John A. Bedford

Cocaine reinforced progressive ratio performance in the rhesus monkey

A series of experiments were conducted to determine the effectiveness of a progressive ratio (PR) procedure in measuring the relative reinforcing efficacy of several intravenous doses of cocaine. In Experiment 1, utilizing much smaller increases in the ratio requirement than previously reported, the animals generally displayed increases in breaking point with increases in the cocaine unit dose up to 0.4 mg/kg/inj. The highest dose studied (0.8 mg/kg/inj.) engendered breaking points lower than the 0.4 mg/kg dose but higher than the remaining lower doses. Experiment 2 was conducted utilizing the same reinforcement schedule as in Experiment 1 but with liquid Tang as the reward. The results demonstrated that this procedure would function to discriminate reinforcing strength with a more traditional reward. Experiment 3 examined a more expedient procedure to see if results similar to those seen in Experiment 1 could be obtained in a shorter period of time. However, the shorter procedure engendered excessive intrasubject variability, suggesting that some intermediate level of baseline experience between the 5-7 days used in Experiment 1 and the 50 reinforced responses used in Experiment 3 would be necessary to obtain consistent breaking point-unit dose functions.

Comparative behavioral profile of cocaine and norcocaine in rats and monkeys.

The effects of cocaine and norcocaine were compared using locomotor activity, fixed-ratio 100 (FR 100) and fixed-interval 4 min (FI 4 min) food reinforcement and free feeding paradigms in rat and intravenous self-administration tests in rhesus monkeys. Cocaine was shown to significantly increase locomotor activity at doses of 20 and 40 mg/kg, while norcocaine had no effect at these doses and produced convulsions and death at 60 and 80 mg/kg. Both compounds significantly reduced food consumption at one or more of the doses tested. Cocaine and norcocaine at doses of 20 and 40 mg/kg, produced decreases in FR responding. Cocaine at doses of 10, 20, and 40 mg/kg, produced increases in FI responding; norcocaine had no effect following 10 mg/kg and decreased responding at 20 and 40 mg/kg. Cocaine (0.2 mg/kg/inj) and norcocaine (0.5, 0.2, 0.8 mg/kg/inj) maintained intravenous self-administration in all three monkeys tested. The data indicate that norcocaine is a pharmacologically active metabolite of cocaine which could account for some of the activity heretofore attributed to cocaine. However, the lack of any stimulatory effect of norcocaine or locomotor activity and the lack of increased responding produced by norcocaine on fixed-interval behavior suggest that norcocaine differs qualitatively from cocaine.

Sociopharmacology of d-amphetamine in Macaca arctoides ☆

This study was designed to assess the effects of acute d-amphetamine pretreatment on the social behavior of a heterosexual group of adult M. arctoides. The dominance status had been previously determined by use of daily group food competition tests. Prior to some sessions amphetamine was administered to a single group member; whereas on other occasions all subjects were drug treated. The effects of both the individual and concurrent pretreatments were compared to those produced by saline. Furthermore, the effects of individual treatment were compared to those following concurrent dosing. The behavior of the group was monitored for one hour after a fifteen minute pretreatment time. Although generally qualitatively similar, the effects of concurrent and individual treatment were in many instances quantitatively different. d-Amphetamine increased vocalization, self-grooming, playing (low doses), social grooming (low doses), and aggression (low doses). At higher doses most forms of social interaction (playing, social grooming) were greatly decreased. Presenting behavior was increased by all doses under both treatment conditions. Mounting was increased to a much lesser extent and only after concurrent dosing. The increased presenting and mounting may be a result of sexual stimulation or perhaps more likely, an indication of increased submissive behavior directed toward more dominant animals.

Pharmacological manipulation of sincalide (CCK-8)-induced suppression of feeding

The current study involves an investigation of the possible neurotransmitter systems involved in the ability of exogenously administered sincalide (cholecystokinin octapeptide, CCK-8) to suppress feeding. Male rats previously trained to obtain food either during a daily 3-hr session, or conditioned to obtain food pellets on a fixed-ratio or fixed-interval schedule of reinforcement, were treated IP with CCK-8, following pretreatment with representative drugs of several pharmacological classes. Pretreatment with phenoxybenzamine, tolazoline, yohimbine, morphine, haloperidol or picrotoxin reduced the efficacy of CCK-8. However, pretreatment with naloxone or clonidine potentiated the suppressant action of CCK-8 on feeding. Propranolol, diphenhydramine, cimetidine, atropine, d-amphetamine, fenfluramine or diazepam pretreatment either had no effect or no consistent action in altering the activity of CCK-8. The ability of CCK-8 to suppress feeding was not altered by subacute treatment with the anorectics, d-amphetamine or fenfluramine, using a regimen known to induce tolerance. These data indicate that CCK-8 exerts a different mechanism of action than that of fenfluramine or d-amphetamine, and furthermore, that noradrenergic, dopaminergic, GABAergic or endogenous opioid systems either mediate or can modify the effect of CCK-8 on feeding.

The anorexic and actometric effects of cocaine and two coca extracts

The effects of cocaine and two extracts of the coca leaf were compared using locomotor activity and limited access food consumption paradigms. The three treatments were tested using both IP and PO routes of administration. The extracts were prepared by first extracting the powdered leaves with 95% ethanol, evaporating the ethanol and then partitioning the residue between water and chloroform. The doses of the extracts studied were 60, 120, 240, and 480 mg/kg. The doses of cocaine studied were 3.45, 6.9, 13.8 and 27.6 mg/kg. These doses corresponded to the amount of cocaine contained in the four doses of the chloroform layer. Cocaine and the chloroform layer (via both routes) produced dose related increases in locomotor activity and dose related decreases in food consumption. The water layer (containing only trace amounts of cocaine) produced no changes in locomotor activity; however, the highest IP dose did significantly reduce food consumption. Furthermore two of the doses (one IP, one PO) of the chloroform layer produced significantly greater effects than an equivalent amount of cocaine. These data suggest that plant constitutents other than cocaine may contribute to the overall effect achieved by chewing the leaf.

Comparative pharmacology of norcocaine in M. Mulatta and M. Fascicularis

Norcocaine was administered intravenously (0.05, 0.5, 5.0 mg/kg) to three chaired unanesthetized male rhesus monkeys and to three chaired male cynomolgus monkeys. Respiration rate, heart rate and rectal temperature were monitored. In the rhesus monkeys tachycardia and hyperventilation resulted. However, similar qualitative and quantitative changes were not observed in the cynomolgus species. There was a statistically significant difference in the response to norcocaine across species. These results indicate that cynomolgus monkeys are either less sensitive or respond differently than rhesus monkeys to some of the pharmacological effects of norcocaine. Furthermore, these data confirm that norcocaine is an active derivative of cocaine in both rhesus and cynomolgus monkeys.

The effects of cocaine free extracts of the coca leaf on food consumption and locomotor activity

Abstract The effects of two cocaine free fractions of an ethanol extract of the coca leaf (E. coca) were compared using actometric and limited access food comsumption paradigms in rats. Several intraperitoneal doses of two different fractions were tested in both procedures. Neither of the fractions produced any alteration in locomotor activity. Both fractions did, however, produce reductions in food consumption at two or more of the doses tested. The results clearly demonstrate that the coca leaf contains constituents other than cocaine that are biologically active.

Effects of d-amphetamine and diazepam on paired and grouped primate food competition

Two male and two female rhesus monkeys (Macaca mulatta) were the subjects of an experiment designed to assess the effect of d-amphetamine (DA; 0.125, 0.5 and 2.0 mg/kg, IM) and diazepam (DZP; 0.5 and 2.5 mg/kg, IM) on food-getting behavior in paired and group competition. Paired competition results show that in some cases submissive animals, that had previously failed to obtain apple pieces, were successful in obtaining some apple pieces when either the dominant animal of the pair or both subjects were given 0.5 mg/kg DA or 2.5 mg/kg DZP. Results revealed the same effect when all animals (group competition) were given 0.125 and 2.0 mg/kg DA and 2.5 mg/kg DZP. These results appear to indicate that the effect of drugs on food-getting behavior in competitive situations is in some manner influenced by the social status of the animal.

Determination of cannabidiol in plasma by electron-capture gas chromatography.

A procedure was developed for the analysis of cannabidiol (CBD) in blood plasma. Tetrahydrocannabidiol was used as an internal standard and was added prior to extraction. The plasma extracts were derivatized with pentafluorobenzyl bromide and the produce purified on a mini-column of Florisil. The pentafluorobenzyl derivatives were then analyzed by gas chromatography on a 5% OV-225 column using an electron-capture detector. A detection limit of 50 ng CBD per ml of plasma was observed. The procedure was used to study the plasma level of CBD after its oral and intravenous administration to monkeys.

Local anesthetic effects of cocaine and several extracts of the coca leaf (E. coca)

Cocaine and a number of different fractions of a crude ethanol extract of the coca leaf (E. coca) were subjected to a local anesthetic screen using rat tail withdrawal from electric shock. Following an intradermal injection of 0.1 ml of a 2.0% (w.v) solution of cocaine HCl, an immediate response was observed. Two of the coca fractions also produced some local anesthesia. An alkaloidal fraction, containing an equivalent amount of cocaine, produced a maximum effect that was approximately 20% less than that observed with cocaine. The only other fraction producing any effect, a water soluble cocaine-free fraction, showed a maximum response that was approximately 30% of that observed with cocaine.