Richard E. Musty

Attenuation of hyperactivity in the spontaneously hypertensive rat by amphetamine

Several experiments show that spontaneously hypertensive rats (SHR) are behaviorally hyperactive when compared with their normotensive Wistar Kyoto (WKY) progenitor rat strain. Behavioral hyperactivity was present in both 3-min open-field tests as well as in 1-hr tests using an automated activity recording chamber. In addition, under certain conditions, d-amphetamine (1.25–3.5 mg/kg) decreased activity in the SHR while inducing the expected increase in activity in the WKY. Further analysis of these data shows that the attenuation of SHR behavioral hyperactivity by amphetamine can be predicted based upon rate dependency of the actions of d-amphetamine. The SHR may provide a valuable animal model for studying spontaneous hyperactivity and for investigating the neurochemical basis of the so-called “paradoxical response” to amphetamine as seen in children.

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.

Effects of Δ9-Tetrahydrocannabinol and Cannabinol in Man

The interaction of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabinol (CBN) was studied in man. Five male volunteers were given placebo, 50 mg CBN, 25 mg Δ9-THC, 12.5 mg

Passive avoidance and amygdala lesions: Relationship with pituitary-adrenal system

Abstract The present study was designed to determine whether or not passive avoidance learning deficits produced by amygdala lesions are related to a lesion produced abnormality in the response of the pituitary-adrenal system to footshock induced stress during conditioning. Rats with amygdala lesions demonstrated significant learning deficits for 1 trial passive avoidance conditioning when compared with unoperated or surgical control rats. The deficits were not a function of altered footshock sensitivity nor increased activity in the animals with lesions. Injections of adrenocorticotropic hormone (ACTH) either prior to or immediately following the conditioning footshock did not significantly attenuate the learning deficits in animals with lesions and had no effect on learning in control animals. No significant alterations in plasma corticosterone levels were found in rats with amygdala lesions in response to the footshock induced stress of conditioning. The results suggest that passive avoidance learning deficits in rats with amygdala lesions are not related to an abnormal pituitary-adrenal response to the stress of avoidance conditioning.

Criterion for learned helplessness in the rat: A redefinition

Numerous investigators have reported difficulty obtaining reliable learned helplessness. Various laboratories have used differing test environments and criteria, making comparisons among experiments difficult. Some use an escape deficit criterion, in which escape is slowed down in a shuttle box, while others have used an escape failure criterion, in which rats do not escape at all on most test trials. Little work has been done to test the validity of LH, i.e., the prediction of persistence of escape failure after exposure to uncontrollable shock. The present studies demonstrate that the reliability and validity of learned helplessness can be improved by 1) modifying the shuttle box to increase task difficulty and decrease random escape behavior and 2) adopting a new escape failure criterion for helpless behavior which is based on statistical prediction of the persistence of escape deficits.

Cannabimimetic effects modulated by cholinergic compounds.

This report is based upon a clinical case series describing five patients who volitionally adultered cannabis with a variety of compounds that shared a common trait—cholinergic modulation. They included a nicotinic agonist, muscarinic antagonist and antiacetylcholinesterase compounds. Some of these compounds (e.g. tobacco) are known to exert pharmacokinetic effects upon cannabinoids (e.g. improved drug absorption). Contrarily, our patients claimed that the compounds altered pharmacodynamic ‘cannabimimetic’ effects. The case series was supported by forensic identification of adulterants and by use of a symptom causality algorithm. A survey of the gray literature and drug culture web sites indicated that the case series portended a larger social phenomenon. Furthermore, many clinical reports, animal behaviour studies and in vitro mechanistic studies substantiated our observations. In conclusion, we provide empirical data regarding a new trend in the drug culture—cholinergic modulation of cannabinoid effects—that presents new research directions.

Interstrain aggression in hypertensive and/or hyperactive rats: SHR, WKY, WKHA, WKHT

Four inbred rat strains, all derived from Wistar-Kyoto (WKY) rats, express hypertension and hyperactivity in all combinations: SHRs have both traits, WKYs have neither, WKHAs are hyperactive/normotensive, and WKHTs are hypertensive/normoactive. Rats of the four strains were tested for aggression, at one time only, by pairing subjects of same sex, same age, but different strain, in a novel arena, i.e., on neutral ground, for three consecutive, 5-min observation periods. Total aggression scores were highest in females, highest in the first 5-min period, and lower at 7-9 months than at younger ages. Allogrooming was more frequently observed than other types of aggression, such as attacks, mounts, aggressive postures, and blocks. Allogrooming scores were significantly elevated in the hypertensive strains, especially WKHT, and very low in the hyperactive strains, especially WKHA. The other forms of aggression were significantly higher in females with hyperactivity. It was concluded that interstrain aggression, as seen in SHRs and WKYs, is differentially expressed by two new strains genetically derived from them. Furthermore, no one strain among these four expresses all components of the behavioral responses seen in this form of aggression.

Propranolol interferes with inhibitory behaviour in rats

Although there have been clinical reports that propranolol is associated with psychotic depression in patients receiving the drug for cardiac conditions (Waal, 1967) and that it is as effective as chlordiazepoxide in reducing anxiety in psychiatric out-patients (Wheatley, 1969), Laverty & Taylor (1968) did not find behavioural effects of propranolol in rats and no subsequent reports of behavioural effects of the drug in animals have appeared. However, we have found that propranolol disrupts the performance of rats on a DRL-20 operant conditioning schedule, a task requiring the inhibition for 20 s of a previously learned response in order to receive reinforcement. Twenty male hooded rats, maintained at 80% of their free feeding body weight by food deprivation, were trained to press the bar in a Skinner Box for food reinforcement. Seven daily 45 inin sessions in which each bar press was reinforced, were followed by 15 daily 45 min sessions of DRL-20 on which only responses at least 20 s apart were reinforced. Five min before each DRL-20 session, 5 rats were given a 5 mg/kg intraperitoneal injection of propranolol dissolved in 0.9% saline, 5 rats received 12.5 mg/kg of the drug, 5 rats had saline, and 5 rats had no injection. A two way analysis of variance of the per cent reinforced responses on the DRL sessions showed a significant difference between the control groups and the two drug groups [F(2,17) = 3.99; P 0.051. Fig. 1 shows that less than 10% of the responses of the two drug groups were reinforced on most of the 15 days of DRL, while the two control groups rapidly improved to 30% reinforced responses. Pellegrino (1968) found that ablation of the baso-lateral amygdala of rats disrupted the performance of a DRL-20 task in much the same way as propranolol did in the present study. Horovitz (1966) suggested that the amygdala is the site of action of antidepressant drugs and therefore that the amygdala is implicated in depression psychoses. Schallek & Kuehn (1965) concluded that the amygdala may be involved in the production of anxiety. Thus the effects of propranolol reported by Waal (1967) on depression, by Wheatley (1969) on anxiety, and by our experiments on the performance of a task requiring inhibition of a previously learned response, all parallel suggested functions of the amygdala.

Effects of Marijuana Extract Distillate and Cannabidiol on Variable Interval Performance as a Function of Food Deprivation

Lever-pressing rates plotted as a function of number of hours of food deprivation produces an inverted U curve, the activation performance curve. Since delta 9-tetrahydrocannabinol depresses the response rate on variable interval (VI) performance, it may be that the response depression reflects changes in this curve. Rats were tested VI performance at five levels of food deprivation and were treated with a vehicle control, marijuana extract distillate (MED) at 7.5 and 11.25 mg/kg, cannabidiol (CBD), at 15 mg/kg or combinations: 7.5 mg/kg MED + 15 mg/kg CBD and 11.25 mg/kg MED + 15 mg/kg CBD. MED produced a depression of VI performance which was greatest at low levels of deprivation. CBD did not depress performance. When CBD was conbined with MED, potentiation of depression occurred. The potentiation depression was not additive, but occurred at high levels of deprivation. It appears that MED depresses performance most at low levels of deprivation and that CBD potentiates the depression produced by MED at high levels of deprivation.

Effects of Δ9-Tetrahydrocannabinol on Active Avoidance Acquisition and Passive Avoidance Retention in Rats with Amygdaloid Lesions

Delta9-Tetrahydrocannabinol was administered to rats with basolateral amygdaloid lesions, control rats, and normal rats in doses of 0.75, 1.5, and 3.0 mg/kg i.v. They were trained in a one-session two-way active avoidance task. Delta9-Tetrahydrocannabinol increased the percentage of avoidance and the intertrial crossing rates in all groups, regardless of lesion treatment. Rats with basolateral amygdaloid lesions were not different from controls on any measure. In a second experiment, delta9-tetrahydrocannabinol was administered to rats with basolateral amygdaloid lesions and control rats in doses of 0.75 and 3.0 mg/kg 24 h after learning of a one-trial passive avoidance task, and retention was measured. No differences were found as a function of drug treatment or lesion condition. It was concluded that the basolateral amygdala is not a necessary condition for the action of delta9-tetrahydrocannabinol on active avoidance acquisition, that the drug has no effect on passive avoidance retention, and the basolateral amygdala is not necessary for two-way active avoidance acquisition or passive avoidance retention. Active avoidance results are discussed in terms of a possible relationship between delta9-tetrahydrocannabinol, ACTH, and avoidance learning.