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PubMed1989

Opiate antagonists and self-stimulation: extinction-like response patterns suggest selective reward deficit.

The present study investigated the response decrement patterns produced by opiate antagonists on intracranial self-stimulation behavior, in order to determine if these drugs affect the reinforcement value of the stimulation or interfere with the ability of the animal to respond. Male rats lever-pressed in 60-min sessions on a continuous reinforcement schedule for self-stimulation of the nucleus accumbens. Naloxone (2.0 and 20 mg/kg) and naltrexone (2.0 and 20 mg/kg) suppressed self-stimulation only after a significant delay, in an extinction-like response decrement pattern, mimicking the effects of reductions in current intensity (75% and 50% of baseline). The increasing behavioral effects characteristic of the extinction pattern were observed despite the fact that testing began after the time point at which maximal suppression of self-stimulation occurs with these drugs, and when brain concentrations of these drugs were declining. Since normal responding was observed for several minutes after the beginning of the session, the results may explain why long sessions are necessary to observe suppression of self-stimulation by opiate antagonists. The extinction-like pattern produced by these drugs suggests that opiate antagonists suppress self-stimulation by reducing the reinforcement value of the stimulation, rather than by interfering with the ability of the animal to respond. These findings are consistent with a role for endogenous opioid peptides in brain stimulation reward.

Animals↗
PubMed1993

Generalization of a tactile stimulus in horses.

Using horses, we investigated the control of operant behavior by a tactile stimulus (the training stimulus) and the generalization of behavior to six other similar test stimuli. In a stall, the experimenters mounted a response panel in the doorway. Located on this panel were a response lever and a grain dispenser. The experimenters secured a tactile-stimulus belt to the horse's back. The stimulus belt was constructed by mounting seven solenoids along a piece of burlap in a manner that allowed each to provide the delivery of a tactile stimulus, a repetitive light tapping, at different locations (spaced 10.0 cm apart) along the horse's back. Two preliminary steps were necessary before generalization testing: training a measurable response (lip pressing) and training on several reinforcement schedules in the presence of a training stimulus (tapping by one of the solenoids). We then gave each horse two generalization test sessions. Results indicated that the horses' behavior was effectively controlled by the training stimulus. Horses made the greatest number of responses to the training stimulus, and the tendency to respond to the other test stimuli diminished as the stimuli became farther away from the training stimulus. These findings are discussed in the context of behavioral principles and their relevance to the training of horses.

Animals↗
PubMed1994

Dopamine receptor density, sensitivity and mRNA levels are altered following self-administration of cocaine in the rat.

The effects of cocaine administration and withdrawal on D1 and D2 dopamine receptor number, affinity, and mRNA levels were examined in rats trained to self-administer cocaine for four weeks on a continuous reinforcement schedule. Two hours after the last infusion of cocaine there was a decrease in the number and agonist sensitivity of dopamine D1 receptors in the anterior forebrain as well as in the limbic region. In contrast, there were no discernible changes in dopamine D2 receptors in any of the brain regions examined. Examination of dopamine receptor gene expression using Northern blot analysis revealed that there was an increase in D1 receptor mRNA levels in the forebrain, whereas D1 and D2 receptor mRNA levels both were increased in the limbic region. One week following the last infusion of cocaine, D1 and D2 receptor mRNA levels had returned to baseline. In the limbic region, D1 receptor numbers also had normalized by this time, whereas in the forebrain, changes in D1 receptors persisted. These data indicate that repeated exposure to cocaine induces regional changes in D1 receptor sensitivity and gene expression, suggesting that the D1 dopamine system plays an important role in mediating the reinforcing effects of cocaine.

Animals↗
PubMed1998

A novel method for self-administering addicting drugs intracerebroventricularly in a free-choice procedure.

This paper describes a safe method for long term intracerebroventricular (i.c.v.) drug administration. Employing a non-preferred lever to control the self-administration the technique offers advantages over existing experimental methods. To check for any innate preference for one of two levers, male Wistar rats were allowed during the training procedure, to press two levers (L1 and L2) for one hour/day to obtain water as reinforcer for one week in a continuous reinforcement schedule (CRF). One week after surgery, during which a double-guide stainless steel cannula was inserted into both lateral ventricles, rats received 2 microliter of sterile cerebrospinal fluid (CEPH) each time they pressed one of two levers during the daily one-hour session. When a stable baseline was reached, rats were divided into three groups on the basis of their lever preference, and submitted to the testing procedure. A potent mu-opiate receptor agonist, etonitazene (0.1-0.2-1 microgram/infusion), was always associated with the non-preferred lever for each rat. When no obvious preference was shown for either lever the opiate was firstly delivered by L1(for 11 days) and then by L2 (for 20 days). The results indicate that, regardless of which lever had been preferred initially, the rats increased the pressing of only the lever associated with the opiate. The daily amount taken increased linearly and was behaviorally active. This model highlights for the first time the reinforcing properties of drugs given i.c.v. in a free-choice situation.

Analgesics, Opioid↗
PubMedDate not supplied

Ethanol as an oral reinforcer in normal weight rhesus monkeys: dose-response functions.

Responding maintained by orally delivered ethanol was studied in three adult male rhesus monkeys with no previous drug-taking histories. The subjects had continuous access to water throughout the study and were fed sufficient food to maintain a positive caloric balance. During daily 3-h experimental sessions, ethanol solution and water were concurrently available under fixed-ratio reinforcement schedules from two liquid delivery systems that were mounted symmetrically on the side of the monkeys' cages. The positions of the ethanol and water alternated daily. A range of ethanol doses (1%, 2%, 4%, 5.7%, 8%, 11.3%, 16%, 22.7, and 32% w/v) was tested in ascending and descending order. Changes in concentration were made after six consecutive stable sessions. Generally, the number of ethanol deliveries increased and then decreased as the ethanol concentration was raised (an inverted U-shaped function). For two of the monkeys, ethanol deliveries exceeded water deliveries at concentrations from 1.0% to 5.7% w/v, whereas for a third monkey ethanol solution was preferred to water at concentrations as high as 16% w/v. Ethanol intake (g/kg) tended to increase linearly and then flatten as the concentration was raised. Blood ethanol levels, measured immediately following sessions in which 8% w/v ethanol was available, ranged from 45 to 146 mg/dl. Although no special training or acquisition procedures were used to establish responding, ethanol functioned as a reinforcer for each of the monkeys tested.

Animals↗
PubMed2003

Prior exposure to phencyclidine decreases voluntary sucrose consumption and operant performance for food reward.

Prior exposure to the psychotomimetic drug phencyclidine (PCP) produces a number of schizophrenia-like behaviors in animals. The goal of the present study was to determine whether prior exposure to PCP produces decreased reward function, thereby modeling one aspect of negative schizophrenic symptomatology. To this aim, the consequences of prior exposure to PCP were assessed on two types of appetitive consumptive behavior. In the first set of experiments, the effects of PCP (15 mg/kg, 20 h before testing) on sucrose consumption were tested for three consecutive days under conditions of deprivation and nondeprivation. In the deprivation condition, animals were water deprived for 4 h prior to injection of PCP or saline (SAL). Twenty hours following the injection (24 h after the onset of water deprivation), animals were allowed access to either 5% sucrose or water for 30 min. In the nondeprivation condition, 5% sucrose consumption was measured for 30 min, 20 h after PCP or SAL injection and water consumption was measured during the 23.5 h preceding sucrose consumption. PCP decreased both sucrose and water consumption under deprivation conditions on the second and third day of testing but selectively decreased sucrose consumption under nondeprivation conditions on all three testing days. LiCl (50 mg/kg, 20 h before testing) did not significantly reduce sucrose consumption in the nondeprivation paradigm, indicating that the effect of PCP was not due to conditioned taste aversion. In the second experiment, PCP (15 mg/kg, 20 h before testing) decreased operant performance when animals were switched from a continuous reinforcement schedule of food delivery to a fixed ratio (FR4) schedule. Apomorphine (APO, 30 microg/kg, 30 min before testing), a positive control, induced a similar performance deficit. However, the PCP-induced deficit was not apparent until the third day of FR4 testing while the APO deficit was apparent on the first day. The effects of PCP on sucrose consumption demonstrate PCP-induced decreases in reward function. However, the delayed appearance of the PCP-induced decrease in operant performance suggests that these results may be better explained by a PCP-induced attentional deficit, also characteristic of schizophrenic psychopathology.

Animals↗
PubMed2006

A comparison of the effects of psychotomimetics and anxiolytics on punished and unpunished responding maintained by fixed interval schedules of food reinforcement in the rat.

Characterization of anxiolytic drugs often employs conflict paradigms in which the drug effects on punished and unpunished responding can be compared. In this study, a fixed interval schedule generating a range of baseline response rates allowed comparison of the effects of anxiolytic drugs with those of psychotomimetic drugs on equivalent and differing rates of punished and unpunished responding. The first response made by the rat after a 40-s fixed interval elapsed resulted in food pellet delivery. In punished intervals, signalled by the illumination of stimulus lamps above each lever, a 0.6-mA shock was delivered after every 20th response, resulting in a lower rate of responding than that in the unpunished intervals. Three psychotomimetic agents, D-amphetamine, MK801 and DOI were compared with the anxiolytics chlordiazepoxide, NS2710 and pregabalin. The three psychotomimetics preferentially increased rates of unpunished responding compared with those of punished responding. Chlordiazepoxide, NS2710 and, to a lesser extent, pregabalin increased rates of both unpunished and punished responding. In comparison studies, yohimbine also increased rates of both unpunished and punished responding whereas the antidepressant citalopram had no effect. In conclusion, stable baseline performance over many months allowed the direct comparison of several different drugs in the same subjects with no need to adjust shock levels or equate baseline response rates. The drugs had systematic and replicable effects in this procedure, which, in the case of amphetamine and chlordiazepoxide, were similar to those in other species, and psychotomimetic drugs could clearly be distinguished from anxiolytic drugs. The procedure, however, has limited value for characterizing novel anxiolytic agents as the examples used here increased punished and unpunished responding to the same extent, and were indistinguishable in that regard from the clinically anxiogenic agent, yohimbine.

Amphetamines↗
PubMed1963

Effects of chlorpromazine and d-amphetamine on escape and avoidance behavior under a temporally defined schedule of negative reinforcement.

Chlorpromazine hydrochloride and d-amphetamine sulphate were administered to two rats responding on a baseline temporally defined schedule of negative reinforcement which produced both "escape-like" and "avoidance-like" behavior. The effects of these drugs appeared similar to those expected on the more customary sort of non-cued avoidance schedule.

Amphetamine↗
PubMed2005

Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats.

RATIONALE: Stress and depression have been linked to relapse of cocaine abuse. Antagonism of the kappa opioid receptor (KOR) has been reported to attenuate some effects of stressors, and antagonism of the KOR has been reported to have antidepressant-like properties. OBJECTIVES: Our objective was to determine whether the potent and selective KOR antagonist, (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), can reduce the ability of a stressor (intermittent footshock) to reinstate cocaine-seeking behavior and to have antidepressant-like effects in the forced swim test (FST). METHODS: Male Long-Evans hooded rats were trained to lever-press, reinforced with 0.5 mg/kg i.v. infusion of cocaine, according to fixed ratio 1 reinforcement schedules during daily 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions, and doses of 0 (vehicle), 3, 10, and 30 mg/kg JDTic were then administered i.g. to separate groups of 12 rats. Twenty four hours later, the rats were given 15 min of intermittent footshock (0.87 mA, 0.5 s activation time, average inter-activation interval of 40 s) or a 17-mg/kg i.p. administration of cocaine prime followed by a 2-h reinstatement test session. JDTic was also evaluated for its ability to block diuresis induced by the KOR agonist, U50,488H (10 mg/kg, s.c.), during 5-h test sessions beginning 1 h after footshock reinstatement tests to verify its KOR antagonist activity. In the FST, male Sprague-Dawley rats were treated with either nor-binaltorphimine (nor-BNI) or JDTic (both at 0.3, 1, 3, or 10 mg/kg, injected s.c. 23 h before), or desipramine (5.6, 10, or 17 mg/kg, injected i.p. 23, 5, and 1 h before) and placed in a cylinder of water, during which the predominance of immobility, swimming, and climbing were scored during 5-s intervals for 5 min. RESULTS: The 10- and 30-mg/kg doses of JDTic significantly reduced footshock-induced reinstatement of responding previously reinforced by cocaine and significantly attenuated U50,488H-induced diuresis. In contrast, JDTic did not affect cocaine-prime-induced reinstatement. Both nor-BNI and JDTic decreased immobility and increased swimming time in the FST, similar to the antidepressant desipramine. CONCLUSIONS: Depression and stress are two states during cocaine abstinence which users identify as precipitating relapse, and JDTic may have properties which attenuate both.

Administration, Oral↗
PubMed1997

A sucrose-based maintenance diet increases sensitivity to appetite suppressant effects of naloxone.

Rats maintained under restricted access to food (but at 100% free-feeding weights) received one of two diets in their home cages: a palatable sucrose-based diet, or regular chow (grain based diet), and could respond for either sucrose- or grain-based reinforcers under an FR 40 reinforcement schedule (crossover design). Naloxone (0, 0.1, 0.3, 1.0, and 3.0 mg/kg) was more potent in reducing operant-chamber responding in rats maintained on a sucrose-based diet in their home cages than those fed a grain-based diet, regardless of the type of pellets available in the operant chambers. Whereas naloxone decreased response rate over the session, it had no effect on initiation of responding. Results support the hypothesis that opioids are involved in the maintenance, but not the initiation of consummatory behavior. Furthermore, increased potency of naloxone following chronic ingestion of palatable food is similar to that observed following chronic opiate administration, suggesting a relationship between palatability and opioids.

Animals↗
PubMed2004

Deprivation of parenting disrupts development of homeostatic and reward systems in marmoset monkey offspring.

BACKGROUND: Early environment is a major determinant of long-term mental health, evidenced by the relationship between early-life neglect or abuse and chronically increased vulnerability to developmental psychopathology, including major depressive disorder (MDD). Animal studies can increase understanding of environmentally mediated causal risk processes. We describe how daily deprivation of biological parenting in primate infants disrupts development of homeostatic and reward systems central to MDD. METHODS: Nine breeding pairs of marmoset monkeys provided control twins (CON) and early-deprived twins (ED); the latter were socially isolated for 30-120 min/day on days 2-28. During the first year of life, basal urinary norepinephrine (NE) titers and cardiophysiologic activity were measured. At the end of year 1 (adolescence), automated neuropsychologic tests were conducted to measure responsiveness to changes in stimulus-reward association (simple/reversed visual discrimination learning) and to reward per se (progressive ratio [PR] reinforcement schedule). RESULTS: The ED monkeys exhibited increased basal urinary NE titers and increased systolic blood pressure relative to CON siblings. The ED monkeys required more sessions to reinstate stimulus-oriented behavior following reversal, suggesting increased vulnerability to perceived loss of environmental control; ED monkeys also performed less PR operant responses, indicating that reward was less of an incentive and that they were mildly anhedonic relative to CON. CONCLUSIONS: In marmoset monkeys, neglect-like manipulation of ED leads to chronic changes in homeostatic systems, similar to those in children and adolescents exposed to early-life adversity and in MDD, and to responses to environmental stimuli similar to those that characterize MDD.

Animals↗
PubMedDate not supplied

Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats.

Five Long-Evans hooded rats were trained to lever press according to fixed-ratio 5 reinforcement schedules for 0.06 ml dipper deliveries of 8% w/v ethanol during daily (M-F) 0.5-h experimental sessions. After ethanol self-administration was established, doses of the serotonin 5-HT3 antagonists, ondansetron (0.03-3.0 mg/kg), granisetron (0.01-1.0 mg/kg), and SC-51296 (0.1-10.0 mg/kg) were administered prior to ethanol sessions to determine their effects on ethanol self-administration. None of the doses of the antagonists had significant effects on numbers of obtained ethanol deliveries. Subsequently, each antagonist (ondansetron, 0.1 mg/kg; granisetron, 0.3 mg/kg; SC-51296, 0.1 mg/kg) was administered b.i.d. for five consecutive daily sessions. During none of these chronic tests with the 5-HT3 antagonists were there significant main effects of drug administration. Overall, these results do not support the hypothesis that the serotonin 5-HT3 antagonists would have robust therapeutic efficacy in the treatment of alcoholism.

Alcoholism↗
PubMed2005

Ionotropic glutamate receptors in the ventral tegmental area regulate cocaine-seeking behavior in rats.

Drug addiction is characterized by compulsive drug-seeking and drug-taking behavior and by a high rate of relapse even after long periods of abstinence. Although the mesocorticolimbic dopamine (DA) pathway is thought to play a critical role in drug craving and relapse, recent evidence also implicates glutamate, an amino acid known to activate DA neurons in the ventral tegmental area (VTA) via ionotropic receptors. To assess whether increased glutamate transmission in the VTA is involved in cocaine-primed drug-seeking behavior, we tested rats in a between-session reinstatement model. They were trained to press a lever for cocaine infusions (0.25 mg/infusion) accompanied by compound stimuli (light and tone) under a modified fixed-ratio 5 reinforcement schedule. Cocaine-primed reinstatement was conducted after lever pressing was extinguished in the absence of the conditioned stimuli. Blockade of ionotropic glutamate receptors in the VTA by local application of kynurenate (0.0, 1.0, 3.2, and 5.6 microg/side) dose-dependently decreased cocaine-primed reinstatement, whereas sucrose-primed reinstatement of sucrose-seeking behavior was unaffected. In addition, the minimum effective dose for decreasing cocaine-primed reinstatement was ineffective in the substantia nigra. Together, these data indicate that glutamatergic activation of the VTA is critical for cocaine-primed reinstatement. Because such activation can increase impulse flow in DA neurons and thus DA release in mesocorticolimbic targets, this glutamate-DA interaction in the VTA may underlie cocaine-primed relapse to cocaine-seeking behavior.

Analysis of Variance↗
PubMed1994

Electrophysiological and pharmacological evidence for the role of the nucleus accumbens in cocaine self-administration in freely moving rats.

The goal of this study was to clarify the role of the nucleus accumbens septi (NAS) in the expression of cocaine self-administration behaviors. Rats were trained in a continuous reinforcement schedule to press a lever to activate a pump that provided an intravenous injection of cocaine. Once the rats were trained, neuronal activity in the NAS was monitored during cocaine self-administration with chronic recording techniques using permanently implanted microwires. In the NAS, 19% of 181 neurons exhibited either increased or decreased firing rates seconds prior to lever pressing (termed "anticipatory responses"), and 48% had altered, predominantly decreased, firing rates for a few minutes after lever pressing ("postcocaine responses"). Two-thirds of the neurons with anticipatory responses had postcocaine responses. Neurons with either of these response patterns were localized histologically to both core and shell regions of the NAS, with no statistically significant differences in the proportion of response types in either area. Analysis of videotaped cocaine self-administration behaviors revealed that anticipatory responses were specifically associated either with the animal orienting toward and pressing the lever or only with movements directly related to pressing the lever. Anticipatory-like phasic spike activity was not observed during similar movements unrelated to lever pressing. In some animals, D1 (SCH 23390) or D2 (pimozide) receptor antagonists were injected systemically prior to or during self-administration sessions to assess the effects of dopamine receptor blockade on anticipatory and postcocaine responses. Each antagonist, given separately, often produced extinction of lever pressing. Both antagonists blocked the post-cocaine inhibitory response of neurons that had anticipatory responses. Neither antagonist modified anticipatory unit responses, nor did they affect postcocaine inhibitory responses in neurons that did not exhibit anticipatory responses. Taken together, these results suggest that the role of the NAS in cocaine self-administration may consist of two different mechanisms: (1) An initiation or trigger mechanism, as represented by the anticipatory neuronal responses, in which the NAS participates in triggering or mediating the goal-directed behaviors (e.g., lever pressing) that lead to the acquisition of the reinforcing agent (e.g., cocaine).(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1966

The reinforcement of least-frequent interresponse times.

A new schedule of reinforcement was used to maintain key-pecking by pigeons. The schedule reinforced only pecks terminating interresponse times which occurred least often relative to the exponential distribution of interresponse times to be expected from an ideal random generator. Two schedule parameters were varied: (1) the rate constant of the controlling exponential distribution and (2) the probability that a response would be reinforced, given that it met the interresponse-time contingency. Response rate changed quickly and markedly with changes in the rate constant; it changed only slightly with a fourfold change in the reinforcement probability. The schedule produced stable rates and high intra- and inter-subject reliability, yet interresponse time distributions were approximately exponential. Such local interresponse time variability in the context of good overall control suggests that the schedule may be used to generate stable, predictable, yet sensitive baseline rates. Implications for the measurement of rate are discussed.

Animals↗
PubMed1984

The effects of quipazine and fluoxetine on extinction of a previously-reinforced operant response in rats.

Previous studies have shown that treatments that reduce serotonergic neurotransmission lead to enhanced responding during extinction. To evaluate the generality of this effect, the present study examined the effects of the serotonin agonists, quipazine and fluoxetine on responding in extinction. In Experiment 1, 72 rats were trained to lever press on a continuous reinforcement schedule for 5 30-min sessions. Four sessions of extinction followed; 30-min prior to each, 3 groups (n = 16) received quipazine (0, 1.0, 5.0 mg/kg) and 3 groups (n = 8) received fluoxetine (0, 1.0, 5.0 mg/kg). The 5.0 mg/kg dose of quipazine resulted in a significant reduction in responding on day 1; the lower dose of quipazine and both doses of fluoxetine were without significant effect. In Experiment 2, 3 similarly trained groups (n = 8) received either saline or quipazine (5.0 mg/kg) prior to each extinction session; additionally, one quipazine group was injected twice with the 5.0 mg/kg dose in its home cage several days before the beginning of extinction. The results of the drug-naive quipazine group replicated those of that group from Experiment 1 whereas the drug-experienced group showed no significant effect of quipazine in extinction. The results suggested that prior drug experience could modify the effects of quipazine on behaviour. Apart from this drug novelty effect the lack of significant effect of either quipazine or fluoxetine suggested that the effects of manipulations believed to increase and decrease serotonin functioning on responding in extinction may not be symmetrical. These results may be understood with reference to the hypothesis that serotonin plays a role in tuning out or reducing responsiveness to nonreinforced or irrelevant stimuli.

Animals↗
PubMed1997

Neuronal responses in prefrontal cortex and nucleus accumbens during heroin self-administration in freely moving rats.

Chronic multi-channel single unit recordings of neuronal responses in prefrontal cortex (PFC) and nucleus accumbens (NAc) were made in 9 male Sprague Dawley rats to determine patterns of neuronal activity during heroin self-administration. Up to 32 neurons were recorded simultaneously in these two brain regions while rats lever pressed on a continuous reinforcement schedule for intravenous infusion of heroin (30 microg/kg/infusion). The variety of neuronal responses observed before and after each self-administered heroin infusion can be classified according to the following categories: (1) neurons that increased or (2) decreased their activity immediately before the lever press; (3) neurons that increased or (4) decreased their activity after the heroin infusion; and, (5) neurons that did not alter their activity either before or after the lever press for heroin infusion. The majority (69% in the PFC and 65% in the NAc) of neurons sampled fell into this last category of no change, indicating that a selected fraction becomes active during this specific task. In general, NAc neurons displayed more post-heroin responses than PFC neurons while the proportion of neurons showing responses before the lever press was similar in the mPFC and the NAc. This initial description of the responses of PFC and NAc neurons during heroin self-administration suggests that the neuronal circuit of the mesocorticolimbic system is involved in heroin self-administration. This circuit appears to contribute both to the initiation of drug-seeking behavior (pre-lever press phasic neuronal responses), as well as the action of heroin infusion itself (post-infusion phasic neuronal responses) by activation of different subsets of neurons.

Analysis of Variance↗
PubMed2000

Delta-opioid and 5-HT3 receptor antagonist effects on ethanol reward and discrimination in C57BL/6 mice.

The effects of the receptor antagonists MDL 72222 (MDL, 5-HT3) and naltrindole (delta-opioid) on ethanol reward and its discrimination were examined in ethanol-preferring C57BL/6 (C57) mice. MDL attenuated lever responding for 12% ethanol delivered on a fixed-ratio 8 reinforcement schedule at a dose that did not influence responding for water reward, thus confirming a previous report that ICS 205-930 reduced ethanol reward for Long-Evans rats. Our study in combination with the reduced ethanol consumption reported for C57 mice injected with odansetron indicates that 5-HT3 receptor systems are involved in mediating behavior directed toward obtaining ethanol as well as its consumption. By attenuating the rewarding effects of ethanol or of ethanol conditioned cues (e.g., the operant environment), 5-HT3 antagonists may be useful in the treatment of alcohol abuse. The 5-HT3 antagonist effects in this study are comparable with the effects of naltrexone on ethanol reward in C57 mice, although higher doses were required to reduce operant responding for ethanol reward. In contrast to the 5-HT3 antagonist and naltrexone effects, naltrindole, an antagonist with greater specificity for the delta-opioid receptor, was without effect on ethanol reward. This result and recent reports for rats and monkeys suggests that the general antagonists might be more efficacious in attenuating ethanol reward. Both MDL and naltrindole produced only slight reductions in the ethanol discriminative cue, suggesting that the rewarding and discriminative effects of ethanol are not likely mediated by identical neural mechanisms as previously suggested.

Animals↗