Robert T. Harris

Evaluation of reinforcing capability of delta-9-tetrahydrocannabinol in rhesus monkeys

Harnessed rhesus monkeys, surgically prepared with indwelling jugular catheters, were given access by means of remotely controlled infusion pumps to unlimited quantities of delta-9-trans-tetrahydrocannabinol. Naive monkeys as well as monkeys which were automatically infused with THC for over 28 days did not self-administer THC. Monkeys which had a history of multiple drug self-administration also did not self-infuse THC.

Discriminative response control by d-amphetamine and related compounds in the rat.

Rats were trained to discriminate between two levers utilizing drug-induced physiological states as discriminative stimuli. Drug injections were associated with reinforcement of response on one lever and saline was associated with reinforcement on the other lever. At equimolar doses, d- and l-amphetamine but not para-hydroxyamphetamine, functioned effectively as cues. Following training, stimulus generalization between these drugs was evaluated. Transfer of response control was observed between the d- and l-isomers, and between para-hydroxyamphetamine and saline in rats trained to utilize d- or l-amphetamine versus saline as cues. These findings suggest the importance of central pharmacological activity in this type of response control.

Behavioral effects in rhesus monkeys of repeated intravenous doses of 9-tetrahydrocannabinol.

In two separate experiments effects were evaluated of chronic administration of δ-9-THC (i.v.) on the behavior of rhesus monkeys trained on a multiple schedule of food reinforcement and a shock avoidance schedule. Rapid tolerance to drug effect was observed on avoidance responding; but only partial tolerance on food reinforced responding. Only a minor degree of tolerance was noted on gross behavior. In both experiments, tolerance to the drug carried over a 30-day drugfree period.

Preference studies of triazolam with standard hypnotics in out-patients with insomnia.

One hundred and four patients suffering from insomnia took part in four different two-night double-blind crossover trials of triazolam. In three separate studies, triazolam 0·5 mg was compared to placebo, flurazepam 30 mg and chloral hydrate 500 mg. Triazolam 0·5 mg was found to be preferred and to be superior to placebo, flurazepam and chloral hydrate in the treatment of insomnia. Analysis of sleep questionnaire data showed triazolam to be superior to the other treatments on the following: How much did the medication help you sleep, onset of sleep, duration of sleep and number of awakenings. Additionally, triazolam was superior to chloral hydrate on the feeling in the morning parameter. In another comparison of triazolam 0·25 mg to flurazepam 15 mg, triazolam was not significantly better than flurazepam on any of the efficacy parameters except that the patients felt more alert the morning following triazolam than following flurazepam. On all efficacy endpoints, trends for all parameters favoured triazolam 0·25 mg over flurazepam 15 mg. Untoward side-effects in these four studies were minimal.

Biological activities of some 5-substituted N,N-dimethyltryptamines, α-methyltryptamines, and gramines

SummaryThree series of derivatives of N,N-dimethyltryptamine, α-methyltryptamine and gramine bearing substituents of varying electronic nature on the C-5 position were tested for acute toxicity, effect on barbiturate sleeping time, antireserpine effect, swim maze, variable interval conditioned behavior, and inhibition of monoamine oxidase. No correlation could be made between the electronic effects and their pharmacological activities. It was thus suggested that there exist different pharmacological receptors for the tryptamines and gramines.

Self administration of minor tranquilizers as a function of conditioning

SummaryAn attempt was made to develop pronlonged preferences in rats for quinine, LSD, nicotinic acid, meprobamate and chlordiazepoxide. It was found that forced ingestions of the drugs had no enduring effects on subsequent free choice preference intakes. When the animals were conditioned to drink the drugs in order to obtain food pellets, it was found that they developed increased preferences for meprobamate and chlordiazepoxide which endured over a 21 day free choice period. The results are interpreted as showing that through pairing with food several of the drugs acquired secondary reinforcing properties which were responsible for their sustained drinking by the animals.

Double-Blind Placebo-Controlled Efficacy Study of Ketazolam (U-28,774)

The safety and efficacy of ketazolam (15 mg capsules) was compared to placebo in seventy-nine out-patients suffering from psychoneurotic anxiety, moderate or worse in severity. A flexible dosage range of 15-75 mg was used in this double-blind study lasting twenty-eight days. The average optimum therapeutic dose of ketazolam was 46.9 mg administered as a once-a-day dose at bedtime. Ketazolam was found to be significantly better than placebo in alleviating anxiety and its concomitant symptomatology as measured by the Hamilton Anxiety Rating Scale, three Physicians Global Impressions, two Patients Global Impressions, and three Target Symptoms. Fifteen patients dropped from the placebo group before completion of the study, and two withdrew from the ketazolam group. The patients receiving ketazolam experienced a greater reduction in symptomatology throughout the study when compared to the placebo group. Side-effects experienced by the ketazolam patients were less than, or equal to, the placebo patients. No deleterious side-effects occurred. No differences between the two groups were found for vital signs, EKGs, laboratory tests, or physical examinations.

Behavioral, biochemical and maturation effects of early DL-para-chlorophenylalanine treatment

DL-para-Chlorophenylalanine was administered to albino rats daily from within eight hours of birth for various lengths of time during the 30 day postnatal cortical development period. In experiment one, whole brain serotonin and plasma phenylalanine were measured 24 and 72 h post treatment in 7, 14, 21, and 28 day rats. The data are interpreted as supporting the hypothesis that DL-para-chlorophenylalanine may be used to institute the biochemical characteristics of phenylketonuria. The DL-para-chlorophenylalanine-treated Ss weighed significantly less at 14 days of age and thereafter and, also, were less strong. One hundred mg/kg DL-para-chlorophenylalanine was administered daily from birth through day 30 for experimental Ss of studies two and three. In experiment two maturation indices were reported to be retarded in drug-treated Ss for behaviors involving the skeletal-muscular system and activity measures were reported to be lower at 25, 45, and 121 days of age. Experiment three showed that acquisition of a conditioned pole climb avoidance and/or escape response measured at 180 days of age was poor in early drug-treated Ss. These data were interpreted as indicating that early DL-para-chlorophenylalanine-treated Ss show some degree of behavioral deficit at maturity.

Suppression of the cardiac conditioned response by ?-9-tetrahydrocannabinol: A comparison with other drugs

Using classical conditioning procedures, the cardiac conditioned response (CCR) was established by pairing one of two tones with the delivery of a peripheral electric shock in Rhesus monkeys. The other tone had no terminal consequence. Such a procedure results in an anticipatory ‘anxiety’ or ‘fear’ response to the impending shock signalled by the reinforced tone. The heart rate before the tone in two of the animals was characterized by tachycardia and by bradycardia in the other animal. The effect of intravenous Δ-9-tetrahydrocannabinol (THC) was compared to various doses of diazepam, chlorpromazine, and morphine. The results indicate that THC blocks the CCR in a dose-related manner. The effects of THC were similar to diazepam, an anti-anxiety drug. Chlorpromazine and morphine affected the conditioned response in an unreliable manner, and both drugs would attenuate the response in some cases and potentiate it in other instances.

Effects of Δ-9-tetrahydrocannabinol on appetitive- and aggressive-rewarded maze performance in the rat

Forty-two rats were trained in a T-maze with the opportunity to obtain food (21 rats) or attack a frog (21 rats) as a reward for choosing the side designated correct Following training, three dosage levels of Δ-9-tetrahydrocannabinol were administered. Differential effects of drug administration on behavior were found to be a function of the type of reward employed, indicating that Δ-9-tetrahydrocannabinol had a more profound inhibitory effect on aggression than on appetite.