The reinforcing effects of ethanol are altered by the endogenous neurosteroid, allopregnanolone

We examined the effect of systemic administration of the endogenously occurring progesterone metabolite, allopregnanolone, on oral self-administration of ethanol by male rats. Rats were trained to perform an operant response for presentation of 0.1 ml of a solution of 10% ethanol in water using the sucrose fading technique. After acquisition of stable lever-press responding on a fixed-ratio 4 schedule, subjects received subcutaneous injections of 1, 3, or 10 mg/kg of allopregnanolone, or vehicle, 20 min prior to the self-administration session. Pretreatment with 3 mg/kg, but not 1 or 10 mg/kg, increased the mean total number of lever press responses made to obtain ethanol, and therefore increased the mean total number of ethanol presentations. The number of responses and response rate were examined as a function of the number of "runs" within the 30-min session; a "run" was defined as a series of consecutive responses with an interresponse interval of <1 min. The increase in total responses after 3 mg/kg was due in part to an increased number of responses for the first run of the session, with no effect on response rates. However, the higher dose of 10 mg/kg decreased response rates within the first run. Thus, allopregnanolone alters ethanol-reinforced responding at concentrations lower than those that depress rates of responding. The effects of administration of the benzodiazepene, diazepam, were determined for comparison with those of the neurosteroid. The subcutaneous injection of 0.3, 1.0, or 3.0 mg/kg of diazepam did not produce any clear dose-dependent changes in measures of ethanol-reinforced operant responding, supporting the suggestion of differences in the contribution of the benzodiazepene and neurosteroid binding sites to GABA(A) receptor function. The results indicate that exogenous administration of allopregnanolone dose-dependently alters ethanol-reinforced operant responding, and suggest that this endogenously occurring neurosteroid could mediate some of the reinforcing effects of ethanol.     

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats

Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex.     

Intravenous self-administration of ethanol in beta-endorphin-deficient mice

Extensive research on both human alcoholics and in animal models of alcoholism has implicated the release of endogenous opioids in the consumption of ethanol. Various experiments using opioid antagonists have indicated that these drugs cause both humans and animals to decrease their consumption of ethanol. However, it remains unclear exactly which of the endogenous opioids mediates the rewarding effects of ethanol. The present experiment used intravenous self-administration of ethanol to determine whether beta-endorphin (BE)-deficient mice differed from wild-type (WT) mice in ethanol self-administration. The BE-deficient mice completely lack BE, but are otherwise similar to the WT mice. By using intravenous self-administration, we were able to rule out any ability of BE to mediate differences in ethanol consumption via palatability factors alone. Both types of mice were 7 generations backcrossed onto a C57BL/6J inbred strain background. During nine daily, 2-hr free-operant sessions, 14 BE-deficient and 17 WT mice could nosepoke for 75 mg/kg ethanol infusions delivered intravenously on an fixed-ratio 3 schedule with a 2-sec time-out after each reinforcer delivery. Reinforcer delivery occurred following nosepokes in only one of two holes. Contrary to what was expected, BE-deficient mice acquired selective operant responding for ethanol, whereas WT mice did not. Although the two genotypes did not differ in either operant or locomotor behavior during the first session, by the end of the nine sessions, BE deficient mice were reliably nosepoking for ethanol, whereas WT mice were not. These findings may indicate that BE is not essential for the postingestive reinforcing effects of ethanol in these animals.     

Food-deprivation level alters the effects of morphine on pigeons' key pecking

Four pigeons pecked response keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated separated by 15-s timeouts; each was presented six times. Pigeons were maintained at 70%, 85%, and greater than 90% of their free-feeding weights across experimental conditions. When response rates were stable, the effects of morphine (0.56 to 10.0 mg/kg) and saline were investigated. Morphine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and at high doses under the fixed-interval schedule. In some cases, low doses of morphine increased rates under the fixed-interval schedule. When pigeons were less food deprived, reductions in pecking rates occurred at lower doses under both schedules for 3 of 4 birds compared to when they were more food deprived. When pigeons were more food deprived, low doses of morphine increased rates of pecking in the initial portions of fixed intervals by a greater magnitude. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of morphine. These effects may share a common mechanism with increased locomotor activity produced by drugs and with increased drug self-administration under conditions of more severe food deprivation.     

Enhanced response acceleration or suppression produced by response-independent food presentations in rats with septal lesions

In two separate experiments, the response rates of rats with septal lesions were compared with those of control rats when response-independent food was presented while subjects were responding on a differential-reinforcement-of-low-rate schedule of reinforcement (Experiment 1) or according to a conjunctive differential-reinforcement-of-high-rate, fixed-ratio schedule (Experiment 2). Free-food deliveries resulted in acceleration of responding of subjects working on the low-rate schedule and in suppression of responding of those animals working on the high-rate schedule. Both of these effects were localized to a brief time period immediately following the free-food deliveries, and baseline rates of responding were not altered. The acceleration and suppression of responding that occurred on the respective schedules were greatly enhanced in rats with septal lesions. This finding supports the suggestion that these animals are hyperreactive to the reinforcing and/or eliciting properties of discrete stimulus events.     

Effects of triazolam, 8-OH-DPAT, and buspirone on repeated acquisition in squirrel monkeys.

The nonserotonergic benzodiazepine, triazolam, was compared with two 5-HT1A receptor agonists, 8-OH-DPAT and buspirone, in squirrel monkeys responding under a repeated-acquisition procedure. In each session, subjects acquired a 4-response sequence by responding sequentially on 3 keys in the presence of 4 discriminative stimuli (colors). Response sequences for each session were maintained by food presentation under a second-order fixed-ratio schedule. Errors produced a brief time-out but did not reset the sequence. In general, all of the drugs produced dose-dependent decreases in overall response rate and increases in the percentage of errors as the cumulative dose was increased. Together, these results indicate that 5-HT1A receptor agonists disrupt learning in squirrel monkeys by producing rate-decreasing and error-increasing effects in a manner comparable with the nonserotonergic benzodiazepine triazolam. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in oral ethanol self-administration patterns resulting from ethanol concentration manipulations

A variety of initiation procedures have been used to develop oral ethanol consumption. Using the sucrose-substitution procedure, oral self-administration of ethanol-water solutions with ethanol concentrations as high as 40% can be initiated in food- and fluid-sated rats. An important question for these models is the relationship between ethanol concentration and self-administration patterns after initiation. This study examined the differential patterns of ethanol self-administration maintained by a range of ethanol solutions (10 to 30%) over a 5-week period, compared with rats maintained on 10% ethanol for 5 weeks. In 43 male Long Evans rats, the sucrose-substitution procedure was used to initiate responding maintained by 10% ethanol on a Fixed Ratio 4 schedule of reinforcement. The ethanol concentration presented was then increased to 30% in stepwise fashion and then returned to 10% [Ethanol Concentration Manipulation (ECM) group, n = 32], or 10% ethanol was maintained as the reinforcer for 5 weeks [Control (Con) group, n = 11]. Significant increases in ethanol intake and decreases in responding were associated with increased ethanol concentration. Although no overall differences in total session responding were observed in either group between week 1 and week 5 (10E vs. 10E), examination of changes in initial low responders of the ECM group revealed significant increases in responding that were not observed in the initial low responders of the Con group. Significant increases in momentary response rates were observed on both the ECM and Con groups, independent of the ethanol concentration presented. Increases in response rate in the ECM group were the result of increases in initial low rate and high rate responders; however, the increased response rates in the Con group were the result of increases only in the initial low rate responders. These data suggest that the ECM procedure can aid in the initiation of ethanol self-administration and may be particularly useful in rats of heterogeneous stock.     

Cleavage experiments with deoxythymidine 3'',5''-bis-(p-nitrophenyl phosphate) suggest that the homing endonuclease I-PpoI follows the same mechanism of phosphodiester bond hydrolysis as the non-specific Serratia nuclease

The present study examined the effects of morphine in pigeons responding under a progressive-ratio 25 schedule of food delivery. Morphine initially reduced response rates and breaking points. With chronic exposure, tolerance developed to these effects. The magnitude of the observed tolerance was not obviously different from that previously reported under a PR 5 schedule of food delivery. In addition, when drug effects were compared under the fixed-ratio 25 and fixed-ratio 100 components comprised by the progressive-ratio schedule, comparable tolerance was observed. Although prior studies using other procedures have shown that ratio size modulates the development of tolerance to morphine and other drugs, the present data suggest that this relation is constrained, and is not easily observed under progressive-ratio schedules.     

Evaluation of the reinforcing and discriminative stimulus effects of the N-methyl-D-aspartate competitive antagonist NPC 17742 in rhesus monkeys

The phencyclidine (PCP)-like effects of the N-methyl-D-aspartate (NMDA) competitive antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 17742) were evaluated in three behavioral tests in rhesus monkeys. The discriminative stimulus properties of NPC 17742 (2-24 mg/kg, i.m.) were tested in four rhesus monkeys trained to discriminate PCP from saline under a fixed-ratio (FR) 50 schedule of food reinforcement. In three of the monkeys, NPC 17742 showed complete substitution for PCP at doses which did not decrease rates of responding. Intravenous self-administration of NPC 17742 (50-800 micrograms/kg/infusion) was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. At least one dose of NPC 17742 functioned as a reinforcer in two of the monkeys. A second self-administration study, employing a 10 min fixed interval schedule of reinforcement, was performed in three monkeys trained to self-administer PCP during three daily sessions. Compared with PCP, NPC 17742 (0.4-1.6 mg/kg/infusion) maintained very low rates of responding; NPC 17742 could not be clearly established as a reinforcer in this procedure. The data show that NPC 17742 has some PCP-like behavioral effects, and may function as a weak reinforcer in some subjects under specific conditions. The results provide further evidence that both similarities and differences exist between the behavioral effects of PCP and competitive NMDA antagonists.     

Pharmacological and behavioral components of tolerance to LSD and mescaline in rats

A fixed-ratio schedule of water reinforcement (FR-10) was used to examine the relative contributions of pharmacological and behavioral mechanisms in the development of tolerance to the disruptive effects of LSD and mescaline in the rat. Rats treated daily with LSD or mescaline before operant testing developed tolerance to the impairement of responding, while rats treated daily after each session did not display tolerance when the drugs were administered before testing. These results indicate that behavioral compensatory mechanisms may be involved in the development of tolerance to the disruptive effects of LSD and mescaline on fixed-ratio (FR-10) performance.     

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.     

Telepathology diagnosis by means of digital still images: an international validation study

Methadone usually is taken orally for drug abuse treatment in humans but oral methadone self-administration by laboratory animals has not been investigated extensively. The present study examines acquisition and maintenance of oral methadone maintained responding in four adult male rhesus monkeys. Drug solution was available from one liquid delivery system and water from a second system during daily 3-h sessions. Locations of liquids were reversed each session, and liquid (0.65 ml per delivery) was delivered according to a fixed-ratio reinforcement schedule. Initially a test for the reinforcing effects of 0.00625-0.4 mg/ml methadone solutions was carried out but a consistent preference for drug over water was not seen. To establish methadone as a reinforcer, a fading procedure was used in which responding was first maintained by solutions of methadone (0.00625-0.4 mg/ml) combined with ethanol (0.0325-2.0% w/v). Subsequently, the concentration of the ethanol in the combination was gradually reduced to zero. Methadone-maintained responding (0.4 mg/ml) persisted when ethanol was no longer present. To confirm that the drug was serving as a reinforcer, the dose was varied: (a) by changing the volume delivered while the concentration was held constant and (b) by changing the concentration of the methadone while the volume per delivery was held constant. Over a wide range of doses, deliveries of methadone solution usually exceeded deliveries of concurrently available water. Orderly relationships were observed among methadone dose, response rate, and drug intake. The study of oral self-administration of opioid drugs by nonhuman primates may be a useful strategy for the development and evaluation of new drug substitution or replacement therapies.     

Acquisition of intravenous cocaine self-administration with concurrent access to food in cynomolgus monkeys.

The present study used a concurrent schedule of food and drug delivery in socially housed male cynomolgus monkeys (Macaca fascicularis; N?=?15) to study variables that influence cocaine acquisition. Each monkey was implanted with subcutaneous vascular access ports, and responding was maintained under a concurrent food, saline schedule with the lever associated with each stimulus presentation varied daily. Next, increasing cocaine doses (0.003–0.3 mg/kg/inj) were concurrently available with food for at least 5 consecutive sessions per dose. Under these conditions, an unexpected lever bias emerged in all 15 monkeys. The development of the lever bias could not be predicted on the basis of cocaine dose or total intake and was not related to social rank. These findings suggest that in monkeys, concurrent fixed-ratio schedules of food and cocaine presentation may result in persistent biased responding that overshadows cocaine preference in studies of acquisition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.     

Sucrose, ethanol, and sucrose/ethanol reinforced responding under variable-interval schedules of reinforcement

Adding sweeteners to ethanol solutions is a common method of inducing rats to consume ethanol. However, it has usually been assumed that it is the sweet taste and/or the calories contained in the sweet solution that controls consumption. The present experiment examined the role of ethanol in controlling responding reinforced by ethanol or an ethanol/sucrose mixture compared with sucrose solutions of various concentrations. After initiation to self-administer 10% (v/v) ethanol using the sucrose-substitution method, rats were trained to respond under a concurrent VI 5" VI 5" schedule. During one condition, responding on one lever was reinforced by the presentation of 10% ethanol, and responding on a second lever was reinforced by water or one of the following sucrose solutions: 1% (w/v), 1.5%, 2%, 2.5%, 3%, and 5%. During a subsequent condition, responding reinforced by a 10% ethanol/2% sucrose mixture was compared under the concurrent schedule with responding reinforced by water, 2%, 2.5%, 3%, 5%, or 10% sucrose (w/v). The results indicated that the ethanol or ethanol/sucrose mixture maintained more responding than did sucrose solutions that were sweeter. Data support the conclusion that, after initiation, the taste and/or pharmacological effects of ethanol had become an important component of the reinforcing stimulus independent of the sweetener.     

Molecular mechanisms resulting in pathogenic anti-mouse erythrocyte antibodies in New Zealand black mice

A procedure was developed with pigeons to extend the experimental analysis of punished behavior and the effects of anxiolytic drugs. Under this procedure the completion of a fixed-ratio requirement on a changeover key switched between two variable-interval schedules of reinforcement that were programmed on a second response key. Under one schedule, correlated with a green keylight, key pecks produced only food; under the second schedule, correlated with a red keylight, key pecks produced both food and electric shock. Pigeons were switched into the component with shock if they did not enter that component within 5 min. Parameter values of the variable-interval schedules were manipulated systematically and the effects of two clinically active anxiolytic drugs, buspirone and chlordiazepoxide, were examined. Responding was suppressed during the component with shock (punishment) and, under non-drug conditions, pigeons infrequently switched into the punishment component; changeover responses occurred rapidly when switched into the punishment component. Both buspirone (0.1-3.0 mg/kg) and chlordiazepoxide (3.0-30 mg/kg) increased punished responding at doses that had little effect on unpunished responding; d-amphetamine (0.3-5.6 mg/kg), which was studied only under one parameter of the variable-interval schedule, produced greater decreases in rates of punished responding than in unpunished responding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response suppression to a shock-predicting stimulus in differentially reared monkeys (Macaca mulatta).

Four rhesus monkeys reared in social isolation for the 1st 9 mo of life and 4 monkeys reared with social contact were trained to leverpress for food reinforcement on a VI 60-sec schedule of reinforcement as adults. A 3-min auditory CS that terminated with the delivery of an electric foot shock was then presented at random intervals during each test session. Results indicate that though preshock response rates did not differ, the isolates failed to suppress responding in the presence of the shock-predicting CS at the same rate or to the same degree as did socially reared Ss. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavior maintained by alfentanil or nalbuphine in rhesus monkeys: Fixed-ratio and time-out changes to establish demand curves and relative reinforcing effectiveness.

A fixed-ratio, time-out schedule of intravenous alfentanil or nalbuphine delivery was used to maintain responding in rhesus monkeys (Afacaca mlulatta) during twice-daily 2-hr sessions of unrestricted access. Four doses of each drug were tested under 10 response fixed-ratio and lO-s time-out baseline conditions. Either the fixed ratio or the time-out was periodically increased during single sessions. Alfentanil maintained higher response rates than nalbuphine under conditions in which response rates were limited by the size of the fixed ratio rather than by unconditioned effects. This indicates that alfentanil is a more effective reinforcer than nalbuphine, which is predicted on the basis of the greater intrinsic efficacy of alfentanil relative to nalbuphine at the mu opioid receptor. Unit price analysis of these data demonstrated that a single demand function could be drawn for each drug, indicating that for these opioids in this situation, increasing the dose per injection was equivalent to decreasing the fixed ratio. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of d-amphetamine and cocaine on strained ratio behavior in a repeated-acquisition task

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. When the fixed-ratio requirement for food presentation was five completions of the chain, d-amphetamine and cocaine disrupted the behavior. As the dose of each drug was increased, the overall response rate decreased, the overall accuracy was impaired (i,e., percent errors increased), and there was less within-session error reduction (acquisition). In contrast, when the fixed-ratio requirement was either 20 or 50 completions of the chain, certain doses of both drugs produced large increases in the overall response rate by eliminating the extended pausing (ratio strain) that was characteristic of the control sessions. These rate-increasing effects were accompanied by error-decreasing effects, both during acquisition and after the response chain had been acquired. Taken together, the results show that the effects of d-amphetamine and cocaine on behavior in a repeated-acquisition task can be modulated by manipulating the value of the fixed-ratio schedule maintaining the behavior.     

d-Amphetamine, operant history, and variable-interval performance

The effects of d-amphetamine on the bar-pressing of rats maintained under a variable-interval schedule of water reinforcement were examined as a function of the operant history of the subjects. One group of rats initially received 51 sessions of exposure to a fixed-ratio 20 schedule, while a second group received equivalent exposure to an interresponse-time-greater-than-12-sec schedule. Mean group response rate when stable was over ten times as high under the fixed-ratio schedule as under the interresponse-time-greater-than-12-sec schedule. Response rates of the two groups largely converged across 47 sessions of exposure to a variable-interval 60-second schedule, at which time response rates for both groups appeared stable. Acute administration of d-amphetamine sulfate similary affected mean response rates of both groups: A 0.25 mg/kg dose did not obviously affect rate, while doses of 0.5, 1.0, and 2.0 mg/kg produced dose-dependent rate decreases. These results indicate that the efficacy of operant history as a determinant of drug effects may be limited to circumstances where current contingencies do not exercise powerful and direct control over behavior.