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PubMedDate not supplied

Enhanced passive avoidance learning and appetitive T-maze learning with post-trial rewarding hypothalamic stimulation.

Experiments were carried out to investigate the effects of post-trial reinforcing stimulation of the lateral hypothalamus on learning in rats. The reinforcing stimulation was always presented for a duration of 20--30 sec (0.2 sec on/0.8 sec off), and was administered either immediately, 30 sec delayed or 300 sec delayed after exposure to the learning situation. In experiment 1 post-trial stimulation led to improved passive avoidance learning of an alcove-avoidance task when presented 30 sec compared to immediately after the footshock. In Experiment 2 reversal learning of a one-way shuttle-box avoidance task was facilitated by 30 sec delayed, but not 300 sec delayed post-trial reinforcing stimulation. In Experiment 3 appetitive left-right discrimination was investigated using a T-maze task. Thirty sec delayed post-trial reinforcing stimulation presented contingent on errors facilitated learning of this task. Together, the 3 studies provide further support for the hypothesis that reinforcers directly influence labile memory processes (such as short-term memory) and thereby improve learning.

Animals↗
PubMed1984

Brain reward circuitry: a case for separate systems.

Anatomical, lesion and pharmacological data pertaining to intracranial self-stimulation are reviewed in the context of multiple independent substrates of brain-stimulation reward. Subsystems related to chemosensitive pathways, motor control and mood are identified. Forebrain dopamine pathways are recognized to be important components of two separate subsystems of reward. Nigrostriatal DA neurons are linked to an extrapyramidal circuit with reinforcement derived from response initiation and it is conjectured that the meso-limbic DA pathway is related to the control and perception of positive affect. Other candidate systems include a trigeminal system in the hind brain that may function independently from forebrain substrates of reward.

Amygdala↗
PubMed1987

Social conflict analgesia: inhibition of early non-opioid component by diazepam or flumazepil fails to affect appearance of late opioid component.

Two forms of analgesia (opioid and non-opioid) are associated with social conflict in mice. The non-opioid form is seen in response to the scent of an aggressive conspecific or defeat experience, whilst the opioid form occurs in response to extended conspecific attack. Recently, it has been reported that the non-opioid reaction is dose-dependently blocked by diazepam and by Flumazepil (Ro15-1788; a benzodiazepine receptor antagonist). In view of the temporal relationship between these two reactions, the present study was conducted to determine whether activation of non-opioid substrates is a necessary precursor to the development of opioid analgesia. Results indicate that inhibition of non-opioid analgesia by diazepam (2-4 mg/kg), or by Flumazepil (20-40 mg/kg), does not alter the opioid analgesic reaction to conspecific attack. Findings are discussed in relation to the presumed adaptive significance of these biologically-meaningful forms of pain inhibition.

Aggression↗
PubMed1989

Drug-reinforced responding: rapid determination of dose-response functions.

Rhesus monkeys were conditioned to press on levers and receive intravenous infusions of cocaine or ketamine. Experimental conditions provided several different doses of drug during each of two daily 130 min sessions; as a result, a dose-response curve relating rate of responding to dose/injection for self-administered drug was obtained within each session. Relative rate-maintaining effects of nomifensine and cocaine in monkeys on baseline conditions of cocaine self-administration, and rate-maintaining effects of ketamine, phencyclidine and MK-801 in monkeys on baseline conditions of ketamine self-administration, compared favorably with relative rate-maintaining effects of these substances obtained in more traditional paradigms.

Animals↗
PubMed1990

Desipramine effects on cocaine self-administration by rhesus monkeys.

The effects of desipramine treatment (0.56-10.0 mg/kg per day) on cocaine self-administration were compared to saline treatment in five rhesus monkeys. Cocaine (0.050 or 0.100 mg/kg per inj) and food (1 g banana pellets) self-administration were maintained on an FR 4 (VR 16:S) reinforcement schedule. Desipramine (or an equal volume saline control solution) was infused over 1 h each day through the second lumen of an intravenous catheter. After 5 days of baseline saline treatment, seven doses of desipramine each were administered for 5 days in an ascending order. Cocaine self-administration increased (P less than 0.01) or remained equivalent to base-line levels in 4 of 5 subjects during the first 15 days of desipramine treatment (0.56 to 1.78 mg/kg per day). Three monkeys continued to self-administer cocaine equivalent to or significantly above base-line levels (P less than 0.01) during days 16-30 of desipramine treatment (3.2-7.86 mg/kg per day). The highest desipramine dose (10 mg/kg per day) significantly suppressed cocaine self-administration in only one of these three monkeys (P less than 0.01). Desipramine treatment (3.2-10.0 mg/kg per day) suppressed cocaine self-administration (P less than 0.01) without a concomitant suppression of food-maintained responding in one of five subjects. A generalized suppression of both cocaine and food-maintained responding (P less than 0.01) during desipramine treatment occurred in one monkey that took the highest base-line levels of cocaine (6.3 +/- 1.03 mg/kg per day). Food-maintained responding remained equivalent to or significantly above (P less than 0.01) base-line levels in four of five monkeys during desipramine treatment. A transient decrease in food self-administration at desipramine doses of 1.78-5.62 mg/kg per day occurred in one monkey (P less than 0.01). Thirty days of desipramine treatment at the highest doses (5.62, 7.86 and 10.0 mg/kg per day for 10 days each) also did not suppress cocaine self-administration in a monkey that took an average of 4 mg/kg per day of cocaine during saline base-line treatment. These primate data are concordant with the extant clinical literature on the inconsistent effects of desipramine treatment; i.e., both stimulation of cocaine use and inconsistent or incomplete attenuation of cocaine abuse during desipramine maintenance have been reported.

Animals↗
PubMed1991

Effects of acute and chronic administration of delta 9-tetrahy-drocannabinol or cocaine on ethanol intake in a rat model.

The acute and chronic administration of delta 9-tetrahydrocannabinol (delta 9-THC) or cocaine were studied in rats trained to obtain all of their daily food by lever pressing during four equally-spaced 30-min periods with water and 5% or 7.5% ethanol solutions freely available. With 5% ethanol available, rats consumed almost all of their daily fluid intake as ethanol, while with 7.5% ethanol available, rats consumed water and ethanol solution in approximately equal amounts. Rats consumed more food pellets with 7.5% ethanol available than with 5% ethanol available. Acute administration of delta 9-THC produced a dose-dependent decrease of 5% ethanol intake and food pellets consumed with a small increase in water intake, especially after the higher doses. Acute administration of delta 9-THC also depressed food intake when 7.5% ethanol was available, but decreases in ethanol solution intake were small. Chronic administration of delta 9-THC initially decreased ethanol intake, but tolerance occurred to this effect, so that during chronic delta 9-THC administration ethanol intake not only recovered, but increased above control levels. When the chronic administration of delta 9-THC was discontinued, ethanol intake was increased for 1 (5% ethanol) to 3 (7.5% ethanol) weeks. Animals with initially high, or initially low, but not with initially moderate ethanol intake, accounted for the increased ethanol intake during chronic delta 9-THC administration and withdrawal. Acute cocaine administration, at doses up to 30 mg/kg, had little effect on eating and drinking; however, during chronic cocaine administration, ethanol intake gradually increased, an increase which was sustained during cocaine withdrawal. The increased ethanol drinking was confined to the first 6-h period after cocaine administration. These data suggest that the chronic administration and withdrawal of other drugs can increase ethanol intake in this rat model.

Alcohol Drinking↗
PubMed1995

Relative reinforcing effects of different doses of orally delivered cocaine.

The relative reinforcing effects of different doses of oral cocaine were investigated in two adult male rhesus monkeys. In the first experiment, a range of cocaine doses (0.1-0.8 mg/ml) was studied with drug and water concurrently available for 3 h each day under identical and independent fixed-ratio schedules. The side positions of the drug and vehicle were alternated from session to session. Drug deliveries always exceeded vehicle deliveries, i.e., orally delivered cocaine functioned as a reinforcer. The highest rates of responding occurred at either the lowest or next to lowest dose (0.1 or 0.2 mg/ml). In the second experiment, pairs of different cocaine doses were systematically presented under identical and independent fixed-ratio schedules. The higher of two concurrently available doses usually maintained the higher response rate. These findings suggest that the relative reinforcing effects of orally delivered cocaine increase with dose. Absolute response rates obtained with single cocaine doses and water concurrently available do not always reflect the magnitude of the reinforcing effects indicated when pairs of cocaine doses are studied together. The results of this study are in agreement with earlier investigations in which the relative reinforcing effects of pairs of intravenous cocaine doses or oral pentobarbital doses were studied. Taken together these findings indicate that, over a range of doses and across pharmacological classes and routes of administration, relative reinforcing effects of a drug increase directly as a function of increases in dose.

Administration, Oral↗
PubMed1994

Discriminative stimulus effects of combinations of pentobarbital and ethanol in rhesus monkeys.

Rhesus monkeys (N = 3) were trained in a 2-lever drug discrimination paradigm to discriminate pentobarbital (PB; 10 mg/kg, i.g., 60 min pre-session) from saline. Lever pressing was maintained under a discrete-trials shock avoidance schedule of reinforcement (30 trials/day, 30-s ITI, FR1). Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with PB and ethanol (EtOH), alone or in combination. Administration of PB alone resulted in a dose-related increase (0-100%) in the percentage of responses emitted on the drug-appropriate lever. The mean ED50 for PB was 7.0 mg/kg (95% C.L. = 6.3-7.7 mg/kg). When administered 60 min pre-session, EtOH engendered a dose-related increase in PB appropriate trials and substituted completely for PB at 3.0 g/kg in two monkeys. In the third monkey, EtOH engendered a maximum of 65% PB-appropriate responding at 1.7 g/kg given 30 min pre-session and predominantly saline-appropriate responding at other pretreatment times. The group ED50 for EtOH at the time of maximum effect was 1.9 g/kg (95% C.L. = 1.4-2.5 g/kg). Administration of 0.3 g/kg EtOH in combination with PB had little or no effect on the PB dose effect function (PB ED50 = 6.7 mg/kg) while 1.0 g/kg EtOH shifted the PB dose-effect function to the left in all monkeys, an average of approximately 3-fold (PB ED50 = 2.1 mg/kg). Isobolographic analysis of the effects of the combination revealed that EtOH and PB were dose additive.

Animals↗
PubMed1994

Functional relationships, previous history and the discrimination of a drug mixture in rats.

These experiments aim to probe the role of different functional relationships between drugs, responses and reinforcers in studies on the discrimination of drug mixtures. Two-lever discriminations based on mixtures of (+)-amphetamine (0.4 mg/kg) plus pentobarbitone (10 mg/kg) have been compared in three groups of rats (n = 8) trained to discriminate: (i) the mixture from saline, called the AND-discrimination; (ii) either the mixture, amphetamine or pentobarbitone from saline, the OR-discrimination; (iii) the mixture from either amphetamine or pentobarbitone, the AND-OR-discrimination. The rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. The rats trained on the AND procedure acquired the discrimination more rapidly than the rats trained on the other two procedures, but after 60 training sessions, all discriminations were performed with similar (90-94%) accuracy. In rats trained under the AND and the OR procedures, there was full generalization from the mixture to the largest doses used of either amphetamine or pentobarbitone. In contrast, in rats trained under the AND-OR procedure, there was no generalization from the mixture to any dose of either drug separately. The training procedures for the OR and the AND-OR groups were changed to AND-discrimination training; the effects of the different previous histories were found to persist for a prolonged period, despite the fact that training conditions were now the same in all groups. The effects of the drugs on rates of responding were also influenced by the previous training history. Thus, using different training procedures to alter functional relationships can substantially and persistently influence the major characteristics of a discrimination based on a mixture of drugs.

Amphetamine↗
PubMed1994

Discriminative stimulus effects of phencyclidine: pharmacologically specific interactions with delta 9- and delta 8-tetrahydrocannabinol.

Rats were trained to discriminate a dose of 1.75 mg/kg phencyclidine (PCP) from saline. During substitution tests, both PCP (0.3-10.0 mg/kg) and the non-competitive NMDA antagonist, MK-801 (0.01-0.3 mg/kg) substituted for the PCP stimulus in a dose-dependent manner. In contrast, delta 9-tetrahydrocannabinol (delta 9-THC, 0.1-5.6 mg/kg) and delta 8-tetrahydrocannabinol (delta 8-THC, 0.3-5.6 mg/kg) failed to substitute for the PCP stimulus, up to doses that substantially decreased rate of responding. However, both delta 9-THC and delta 8-THC partially attenuated the discriminative stimulus effects of the PCP training dose. Furthermore, a dose of 3.0 mg/kg delta 9-THC shifted the PCP dose-effect curve for discriminative stimulus effects to the right and shifted the PCP dose-effect curve for rate of responding to the left. The attenuation of the PCP stimulus by delta 9-THC lacked a strong dose-dependent relationship and was observed both at doses which did not alter rate of responding, as well as at doses which substantially decreased rate. In contrast to the effects observed with delta 9-THC and delta 8-THC, morphine, d-amphetamine and chlordiazepoxide failed to attenuate the discriminative stimulus effects of PCP, even at doses that markedly decreased rate of responding. The present findings suggest that delta 9-THC and delta 8-THC alter the discriminative stimulus effects of PCP in a pharmacologically specific manner.

Animals↗
PubMed1995

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.

Animals↗
PubMedDate not supplied

Human conditioned compensatory response to alcohol cues: initial evidence.

Alcohol cues elicited a conditioned autonomic response that was opposite in direction to the effect of alcohol. Normal male social drinkers given placebo following four alcohol conditioning sessions showed a compensatory response consisting of decreased pulse transit time, vasomotor activity, and finger temperature. This pilot research, supports the application of a classical conditioning model to human alcohol problems.

Adult↗
PubMedDate not supplied

Effect of prenatal ethanol exposure on response to abrupt reward reduction.

The purpose of this study was to examine the effects of prenatal ethanol exposure on an appetitively-motivated behavioral task (consummatory negative contrast) that involves quantification of an animal's response to an abrupt, unexpected reduction in reward (sucrose solutions). Pregnant Long-Evans rats received isocaloric liquid diets containing either 35% or 0% ethanol-derived calories on days 6-20 of gestation. A pair-feeding procedure was employed, and a lab chow control group also was included. Adult male offspring from these three prenatal treatment groups were used for behavioral testing. Results indicated all groups exhibited suppressed responding subsequent to reward reduction. This effect gradually diminished in all prenatal treatment groups over several test sessions. While there was a numerical tendency for ethanol-exposed offspring to exhibit a smaller initial contrast effect (less response inhibition) and recover to control levels at a faster rate than the sucrose and lab chow control groups, this effect was not statistically significant. Thus, prenatal ethanol exposure does not appear to greatly influence the response to abrupt, partial reward reduction in adult rat offspring.

Animals↗
PubMed2003

Further evidence for the mediation of both subtypes of dopamine D1/D2 receptors and cerebral neuropeptide Y (NPY) in amphetamine-induced appetite suppression.

Amphetamine (AMPH) is known as an anorectic agent. Repeated treatments of AMPH for several days induced a marked anorexia on day 1 followed by a gradual return of food intake to normal level. Previously, using daily food intake (DFI) as an indicator, we found that both dopamine (DA) D1 and D2 receptors were involved in AMPH anorexia. In the present study, using DFI and body weight change (BWC) as indicators, we took a further step to examine whether repeated co-administrations of D1 and D2 agonists might produce an AMPH-like action. Results revealed that repeated co-administrations of D1 and D2 agonists, but not D1 or D2 agonist alone, produced an AMPH-like action (i.e., tolerant DFI and BWC), confirming the previous study. In addition, we examined whether cerebral neuropeptide Y (NPY), an orexigenic neurotransmitter reported to mediate AMPH anorexia, was involved in the anorectic action of D1/D2 co-administration. Our result revealed that injection of NPY antisense into brain could modify the anorectic action of repeated D1/D2 agonists, indicating the involvement of NPY. Taken together, the present results confirmed that both subtypes of D1 and D2 receptors and cerebral NPY were involved in the anorectic action of AMPH.

Amphetamine↗
PubMed2004

On the relationship between anticipatory behaviour in a Pavlovian paradigm and Pavlovian-to-Instrumental Transfer in rats (Rattus norvegicus).

The present rat study assessed the relationship between, and the sensitivity of, two different tests for appetitive conditioned responding to differences in the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), and to differences in US magnitude. The first test used a Pavlovian-to-Instrumental Transfer (PIT) paradigm, assessing the capacity of the CS to enhance instrumental responding for food. The second test employed a Pavlovian conditioning paradigm with an extended CS-US interval, and total number of behavioural elements in this interval as a dependent measure. The PIT test proved to be sensitive to contingency but not reward magnitude differences, whereas the reverse was true for the Pavlovian test. Although there was a significant correlation between tests in the magnitude of the CS-induced increase of food-magazine entries, the main dependent measure from PIT (number of lever presses) and that from the Pavlovian test (total number of behavioural elements) did not correlate. It is suggested that in the PIT procedure, the CS induces a chain of behavioural responses of which lever pressing is just a single element and that the Pavlovian test, in principle, is more sensitive.

Animals↗
PubMed2004

Effects of changing reward on performance of the delayed spatial win-shift radial maze task in pedunculopontine tegmental nucleus lesioned rats.

Because it was designed to assess working memory, the delayed spatial win-shift (DSWS) radial maze task has been used to investigate the involvement of corticostriatal structures in executive processing. Excitotoxic lesions of the pedunculopontine tegmental nucleus (PPTg) produce profound deficits in performance of this task that are not accounted for by motor impairment. Thus, PPTg DSWS deficits are hypothesized to support a role for PPTg in complex cognitive processing. However, other studies indicate that the behaviour of PPTg lesioned rats varies depending on level of motivational excitement, assessed by the presence or absence of deprivation, or by manipulations of reward value. Since DSWS performance may also be affected by motivational dysfunction, the present experiment was conducted to examine the effects of post-surgical presentation of a more positive food reward (chocolate drops) on the DSWS retention performance of PPTg lesioned rats. Results confirmed a PPTg lesion deficit: lesioned rats made significantly more errors in both training and test phases, and made errors significantly earlier in their choice sequence in the test phase. Main effects of phase on number of errors indicated that the PPTg test phase deficit was not simply the result of a carry-over impairment from the training phase. PPTg rats receiving chocolate made significantly fewer errors than PPTg rats receiving food pellets. Results suggest that PPTg DSWS deficits are not the result of altered motivation or hedonic appreciation of reward value (or reward change) and therefore support the hypothesis of executive cognitive deficits in PPTg lesioned rats.

Animals↗