Role of experience in acquisition and loss of tolerance to the effect of delta-9-THC on spaced responding

Albino rats were given extensive training in spaced responding, using a DRL 30 sec schedule of food reinforcement (only lever presses more than 30 sec apart were reinforced). All rats then went 12 days without behavioral testing. During this period half the rats received daily intragastric doses of delta-9-tetrahydrocannabinol (THC) and the rest equal volumes of the THC vehicle. On day 13, some rats received THC 3 hr before behavioral testing while others received only vehicle. The former showed a sharp increase in lever press rate over baseline levels, but the vehicle control rats were unaffected. The rats with 12 prior THC doses were no less affected than those with no previous drug history. Continued testing resulted in recovery of baseline performance within 5 sessions, again with no effect of previous drug history. Similar results were obtained with doses of 4 mg/kg and 16 mg/kg, though the drug's effects were more pronounced at the higher dose. These results demonstrate that performance in the drug state can be a far more important determinant of tolerance than mere exposure to THC. Drug administration was then suspended for 1 week. Rats that had become tolerant to 4 mg/kg THC were then redivided into 3 new groups. One group received daily doses of vehicle and DRL sessions, a second received DRL sessions without vehicle, and 1 group received neither vehicle nor DRL sessions for this week. Subsequent DRL testing after THC administration showed that only the groups receiving DRL sessions in the intervening week lost their previously acquired tolerance. Experience thus appears to play an important role in loss of tolerance to THC as well as in acquisition of tolerance.     

The effects of chlordiazepoxide on low-rate behavior are gender dependent

Gender differences in anxiety have long been assumed to exist, but the experimental evidence is contradictory. It has also been suggested that antianxiety agents may have gender-dependent behavioral effects. The present experiment was designed to establish whether or not intact male and female rats behave differently when exposed to a Differential-Reinforcement of Low-Rate 72-s schedule of reinforcement (assumed to assess some of the inhibitory behavioral tendencies associated with anxiety), and whether or not the behavioral effects of acute chlordiazepoxide administration would differ between the sexes. There were no differences between male and female rats in the total number of responses, the total number of obtained reinforcers, or response efficiency in the absence of drug administration. Male and female Wistar rats were then challenged with different doses of chlordiazepoxide (vehicle, 1, 3, 10, 17, and 30 mg/kg). Low doses of chlordiazepoxide (1 and 3 mg/kg) decreased response efficiency, and medium doses (10 and 17 mg/kg) increased response efficiency in male and female rats. The highest dose of CDP (30 mg/kg) further increased response efficiency in male rats, but decreased response efficiency in female rats. These results suggest that the behavioral effects of chlordiazepoxide are dose dependent and that the effects of a large dose of chlordiazepoxide differ between male and female rats. Whether or not gender differences in drug metabolism or whether schedule contingencies played an important role in these observations remains to be determined in future experiments.     

Behavioral tolerance and sensitization to alcohol in humans: The contribution of learning.

This experiment tested the hypothesis that tolerance or sensitization to repeated alcohol doses is predicted by the particular response (diminished or augmented impairment) that is reinforced under drug. Twelve male social drinkers were assigned to a tolerance (T) or sensitization (S) group (n?=?6) and performed a psychomotor task under 0.62 g/kg of alcohol on 5 separate sessions. The 1st session preceded training and determined that the groups' drugged performance did not differ. On 3 subsequent sessions verbal feedback reinforced diminished impairment in Group T and augmented impairment in Group S. During these sessions, Groups T and S displayed tolerance and sensitization, respectively. The final session showed that training effects were retained without reinforcement. The results extend the evidence on the effect of reinforcement to show that it can enhance sensitization as well as tolerance. The findings demonstrate that behavioral variables modulate the response to alcohol and imply that tolerance and sensitization may be affected by a common learning process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of chlordiazepoxide, buspirone and cocaine on behavior suppressed by timeout presentation

Male Wistar rats were exposed to a two-component multiple schedule: a random-interval 30 s schedule of pellet presentation and a conjoint random-interval 30 s schedule of pellet presentation, random-interval 2 s schedule of timeout 10 s presentation. Once responding had stabilized subjects were injected intraperitoneally with vehicle, chlordiazepoxide (1-30 mg/kg), buspirone (0.1-4.2 mg/kg) or cocaine (1-30 mg/kg), 15 min before the start of the experimental session. Before drug administration, punished response rates were less than 30% of unpunished response rates for four of the six subjects, and 60% and 75% for the other two. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased punished responding (range 25-300%), and slightly increased unpunished response rates (by 25% in all but one subject, whose rates increased by 75%). The higher doses of chlordiazepoxide (10-30 mg/kg) dose-dependently decreased response rates in both components. The lower doses of buspirone (0.1 and 0.3 mg/kg) either did not affect, or decreased response rates in both components of the schedule; the higher doses produced dose-dependent decreases. Low doses of cocaine (1, 3 and 5.6 mg/kg) did not affect response rates in either component of the multiple schedule, whereas higher doses produced a dose-dependent decrease in response rates, except for one subject whose punished response rates increased substantially. The behavioral effects of chlordiazepoxide and buspirone observed in the present experiment were similar to those observed in experiments in which response rates were suppressed by shock presentation.     

Discriminative stimulus effects on enadoline in pigeons

The discriminative stimulus effects of enadoline were characterized in pigeons responding under a fixed-ratio 20 schedule of food presentation and discriminating between intramuscular injections of the kappa opioid agonist enadoline and saline. Cumulative doses of enadoline dose-dependently increased drug-key responding with the training dose of enadoline (0.178 mg/kg) producing > or = 90% drug key responding (% DR). In time course studies, doses of enadoline larger than 0.32 mg/kg produced > or = 90% DR for more than 40 min. Naltrexone antagonized both the discriminative stimulus and the rate-decreasing effects of enadoline (pA2 = 6.79 and 6.73, respectively); in some pigeons, naltrexone produced an unsurmountable antagonism of the enadoline discriminative stimulus. Substitution tests using the kappa agonists U-50,488, spiradoline, U-69,593 and ethylketocyclazocine resulted in > or = 90% DR in most, but not all, pigeons; at larger doses, all compounds markedly decreased response rates. Up to rate-decreasing doses, nalorphine, dynorphin A(1-13) amide (DYN), nalbuphine, butorphanol, morphine and ketamine failed to occasion > or = 90% DR; nalbuphine, nalorphine, butorphanol, but not DYN, antagonized the discriminative stimulus and the rate-decreasing effects of enadoline. This study established stimulus control with enadoline in pigeons and results from substitution studies in these pigeons support the view that the enadoline discriminative stimulus is mediated by kappa opioid receptors; these results further demonstrate that nalbuphine and butorphanol have kappa antagonist actions in pigeons. The negative results obtained with DYN are in contrast to previous demonstrations of kappa agonist effects for DYN and might provide support for the hypothesized importance of nonopioid systems in the effects of this peptide.     

Environmental and pharmacological factors in the development of noncontingent tolerance to cocaine in pigeons.

Previous research with rats and monkeys has shown that tolerance to behavioral effects of cocaine developed if the drug was administered before behavioral test sessions but not if it was administered after sessions, a finding known as contingent tolerance. In contrast, a recent experiment using pigeons found that they showed tolerance resulting from postsession drug administration (noncontingent tolerance). The 4 experiments reported in this article were conducted to examine that result more fully. Experiment 1 found that immediate presession administration of cocaine to pigeons reliably led to tolerance to effects on food-reinforced operant key pecking and that immediate postsession administration of cocaine also led to tolerance in half the subjects, those whose key pecking was not suppressed by postsession dosing. Experiment 2 showed that eating in the home cage under the effects of postsession cocaine was not necessary for tolerance to develop to effects of postsession cocaine and that the majority of subjects developed tolerance from postsession cocaine administration. Experiment 3 found that mere drug exposure in the home cage without exposure to an experimental session did not reliably produce tolerance during the behavioral session. Experiment 4 showed that tolerance from postsession cocaine administration could be observed even when daily dosing was discontinued during dose–response curve assessment. Therefore, the combined results showed that pigeons often developed tolerance to effects of cocaine during the behavioral session when cocaine was administered postsession and that this tolerance was not the result of feeding under effects of the drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Associative control of tolerance to the sedative effects of a short-acting benzodiazepine.

The role of Pavlovian conditioning in tolerance to the depressant effect of a benzodiazepine (midazolam) on the ambulatory activity of rats was examined. The depression of activity by low doses (1.0 and 4.0 mg/kg, ip) of midazolam diminished quickly over repeated doses given at 48-hr intervals (Experiment 1). Equivalent tolerance was observed in groups measured at 2 min and 30 min after drug injection. When challenged with saline, however, drug-tolerant animals tested immediately after injection were hyperactive in comparison with nontolerant controls, whereas equivalent groups tested 30 min after injection were not. A second context was designed, and its discriminability from the original was established by assessing context-specific suppression of activity following exposure to mild electric shock (Experiment 2). In Experiment 3A, although tolerant animals tested in the drug-associated context remained fully tolerant, a second group demonstrated a complete loss of tolerance when given the drug in a saline-associated context. Both groups were fully tolerant when tested again in the drug-associated context after 14 drug-free days. In Experiment 3B, tolerance was significantly reduced by 14 extinction exposures to the drug-associated environment without the drug. These results are uniquely predicted by associative models of drug tolerance and may have implications for the clinical use of this class of drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of levo-alpha-acetylmethadol and its metabolites on schedule-controlled behavior in the pigeon

The effects of orally administered levo-alpha-acetylmethadol (LAAM) on the schedule-controlled behavior of the pigeon were compared with those of methadone. Both LAAM and methadone decreased rates of responding under a multiple fixed-interval 5-min, fixed-ratio 30-response schedule of food presentation. Although LAAM had a longer duration of action than methadone, both drugs were similar in the onset and potency of their behavioral effects. The chronic administration of either LAAM or methadone produced tolerance to the respective behavioral effects of each drug. In one set of experiments, the behavioral effects of intramuscularly administered LAAM were compared with those of its active metabolites, levo-alpha-noracetylmethadol and levo-alpha-dinoracetylmethadol. All three drugs decreased rates of responding under both components of the multiple schedule. The onset of these rate-decreasing effects was rapid and the order of potency for the production of these rate-decreases was levo-alpha-noracetylmethadol greater than levo-alpha-dinoracetylmethadol greater than or equal to LAAM. The rate-decreasing effects of LAAM and its metabolites were typical narcotic effects as defined by their reversal by naloxone.     

Comparison of zolpidem and midazolam self-administration under progressive-ratio schedules: Consumer demand and labor supply analyses.

Progressive ratio (PR) schedules of intravenous drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs. The authors compared the reinforcing effects of 2 short-duration benzodiazepine-type drugs differing in their receptor selectivity: zolpidem (selective for gamma aminobutyric acid Type A [GABAA] receptors containing α1 subunits) and midazolam (nonselective). Reinforcing effectiveness was evaluated using a PR schedule of intravenous drug injection in rhesus monkeys in which the response requirement increased across the experimental session and the initial response requirement (IRR) was varied. Analyses based on consumer demand and labor supply models of behavioral economics revealed that the relative reinforcing effectiveness of zolpidem was greater than that of midazolam. For consumer demand analyses, the degree of difference between zolpidem and midazolam depended on whether price was calculated on the basis of different IRRs or different doses of drug. According to labor supply analysis, the reinforcing effects of midazolam were influenced by the economic concept referred to as a price effect to a greater degree than those of zolpidem. These findings suggest that a compound with selectivity for GABAA receptors containing α1 subunits has greater reinforcing effectiveness than a nonselective compound with similar pharmacokinetics, albeit under a limited range of conditions (high response costs). Differences in price effects may play a key role in determining the relative reinforcing effectiveness of selective versus nonselective benzodiazepine agonists. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of daily administration of methamphetamine on multiple active/passive avoidance performance in rats

The effects of daily methamphetamine (M-Amp) treatment with (2 mg/kg/day, i.p.) were examined on multiple active/passive avoidance performance (MAP) in rats. After avoidance training, the animals were given M-Amp every day; on the days of learning sessions, which were on alternate days, the drug was administered at 15 min before the session. Daily administration of M-Amp produced enhancement of the number of respondings (running) as an excitatory dimension of behavior, disruption of immobilities as an inhibitory dimension, and impairment of successes as a discriminatory dimension, when compared with saline-treated rats. Following M-Amp withdrawal, recovery from these damages of learned behavior was observed, except the deterioration in the discriminative dimension. In conclusion, the MAP paradigm is good for assessing the behavioral effects of M-Amp treatment, making it easy to distinct the behavioral effects of M-Amp into excitatory-inhibitory and discriminative dimensions. It is important to distinguish the behavioral components induced by M-Amp, since the damage of learned avoidance performance consists of different dimensions in the M-Amp-treated rats. Impairment of discriminative behavior appears to demonstrate an attentional deficit, which may explain the behavioral disorderliness in M-Amp abusers who display no disturbance of apparent consciousness. These results are discussed with association of brain monoamine alterations.     

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.     

The dose-dependent effects of oral premedication with midazolam

OBJECTIVE: The aim of this study was to examine the psychological effects, well-being and side effects after various doses of oral midazolam medication. METHODS: After informed consent has been obtained and following the approval by the institutional ethical committee, 80 adult patients in the ASA physical status I and II were randomly assigned to one of five different premedication groups: 3.75, 7.5, 11.25, 15 mg midazolam, and placebo. The medication was given in a double-blind fashion 60 min before induction of general anaesthesia for various surgical procedures. At 3 definite stages (before premedication, 30 and 60 min after premedication), blood pressure, heart rate, transcutaneous oxygen saturation and respiratory rate were measured. Sedation and well-being were graded according to a 5-point scale, and the subjective anxiety level was assessed according a visual analogue scale (range 0-100 mm). Anterograde and retrograde amnesia were measured by recall of auditive and visual stimuli. Finally, patients were asked whether in case of future surgery they would prefer the same or a different medication. RESULTS: Demographic data were similar in all groups. There was no significant difference in respiratory rate, oxygen saturation, blood pressure or heart rate. Alertness declined only after 60 min in the groups treated with 7.5 mg and more midazolam. During the entire measurement period, anxiolysis was not different from placebo in any of the midazolam groups. In comparison to placebo, all midazolam groups showed a statistically significant and dose dependent anterograde amnesia for visual stimuli. Subjective well-being scores showed no differences between the groups. Only few side effects were seen following doses of 7.5 mg and higher, including ptosis, strabismus, diplopia, speech disorders, disorientation and vertigo. The majority of patients in all groups indicated a wish for the same medication in case of future anaesthesia for surgical interventions. CONCLUSIONS: Midazolam administered orally prior to surgical procedures showed marked interindividual variability. Sedation and amnesia were dose-dependent and were evaluated by the patients as acceptable. Anxiolysis was not significantly different from placebo. A dose of 7.5 mg midazolam showed the best relation between desirable and undesirable effects. Adequate attention given to the patient by the anaesthesiologist prior to surgery seems to be as important and beneficial as oral medication with midazolam.     

Punishment alters the discriminative stimulus effects of midazolam.

Experiment 1 examined the effects of punishment on the discriminative stimulus (DS) effects of midazolam (M) and pentobarbital (P) in 3 pigeons. Sessions began with a fixed-interval (Fl) 3-min schedule of food reinforcement. After 40 min, either saline (S) or 0.56 mg/kg of M was injected. A drug-discrimination (DD) component began 10 min later. Pecking the left key produced grain after S injections, whereas pecking the right key produced grain after M. Dose-response curves for M and P were obtained under these conditions and also when every 30th peck during the Fl was punished by shock. The introduction of punishment increased sensitivity to the DS effects of M and P. Experiment 2 examined whether a punishment history increases sensitivity to the DS effects of M. After DD training and testing, pecking was punished for 10 sessions. This history shifted the M dose-response curve to the left for 3 of 4 pigeons. These results emphasize the contribution of behavioral variables to the DS effects of drugs. Environmental variables appear to play a prominent role in guiding sensitivity to the subjective effects of drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nutrients that modify the speed of internal clock and memory storage processes.

Two experiments assessed the effects of nutrients on timing behavior by rats. The nutrients were laced with saccharin and given to rats as a snack before training on a 20-s peak-interval procedure. The primary component of the snacks for four groups of 10 rats was lecithin (phosphatidylcholine), protein (casein), carbohydrate (sucrose), or a nonnutrient (saccharin). The primary measure of behavior was the time of the rat's highest response rate during a trial (peak time), which represented the interval during which the rat maximally expected food. With a lecithin snack, peak time was gradually shifted over sessions to a shorter time, remained shifted to the left of the normal function with additional testing, and then remained at the shorter time on two sessions after the snack was discontinued; with the protein snack, peak time was abruptly shifted to a shorter time, returned to normal with additional testing, and then rebounded to a longer time when the snack was discontinued; with a carbohydrate, snack peak time was abruptly shifted to a longer time, returned to normal with additional testing, and then rebounded to a shorter time when the snack was discontinued. The behavioral patterns produced by the nutrients were interpreted in terms of precursor effects on central neurotransmitter synthesis and release, psychological stages of an information-processing model, and mathematical parameters of a scalar timing theory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Group sensitivity training: Update, meta-analysis, and recommendations.

This investigation was a meta-analysis of the effectiveness of group sensitivity training. Analysis of 63 studies revealed a moderate size, heterogeneous effect (weighted mean d?=?0.62) on all outcome measures. Categorical model testing indicated that group sensitivity training had significantly larger effects on behavioral measures than on self-report measures (mean ds?=?1.03 and 0.44, respectively). Moreover, effect sizes for behavioral measures were moderated by the size of treatment groups, the number of sessions, and the precision of measurement recording. That is, interventions involving larger groups and meeting for more sessions had larger effect sizes, as did studies involving more discrete outcome measures. As recommended elsewhere, future studies need to explore group processes and mechanisms of change in group sensitivity training. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of a sexual enhancement and a communication training program on sexual and marital satisfaction.

A total of 30 volunteer couples were randomly assigned to a sexual enrichment, a communication training, or a wait-list control condition. The sexual enrichment and communication training groups met for 3-hr sessions, 1 day per week for 4 consecutive weeks. All three conditions were assessed immediately before, immediately after, and again 3 months after completion of the programs. Analyses of covariance revealed that wives who participated in the sexual enhancement program derived more pleasure from their sexual relationships than did wives in the other two groups. In addition, participants in the sexual enhancement program felt there was a greater amount of affectional expression, and rated their overall marital satisfaction as significantly improved. Couples participating in the communication training program also evinced limited changes in their sexual and marital relationships, whereas couples in the wait-list control condition reported no changes. We conclude that communication training is an important component in sexual enrichment programs and that more evaluative research is needed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Some sources of variation in the bar-pressing versus freeloading phenomenon in rats.

Gave 40 albino rats a choice between barpressing for food or taking it freely from a dish. In Exp I Ss were given 3 days of free-food training and 6 days of barpress training before the choice. In Exp II the number of prechoice bar presses was varied within the choice sessions, and in Exp. III the choice sessions were extended over 10 days. In all 3 experiments the mean number of pellets obtained via bar pressing was over 70%. In Exp IV and V the amount of time spent and the number of pellets obtained in freeloading and barpressing were equalized. In both studies Ss greatly preferred to freeload. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of oral cocaine on intravenous cocaine discrimination in humans.

This study was designed to evaluate the drug discrimination paradigm as a model for assessing the ability of potential agonist medications to block the effects of intravenous cocaine. Previous research has demonstrated that oral cocaine attenuated the subjective and physiological effects of intravenous cocaine injections, and in the absence of a known efficacious medication for cocaine use disorders, a proof-of-concept approach was used in which cocaine was acutely administered orally to block intravenous cocaine's discriminative-stimulus effects. During training, 11 cocaine-dependent participants were able to discriminate between intravenous saline and 20 mg/70 kg iv cocaine, and 8 of these participants completed the study. After training, participants ingested capsules containing either placebo or 300 mg/70 kg cocaine 60 min prior to the intravenous injection of different doses of cocaine during test sessions with no contingencies in place. Each cocaine dose was administered twice, once under each oral pretreatment condition. Training sessions were interspersed among the test sessions. Physiological and subjective effects were measured throughout each session. Oral cocaine moderately increased some of the subjective and physiological effects of the lower doses of intravenous cocaine, whereas effects at the higher doses were unaltered. Similar changes were seen for the discrimination results. Thus, although oral cocaine given acutely likely is not a viable treatment medication for cocaine dependence, the usefulness of the drug discrimination model in the evaluation of agonist treatment medications remains unclear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of Exercise on Pavlovian Fear Conditioning.

Exercise promotes multiple changes in hippocampal morphology and should, as a result, alter behavioral function. The present experiment investigated the effect of exercise on learning using contextual and auditory Pavlovian fear conditioning. Rats remained inactive or voluntarily exercised (VX) for 30 days, after which they received auditory-cued fear conditioning. Twenty-four hours later, rats were tested for learning of the contextual and auditory conditional responses. No differences in freezing behavior to the discrete auditory cue were observed during the training or testing sessions. However, VX rats did freeze significantly more compared to controls when tested in the training context 24 hr after exposure to shock. The enhancement of contextual fear conditioning provides further evidence that exercise alters hippocampal function and learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)