, ethanol produced a dose-dependent increase in activity that was greater in DBA/2J than in C57BL/6J mice. Both strains showed conditioned place preference with morphine, but only the DBA/2J strain showed conditioned place preference with ethanol. No conditioned place aversion was seen. With both drugs, stronger place preference conditioning was obtained in DBA/2J mice, supporting the general conclusion that sensitivity to drug reward is influenced by genotype. The fact that the same genotype is more sensitive to the rewarding effects of two different drugs supports theories postulating commonality in the biological mechanisms of drug reward. Although the outcome of the ethanol study supports predictions of the psychomotor stimulant theory of addiction concerning the relationship between drug-induced activation and reward, the outcome of the morphine study does not.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference.
This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP)+ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.
Animals↗
Context-drug pairings enhance tolerance to ethanol-induced disruption of operant responding.
Much of the research implicating learning in the development of tolerance to ethanol-induced impairment has used an experimental design in which different groups receive drug either before or after an opportunity to perform an instrumental or operant task. The stronger tolerance observed in subjects who perform while intoxicated is most often attributed to the reinforced practice of a learned compensatory response. Using an experimental procedure modeled after Chen (1979), the present study examined an alternative theoretical basis for tolerance in the before-versus-after design. Specifically, the effects of Pavlovian context-drug pairings were assessed under circumstances that precluded reinforced practice of the operant response. Three groups of food-deprived rats were initially trained to barpress for sucrose on an FR15 schedule. After 30 sessions, the bar was retracted and the dipper was covered for a 3-day tolerance acquisition phase. During this phase, each group received an IP injection 15 min before and 45 min after each session. The Paired group received ethanol (1.2 g/kg) before and saline after the session, thus pairing ethanol with cues of the test chamber. The Unpaired group received saline before and ethanol after the session, while the No-Drug group always received saline. During a final test phase, all groups received ethanol (1.5 g/kg) before access to sucrose on the FR schedule. The Paired group completed the first FR15 sequence more rapidly than either control group, indicating that context-ethanol pairings enhanced tolerance to the drug's disruptive effect on the initiation of operant responding.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Genetic differences in ethanol-induced hyperglycemia and conditioned taste aversion.
Genetic differences in the hyperglycemic response to acute ethanol exposure and ethanol-induced conditioned taste aversion were examined using inbred mice. Adult male C57BL/6J and DBA/2J mice were injected with ethanol (0-6 g/kg, I.P.) and blood glucose levels determined over 4 h. C57 mice demonstrated greater dose-dependent elevations in blood glucose compared to DBA mice. In a conditioned taste aversion procedure, water deprived mice received ethanol injections (1-4 g/kg, I.P.) immediately after access to a NaCl flavored solution. DBA mice developed aversion to the ethanol-paired flavor at a lower dose (2 g/kg) than C57 mice. These results provide further support for a possible inverse genetic relationship between sensitivity to ethanol-induced hyperglycemia and sensitivity to conditioned taste aversion.
Animals↗
Effect of Ro 15-4513 on ethanol-induced conditioned place preference.
The benzodiazepine receptor inverse agonist Ro 15-4513 reverses a number of ethanol's effects, including its reinforcing properties as measured through self-administration. The present study examined the effect of this putative ethanol antagonist in a place conditioning design that has been shown to be sensitive to ethanol's rewarding properties in mice. Using an unbiased differential conditioning procedure, DBA/2J mice received, on alternate days, pairings of a distinctive floor stimulus (CS+) with either ethanol (2 g/kg), Ro 15-4513 (3 mg/kg), or a combination of ethanol and Ro 15-4513. On alternate days, a different distinctive floor stimulus (CS-) was paired with vehicle. Under these conditions, ethanol produced a conditioned place preference that was unaffected by Ro 15-4513. Ro 15-4513 alone did not produce either a place preference or aversion. Ro 15-4513 did produce reductions in locomotor activity during conditioning, indicating it was behaviorally active. These results indicate that a dose of Ro 15-4513 that alters general activity does not affect ethanol reward.
Animals↗
Conditioned activation induced by ethanol: role in sensitization and conditioned place preference.
Previous studies of ethanol-induced activation and place preference conditioning have shown that repeated exposure to ethanol produces sensitization to ethanol's locomotor activating effect in mice. This experiment was designed to determine whether the behavioral sensitization to ethanol that occurs during place preference conditioning is due to development of a Pavlovian conditioned activity response. Mice (DBA/2J) in the experimental group (BEFORE) received four pairings of a distinctive floor stimulus with ethanol (2 g/kg, IP); a different floor stimulus was paired with saline (counterbalanced). Mice in two control groups were exposed equally to each floor stimulus and were handled and injected as often as experimental mice. One control group (AFTER) always received ethanol in the home cage 1 h after exposure to the floor stimulus, while the other control group (NO-DRUG) never received ethanol during conditioning. BEFORE group mice showed a significant conditioned place preference, whereas control mice did not. Activity tests after saline or ethanol indicated higher activity levels in BEFORE mice compared to control mice, regardless of floor stimulus. Moreover, BEFORE mice were more active on their CS+ floor than on their CS- floor during saline tests; activity was equally elevated on both floors during ethanol tests. These results support the hypothesis that sensitization to ethanol's activating effect is mediated by Pavlovian conditioning. Further, they suggest that place conditioning established-associative control by two kinds of stimuli; the specific tactile cues serving as CS+ and CS- and the general environmental cues common to both CS+ and CS- trials.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ambient temperature effects on taste aversion conditioned by ethanol: contribution of ethanol-induced hypothermia.
Six experiments examined the effects of low (5-10 degrees C), normal (21 degrees C), or high (32 degrees) ambient temperature on conditioned taste aversion and body temperature changes produced by ethanol, lithium chloride, or morphine sulfate. Fluid-deprived rats received five to seven taste conditioning trials at 48-hr intervals. On each trial, access to saccharin at normal ambient temperature was followed by injection of drug or saline and placement for 6 hr into a temperature-controlled enclosure. Exposure to low ambient temperature facilitated, whereas exposure to high ambient temperature retarded acquisition of ethanol-induced conditioned taste aversion. The ability of an alteration in ambient temperature to influence conditioned taste aversion varied as a function of ethanol dose and was related to ambient temperature's effect on ethanol-induced hypothermia. More specifically, strength of conditioned taste aversion was negatively correlated with core body temperature after ethanol injection. Alterations in ambient temperature alone did not affect ingestion of a paired flavor solution in the absence of drug. Moreover, alterations in ambient temperature did not appear to influence conditioned taste aversion by changing ethanol pharmacokinetics. Finally, high and low ambient temperature did not affect development of taste aversion conditioned by lithium chloride or morphine sulfate. The overall pattern of data presented by these experiments supports the hypothesis that ambient-temperature influences strength of ethanol-induced conditioned taste aversion by altering the hypothermic response to ethanol. More generally, these data support the suggestion that body temperature change induced by ethanol is related to ethanol's aversive motivational effects and may be involved in modulating ethanol intake.
Animals↗
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 flavor cues, and 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. (ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol Drinking↗
The relationship between ethanol-induced hyperglycemia and hypothermia: evidence of genetic correlation.
The hyperglycemic and hypothermic responses to acute ethanol exposure (0, 2, 4, 6 g/kg, intraperitoneally) were examined in non-fasted mice selectively bred for sensitivity (COLD line) or insensitivity (HOT line) to ethanol-induced hypothermia. Blood samples and rectal temperatures were obtained immediately before injection and hourly for 4 hr after injection. As expected, COLD mice demonstrated greater and more prolonged reductions in body temperature than HOT mice, especially at the 4 g/kg dose (HOT: -2.58 degrees C, COLD: -5.08 degrees C). Ethanol produced significant dose-dependent elevations in blood glucose levels over the 4-hr sampling period in both lines. The greatest elevations in blood glucose levels were seen at 4 g/kg, with COLD mice (mean = 225.1 mg/dl) showing significantly greater elevations in blood glucose levels compared to HOT mice (mean = 177.0 mg/dl). These results support the hypothesis that the thermic and glycemic effects produced by ethanol are due to related neural processes that share a common genetic component.
Animals↗
Conditioned stimulus control of morphine hyperthermia.
Classical conditioning of morphine hyperthermia was examined using an explicit conditioned stimulus (CS) paired with intravenous (IV) morphine administration. Rats were implanted with a jugular vein cannula and a biotelemetry device for monitoring body temperature. The animals were housed 24 h/day in the chambers in which all testing occurred. The CS was a 15-min light/noise stimulus. The unconditioned stimulus (US) was an infusion of morphine (5 mg/kg). Rats were assigned to either the Paired group, which received morphine with the CS, or the Unpaired group, which received explicitly unpaired presentations of the CS and US. The CS-morphine pairings resulted in development of a conditioned hyperthermic response in the Paired group evoked by the CS in the absence of morphine. The development of morphine hyperthermia was more rapid in the Paired group in the presence of the CS than in its absence in the same group and more rapid in the Paired group than in the Unpaired group during the CS. These results clearly show that learning affects the response to morphine administered repeatedly. In contrast to previous studies, conditioned hyperthermia was elicited within 15 min by a discrete CS in a situation where the response was not confounded by handling or the stress of injection.
Animals↗
Thermoregulation and performance of heat-reinforced autoshaped keypecking in chicks.
Performance of autoshaped keypecking reinforced by heat was found to increase and then to decrease when chicks were exposed to training under a constant thermal load on a daily basis over the first 1-2 weeks after hatching. The decline in performance was not affected by variation in US duration (Experiment 1). No decline in performance was observed when food reinforcement was used (Experiment 2), suggesting that the effect depended on the use of thermal motivation. When thermoregulation was disrupted by pharmacological blockade using propranolol hydrochloride (10 mg/kg), keypecking was reinstated (Experiment 3). The increase in keypecking produced by propranolol was not due to a nonspecific energization of behavior inasmuch as the drug depressed autoshaped keypecking established with food reinforcement (Experiment 4). These findings support the conclusion that the decline in autoshaped keypecking reinforced by heat is due to development of the chick's thermoregulatory system. Various physical changes (e.g., feathering) and the increasing effectiveness of autonomic and behavioral thermoregulatory responses reduce the net motivational value of external heat sources, thus leading to a decline in the likelihood of approach and contact with signals for heat.
Age Factors↗
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 degrees 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.
Animals↗
Tolerance and sensitization to the heart-rate effects of morphine.
The effect of daily exposure to one of several doses of morphine (0, 2.0, 4.0 and 8.0 mg/kg IV) on heart rate was assessed in restrained (R) and unrestrained (U) rats. Initially, morphine produced a biphasic heart-rate response; bradycardia followed by tachycardia. Tolerance to the bradycardic effect was established in the 4 and 8 mg/kg U groups and in the 2 and 4 mg/kg U groups. Sensitization developed to the tachycardic effect in the 2 and 4 mg/kg U groups but not in the 8 mg/kg U group or any of the R groups. After several exposures to morphine, mean preinfusion heart rate increased in the 4 and 8 mg/kg dose groups but not in the 0 and 2 mg/kg dose groups. These results are generally consistent with the other data suggesting that tolerance develops only to the depressant effects of morphine, and either no change or sensitization develops to its stimulant effects. The development of higher preinfusion heart rates in the higher dose groups may represent a learned anticipatory response.
Animals↗
Stress and ethanol-induced hypothermia.
Three experiments examined the effects of three stressors on the hypothermic response to IP injection of ethanol in rats. Although all three stressors elicited hyperthermia in the absence of ethanol, only electric footshock reduced ethanol hypothermia. Handling/rectal-probing and bright, flashing light enhanced ethanol hypothermia. Type of cage floor (solid vs. grid) affected overall magnitude of ethanol hypothermia, but did not affect handling-induced enhancement of ethanol hypothermia. It is suggested that events which trigger release of endogenous opioids may enhance ethanol hypothermia. This kind of ethanol-stress interaction has important implications for studies of the acute and chronic effects of ethanol, including studies of learned tolerance. It may also have implications for understanding the impact of stress on voluntary consumption of ethanol.
Animals↗
Effects of restraint and naltrexone on the biphasic heart rate response to morphine in rats.
The effect of several doses of morphine (0, 0.5, 2, 5 or 10 mg/kg, i.v.) on heart rate was assessed in restrained and freely-moving rats. Morphine produced a dose-dependent bradycardia followed by tachycardia. The magnitude and duration of bradycardia were greater in restrained rats, whereas the magnitude and duration of tachycardia were greater in unrestrained rats. Naltrexone (5 mg/kg) pretreatment completely blocked the biphasic heart rate response to morphine (8 mg/kg). When naltrexone was given after the bradycardic portion of the response, tachycardia declined to baseline levels. These results suggest that one or both components of the biphasic response are mediated by opioid receptors.
Animals↗
Stress enhances the development of tolerance to the hypothermic effect of ethanol.
Handling procedures used for body temperature measurement in rats, such as repeated rectal probing during restraint, raise body temperature in a manner similar to other stressors. Thus, the common use of this procedure to monitor temperature may actually obscure the results of experiments measuring the acute and chronic effects of alcohol. In the present experiment, temperature was continuously monitored with implanted biotelemetric sensors, thus eliminating the need for repeated stressful handling. Handling stress was found to interact with the effects of ethanol intoxication to augment the initial hypothermic effect of ethanol. Moreover, the rate and extent of tolerance development to ethanol-induced hypothermia was enhanced.
Animals↗