Effects of drug-state changes upon black-white discrimination learning in rats

Rats were trained on a black-white discrimination task, being motivated by electric shock. After reaching a criterion of 18 out of 20 correct responses in the original discrimination learning (L1), the same discrimination learning was repeated twice (L 2 and L 3) to the same criterion. Rats were exposed to either a drug-induced state (20 mg/kg CDP) or an undrugged state (saline) at each stage of discrimination learning.Chlordiazepoxide (CDP) was generally found to retard the discrimination learning both in terms of correct responses and of running times, although the latter effect was more immediate. A shift in drug state produced a decrease in the percentage of correct responses and this effect was quantitatively about the same whether responses had been overlearned (L3) or not (L2). The same dissociative effect was not found in L3 for those rats which had previously been trained in both drug states. Contrary to some previous studies, running times were not state dependent.     

The influence of learning on morphine analgesia and tolerance development in rats tested on the hot plate

The influence of learning on the development of tolerance to the analgesic effect of morphine in rats was examined employing the hot plate procedure. A tested-reinforced (Tr) group and its yoked-control, a tested-non-reinforced (Tnr) group, received identical exposure to the testing procedure; the Tr group was reinforced daily for its behavior on the heated plate whereas the Tnr group was reinforced only on the last day of the experiment. Paired statistical comparisons between these two groups on the last day of the experiment revealed that: 1. premorphine control reaction times on the heated plate were significantly lower in Tr than in Tnr animals; and 2. post-morphine increases in reaction time did not differ between Tr and Tnr animals. It was concluded that whereas some learning does occur in this testing procedure, learning does not influence the behavioral tolerance to morphine which develops in this analgesiometric method. An hypothesis which accommodates this behavioral tolerance and a mechanistic scheme is offered.     

Failure obtain “cannabis-directed behavior” and abstinence syndrome in rats chronically treated with Cannabis sativa extracts

Experiments were performed to verify whether chronic treatment with Cannabis saliva extracts would induce dependence and/or abstinence symptoms in rats. In Experiment one, rats ingested cannabis extract as the only fluid for 126 days. On days 1, 43, 48, 62, 80, 92 and 119 when the animals were in abstinence from previous administration of marihuana for 0 to 96 h, behavioral measures and choice tests between marihuana suspension and control solution were carried out; the rats preferred to drink the control solution and no behavioral symptoms indicating abstinence were noted. In Experiment two, rats were trained to drink a marihuana suspension or control solution in order to be rewarded with sweetened milk. After 22 sessions water was substituted for the milk. Extinction curves for both groups were similar, and in choice tests among cannabis suspension, water and control solution, the animals refused to drink the marihuana suspension. In Experiment three, rats received i.p. injections of a cannabis extract or control solution during 36 days. From days 37–40 the drugs were withheld and sensitivity to penty-lenetetrazol was assessed. Marihuana chronically treated rats were more resistant to convulsions and fewer died after pentylenetetrazol. In Experiment four, rats were treated with marihuana extract, control solution or sodium barbitone during 73 days. At days 74–76, when undergoing 24, 48 and 72 h of abstinence, the animals were exposed to sound from a bell. Animals in abstinence from barbitone showed a high incidence of convulsions; marihuana treated rats did not differ from control animals.These results suggest that rats do not self administer marihuana (Experiments one and two) and do not present abstinence symptoms after prolonged periods of ingestion of the drug (Experiments 1, 3 and 4).This work was partially aided by CNPq and is part of the thesis of Doctor of Sciences by J. R. Leite. A summary of experiment one of this paper was read at the Symposium on Cannabis and its derivatives-Pharmacology and Experimental Psychology, arranged by the Institute of Drug Dependence, London, May 1972.With a fellowship from FundaÇÃo de Amparo á Pesquisa do Estado de SÃo Paulo (FAPESP).Pesquisador conferencista-Bolsista de Conselho Nacional de Pesquisas (CNPq).     

The effects of chronic cannabis treatment upon brain 5-hydroxytryptamine,plasma corticosterone and aggressive behavior in female rats with different hormonal status

Ovariectomized rats, chronically treated with cannabis extract or control solution, were given different hormonal treatments. Results indicated that both cannabistreated and estrogen-treated animals were more aggressive than controls. Furthermore, aggressiveness was virtually abolished when cannabis-treated females were made sexually receptive by estrogen and progesterone treatments. After 25 days of cannabis or control solution treatment, all subjects were sacrificed. The levels and turnover rate of brain 5-HT and peripheral plasma corticosterone were then assayed. Data indicated both a significant inverse relationship between plasma corticosterone and whole brain levels of 5-HT (r=–0.742 to –0.985) for all groups and a significant positive relationship between aggressive behavior and plasma corticosterone (r=+0.675 to +0.946) in all groups that were fighting prior to decapitation. Results are tentatively explained, suggesting that the variability of the female response to stress during the different phases of the estrus cycle, permitted them to perform differently after chronic cannabis treatment. 5-HT is apparently involved, either directly in its effects on aggressive behavior or indirectly through the pituitary-adrenocortical axis activation.     

Structure activity relationship of four tetrahydrocannabinols and the pharmacological activity of five semi-purified extracts of Cannabis sativa

The structure activity relationships of four tetrahydrocannabinols and the pharmacological activity of five semi-purified extracts from Cannabis sativa were studied using four biological methods: corneal areflexia in rabbits (Gayer test) and catatonia, decrease of motor activity and suppression of isolation-induced aggressiveness in mice. Modifications in the structure of pure, natural ⁹-THC rendered the resultant compounds inactive only when activity was measured by the Gayer test; by the other three methods the activity ranged from 1/5th to equal to the activity of pure ⁹-THC. It was concluded that of the methods employed, the Gayer test was the only useful procedure to measure ⁹-THC content in mixtures. This was confirmed by the relationship found between ⁹-THC content and activity using five semi-purified extracts.Read before the XX Annual Meeting of the Brazilean Society for the Advancement of Science. This research was partially supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).     

Learned behavioral tolerance to marihuana in rats

Rats were trained to press a lever for food reinforcement in one study and water reinforcement in a second. Rats which received marihuana extract each day before behavioral testing showed an impairment of responding on the first day of drug application, but developed behavioral tolerance to the drug by the sixth day of drug application. Rats which received equal doses of marihuana after each session, rather than before, over the same period, showed little or no evidence of behavioral tolerance when the drug was administered before testing. This result was interpreted to indicate that the development of behavioral tolerance to marihuana involves a learning process.     

A test of state dependency effects in marihuana intoxication for the learning of psychomotor tasks

Cannabis cigarettes calibrated to deliver 7 mg ⁹-THC were administered to experienced cannabis users and to novices in a 2×2 state-dependency learning design using psychomotor tasks. Subjects given four training sessions under marihuana performed no better on the fifth (test) session with the drug than those subjects who had trained in the non-drug condition and were tested in the drug condition. Cannabis-induced impairment in the performance of these tasks is such that prior training in the non-drug condition appears to confer no advantage to the subject. There was no evidence of state-dependency effects in psychomotor performance between drug and non-drug conditions.     

Aggressive behaviour elicited in rats by Cannabis sativa: effects of p-chlorophenylalanine and DOPA

The influence of p-chlorophenylalanine (PCPA) and dihydroxyphenylalanine (DOPA) on aggressiveness elicited by marihuana in starved rats was studied. PCPA and DOPA potentiated several-fold this behavioural manifestation; the potentiation was still greater when the animals received both drugs. On the other hand, PCPA and DOPA alone or in combination, but without marihuana, failed to elicit aggressive behaviour in starved rats. Aggressiveness did not appear when rats fed ad libitum were treated with PCPA, DOPA and marihuana. The role played by starvation, PCPA and DOPA on the capability of marihuana to induce aggressive behaviour in rats is discussed.     

The effects of Cannabis sativa on the behavior of adult female chacma baboons (Papio ursinus) in captivity

Indices of locomotory and social activity were quantified during 102 h of daily tests with two pairs of baboons under three conditions: baseline, cannabis administration, and postdrug withdrawal. Six percent of whole dried plants of cannabis (33 g) was incorporated into the daily feed. In one pair, social activity increased during cannabis administration, with no clear effect on locomotory behavior. In the second pair locomotory activity decreased, but there was no consistent change in social interaction. Thus individuals responded differently to the drug, and the social environment of each pair appeared to be implicated as a determining factor.     

Effects of marihuana extract on the operant behavior of chimpanzees

Six chimpanzees were trained to panel push under a food reinforcement baseline in which three operant schedules, each associated with a different stimulus, were presented successively. The fixed ratio (FR) reinforcement schedule required the emission of 40 responses for reinforcement. Reinforcement under the differential reinforcement of low rate (DRL) schedule was delivered only when successive responses were spaced by at least 10 sec. During the extinction or time out from positive reinforcement schedule (TO), no responses were reinforced. In Experiment 1, amounts of marihuana extract containing from 0.2 to 4.0 mg/kg (?)-Δ ⁹-trans-tetrahydrocannabinol (Δ ⁹-THC) were orally administered 1 h prior to experimentation. In Experiment 2, 1.0 mg/kg Δ ⁹-THC was orally administered between 1 and 23 h prior to experimental sessions. No disruption of stimulus control or drug effects during TO were observed. Both DRL and FR response suppression occurred at the highest drug dose. Lower Δ ⁹-THC doses produced facilitation of DRL responding up to 12 h following drug administration. Although FR responding was less sensitive, Δ ⁹-THC stimulated FR behavior from 2 to 5 h following drug administration. It was concluded that marihuana has a biphasic effect on food reinforcement schedule controlled operant behavior.     

Impaired tolerance to the effects of oral amphetamine intake in rats with frontal cortex ablations

When offered a solution of d-amphetamine sulphate (0.025 mg/ml) in place of water, normal rats initially drank more drug solution per day than previously consumed water. The drug solution quickly became aversive to normal rats as daily intake decreased. Tolerance to the anorexic effect of d-amphetamine paralleled the decrease in daily drug intake. Rats with bilateral lesions of frontal cortex initially consumed as much drug solution and as much food as normal rats. Although frontal rats' daily intake of drug solution also decreased, an aversion never developed. Tolerance to d-amphetamine's anorexic effect took much longer to occur in frontal rats. The results indicated possible roles for both cumulative drug effects and conditioning factors in the response to chronic d-amphetamine use. A possible mechanism by which frontal cortical lesions interfered with chronic changes was suggested.This research was supported by NIMH grant 1 R01 MH-21554-01 to S. D. Glick. The author thanks S. Greenstein and M. Angerola for indispensable technical assistance.     

The nature of ecstasy-group related deficits in associative learning

Rationale/objectives Research has revealed associative learning deficits among users of ecstasy; the present study explored the component processes underlying these deficits.Methods Thirty-five ecstasy users and 62 non-ecstasy users completed a computer-based, verbal paired-associates learning task. Participants attempted to learn eight sequentially presented word pairs. After all eight had been presented, the first member of each pair was displayed and participants attempted to recall the second. Eight trials were administered. Correct responses on each trial, forgetting at various levels of learning, perseveration errors and the rate at which the associations were learned (trials to completion) were all recorded.Results MANOVA revealed that ecstasy users performed worse overall and subsequent ANOVAs showed that users performed significantly worse on virtually all measures. Regression analysis revealed that over half of the ecstasy-group related variance in trials to completion was attributable to group differences in initial learning and forgetting. In relation to forgetting, it appears that cannabis use may be an important determinant. In relation to rate of learning (trials to completion) and initial learning, both ecstasy and cannabis may be implicated.Conclusions There appears to be abundant evidence of associative learning deficits among ecstasy users. However, it appears that a range of illicit drugs including cannabis and ecstasy may contribute to these deficits.     

Avoidance conditioning in different strains of rats: Neurochemical correlates

Two-way avoidance conditioning was compared in three strains of rats: Roman high avoiders (RHA), Roman low avoiders (RLA) and control Sprague-Dawleys (SD). RHAs performed more and RLAs fewer avoidance responses than SDs. RLAs injected with d-amphetamine improved their performance to levels comparable to SDs; however, d-amphetamine caused a time-dependent increase in intertrial crossings for the RLAs. Of the three strains, the RLAs had the lowest activities of tyrosine hydroxylase, dopamine--hydroxylase and phenylethanolamine-N-methyltransferase in their adrenal glands. Although there were no significant differences among the strains in respect to tyrosine hydroxylase activity in whole brain or regions, RLAs had higher dopamine--hydroxylase activity in the whole brain and cerebral cortex as compared to the SDs. RLAs and RHAs together had a significantly different turnover of intracisternally administered ³H-norepinephrine than SDs. After the intracisternal injection of ³H-L-tyrosine, twice as much ³H-dopamine accumulated in the brains of RLAs as compared to RHAs and SDs.     

Comparison of behavioral effects of synthetic (−)δ9-trans-tetrahydrocannabinol and marihuana extract distillate in chimpanzees

Eight chimpanzees emitted panel push responses under a procedure in which three operant schedules of positive reinforcement, each associated with a different stimulus, were presented successively. The fixed ratio (FR) schedule required the emission of 40 responses for reinforcement. Reinforcement under the differential reinforcement of low rate (DRL) schedule was delivered only for a response that followed the immediately preceding response by 10 or more sec. No responses were reinforced under the extinction or time out from reinforcement (TO) schedule. The behavioral effects produced by a marihuana extract distillate containing a known amount of (–) ⁹-trans-tetrahydrocannabinol ( ⁹-THC) were compared with those produced by a totally synthesized ⁹-THC. On four separate drug days each chimpanzee was orally administered one of the two compounds 2.5 h prior to experimentation in amounts yielding 1.0 mg/kg ⁹-THC. Only the DRL schedule performance was significantly affected by either drug compound. Both the marihuana extract and the synthetic ⁹-THC produced a statistically significant decrease in the percentage of correct DRL responses. However, no statistically significant differences between the drug effects produced by the two ⁹-THC dose forms were obtained.The authors wish to thank Michael Grisham for his help in collecting the data and Dr. Monique Braude for her continued support and guidance. Research supported by National Institute of Mental Health Contract No. HSM-42-71-15. Synthetic ⁹-THC and Marihuana Extract Distillate obtained by approval of the FDA-NIMH Psychotomimetic Agents Advisory Committee. The animals involved in this study were maintained in accordance with Guide for Laboratory Animal Facilities and Care as published by the National Academy of Sciences-National Research Council.     

Reduction of the antinociceptive effect of 5-hydroxytryptophan in morphine tolerant rats

The effect of 5-hydroxytryptophan on pain threshold was studied in rats both tolerant and nontolerant to the analgesic action of morphine as assessed using a procedure of electrical stimulation. The compound elevated pain threshold and exhibited an additive effect with morphine analgesia in nontolerant rats. A marked reduction of the antinociceptive action of the serotonin precursor as well as absence of the additive effect with morphine was observed in rats tolerant to the analgesic. These results are discussed in terms of the possible mechanism of action of serotonin on morphine effects.     

Pirenperone does not attenuate morphine analgesia in spinal rats

In the elevated plus-maze test of anxiety the scores of control animals remain stable over repeated tests. However, a single prior exposure to the plus-maze renders an animal insensitive to the anxiolytic effects of chlordiazepoxide. This phenomenon of one-trial tolerance persisted even when the two trials were separated by as much as 2 weeks. It has previously been shown that the drug state of the animal on trial 1 is not important to the development of the phenomenon, but one-trial tolerance did not develop if a very high dose (75 mg/kg) of chlordiazepoxide was given on trial 1; it is suggested that this is due to the amnesic effects of the drug. The learning on trial 1 was not specific to a particular plus-maze and tolerance could be observed even when the maze on trial 1 was made from different material. The crucial experience on trial 1 was experience of an open arm of the maze. Whereas tolerance could be obtained as a result of a previous plus-maze experience, there was no evidence of an anxiogenic withdrawal response when rats were tested the following day undrugged. The phenomenon of one-trial tolerance is explained within our recently proposed two-factor theory of benzodiazepine dependence; it is suggested that one-trial tolerance provides a method for studying the mechanism underlying the development of tolerance to anxiolytic effects, independently from the mechanism underlying the development of withdrawal responses.     

Impairments in water maze learning of aged rats that received dextromethorphan repeatedly during adolescent period

Rationale Dextromethorphan (DM), an over-the-counter cough suppressant, has been recently used as a drug of abuse by teenage groups in some countries, such as the United States, Canada, and Korea. We previously showed that repeated administration of DM, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors, impairs spatial learning performance in adolescent rats. Objectives In the present study, long-term adverse effects of repetitive DM use at adolescence were examined in rats. Methods Male and female Sprague–Dawley rat pups received either intraperitoneal DM (40 mg/kg) or saline daily during postnatal days 28–37, and were then subjected to the Morris water maze task at the age of 18 months. Expression levels of NMDAR1, functional subunit of NMDA receptors, in the prefrontal cortex and the hippocampus were examined by Western blot analysis. Changes in plasma corticosterone levels responding to stress were determined by radioimmunoassay. Results DM-experienced male rats exhibited deficits in the probe trial, and female rats in the initial learning and the reversal training, in water maze performance. Expression levels of NMDAR1 in the brain regions were significantly increased in DM-experienced rats, compared to control rats. Stress-induced increases in plasma corticosterone levels were blunted both in male and female DM rats. Conclusions The results suggest that repeated administration of DM at high doses during adolescent period may induce permanent deficits in cognitive function and that increased expression of NMDAR1 in the prefrontal cortex and the hippocampus may take a role in DM-induced memory deficits.     

Analysis of the acquisition and extinction of food-reinforced behaviour in rats after the administration of chlorpromazine

The effects of chlorpromazine (2 mg/kg) on the acquisition of lever-pressing behaviour for food rewards have been examined in rats. The drug greatly impaired performance during acquisition but, during a subsequent non-drug testing session, performance was only slightly below that of controls trained and tested under saline; giving the drug to control rats before the testing session markedly impaired performance. It was concluded that chlorpromazine acted mainly on factors, such as attention or motor ability, which were important both during and after acquisition, and that it had little action on central learning processes. Dissociation of learning between drugged and non-drugged states did not occur; changes in drug state even increased responding during extinction, but not during continuous reinforcement. Simple depressant effects of chlorpromazine on attention and motor ability do not seem adequate to account for this, and a further possibility is that the changes in drug state minimised emotional responses elicited by the omission of rewards.     

Anorexic activity of cocaine and coca extract in naive and cocaine tolerant rats

Dose response curves for reducing limited access food consumption were determined for cocaine HC1 IP, cocaine HC1 PO, and whole Erythroxylum coca extract PO. The ED₅₀'s for cocaine HC1 in drug naive rats were 19.6 mg/kg (IP) and 34.6 mg/kg (PO). When the dose of E. coca extract was expressed in terms of cocaine HC1 content, the ED₅₀ was 52.6 mg/kg (PO). When dose response curves were determined in rats that had received cocaine (45 mg/kg, PO) for 30 days, a shift to the right in the cocaine HC1 curve (an ED₅₀ of 98.4 mg/kg PO) indicated tolerance. However, the shift to the right was less for E. coca extract than for cocaine HCI. Although the anorexic activity of E. coca extract was less than that of an equivalent amount of cocaine in naive rats it was often more than that of equivalent doses of cocaine HC1 in tolerant rats. Interaction with other constituents of E. coca extract appears to alter the potency of the cocaine content of the extract in different directions in naive and tolerant rats.     

(+)-Amphetamine oral 'drug taking behavior' in naive and tolerant rats

The drinking behavior of naive rats changes predictably in a free choice experiment involving water vs. 0.02%, 0.01% and 0.003% (+)-amphetamine solutions: The higher the concentration of the amphetamine solution, the sooner a number of rats quit drinking it, and the less is ingested by those still drinking it. Physically dependent rats having undergone three withdrawals immediately reject (+)-amphetamine solution in a free choice test with water available. The avoidance of withdrawal symptoms does not motivate further self-administration. Therefore, (+)-amphetamine self-administered in drinking water is neither a reinforcer for naive nor for physically dependent rats in sustaining drug taking behavior. In acute and chronic experiments, the transition from increased motor activity to stereotypical behavior could be demonstrated and evidence was produced that tolerance develops to the (+)-amphetamine-induced increase in motor activity.