Marvin C. Wilson

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 discriminative stimulus properties of dl-rmcathinone, d-amphetamine, and cocaine in rats

The discriminative stimulus properties of dl-cathinone (dl-CAT), d-amphetamine (d-A), and cocaine (COC) were compared and effects of haloperidol pretreatment on these properties were studied in rats. The ED50s of each drug were also determined. Stimulus generalization (i.e., greater than 75% of responses occurring on the drug lever) occurred with each of the three training drugs to all three test drugs. The degree of generalization was less between d-amphetamine and dl-cathinone than between d-amphetamine and cocaine or between cocaine and dl-cathinone. No significant differences were observed among the ED50s of each test drug obtained in all three training groups. Pretreatment with haloperidol failed to alter the stimulus properties of dl-cathinone. Haloperidol administration did partially antagonize the stimulus complex induced by d-amphetamine and cocaine. It is concluded that all three agents share somewhat similar but not identical, stimulus properties. The stimulus properties of the training dose of d-amphetamine may be somewhat different from those of dl-cathinone and may be more dependent on functional dopaminergic pathways.

In a drug discrimination procedure isolation-reared rats generalize to lower doses of cocaine and amphetamine than rats reared in an enriched environment

Rats with different behavioral histories, defined by rearing and housing in either an enriched condition (EC) or an isolation condition (IC), were trained in a two-lever operant procedure to discriminate 5.0 mg/kg cocaine from saline. In cocaine dose-generalization tests, the IC rats exhibited an ED50 (1.01 mg/kg) significantly lower than the EC rats (ED50:1.55 mg/kg). The cocaine-appropriate responding was emitted when the rats were treated withd-amphetamine, and for thed-amphetamine test doses the ED50 (0.19 mg/kg) was again significantly lower for the IC rats compared to the ECs (ED50:0.33 mg/kg). These data suggest that IC rats are more sensitive to the stimulus properties of indirect dopaminergic agonists than EC rats and highlight the importance of environmental variables in governing an organisms response to the stimulus properties of abused drugs.

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.

Reproductive toxicity of methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) in male Wistar rats.

Methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) is a systemic fungicide which has been implicated in producing damage to the testes. The present investigation was undertaken to evaluate the functional and behavioral significance of this reported benomyl-induced damage to male rats using a 70-day feeding study followed by a 70-day recovery study. Adult male Wistar rats were fed laboratory chow containing 1.0, 6.3, or 203 ppm benomyl, with control animals receiving standard laboratory chow. Ejaculate sperm counts were significantly depressed (P less than or equal to 0.05) in male ingesting 203 ppm benomyl during the 70 day feeding phase. A significant decrease in relative testicular weights and a lowered male fertility index were observed in all benomyl-treatment groups. No significant alterations in plasma testosterone, LH, or FSH levels were observed during the feeding phase. Benomyl ingestion did not alter male copulatory behavior, nor was benomyl found to be an inducer of dominant lethal mutations. Identical studies performed during the recovery phase demonstrated that the benomyl-induced alterations in testicular function were reversible. The male fertility index, ejaculate sperm content, and testicular weights returned to control values during this phase.

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.

Acute toxicity and gross behavioral effects of amphetamine, four methoxyamphetamines, and mescaline in rodents, dogs, and monkeys

Abstract Mescaline (MES) and d -amphetamine (AMP) served as reference agents in a study of acute toxic and behavioral effects of four methoxy derivatives of AMP: dl -4-methoxyamphetamine (PMA), dl -2,5-dimethoxyamphetamine (DMA), dl -2,5-dimethoxy-4-bromoamphetamine (DOB), and dl -2,5-dimethoxy-4-methylamphetamine (DOM). Acute (24-hr) LD50 values were determined in mice (iv and oral), rats (ip), and dogs (iv). Estimation of the iv lethal dose range for each agent was conducted in a small number of rhesus monkeys. In terms of millimoles per kilogram of the base, MES was consistently the least toxic, whereas DOB or DOM was the most toxic for all species except the mouse. AMP was the most toxic for the mouse and was third in toxicity for all other species. At lethal and sublethal doses of these agents, observations were made for their effects on automatic, motor, and CNS functions and on behaviors possibly correlating with human hallucinogenic effects. According to the resulting profiles, DMA, DOM, and DOB had effects most similar to those of MES, whereas PMA had more in common with AMP. Howeve, PMA, like the other three derivatives and mescaline, caused visual tracking in monkeys and dogs, a sign which may reflect a hallucinatory action.

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.

A comparative analysis of the acute toxicity of technical-grade pyrethroid insecticides and their commercial formulations.

Seventy-two-hour LD50 studies involving the fenvalerate formulation, Pydrin 2.4 E.C., and the permethrin formulation, Ambush, were performed with male Swiss mice to compare the toxicity of the commercial formulations to that of the technical-grade pyrethroids. Comparison of the formulation ip and po LD50 values and the lethality of technical-grade pyrethroids revealed an increased toxicity of the technical-grade material when administered as the commercially formulated products. The calculated ip and po LD50 values for Pydrin 2.4 E.C. and Ambush were calculated to be 62 and 72 mg/kg, respectively, whereas those for Ambush were 429 and 424 mg/kg. Administration of doses of technical-grade fenvalerate which corresponded to the amount of fenvalerate contained in the calculated LD99 value of Pydrin resulted in no deaths. Administration of the LD99 value of Ambush, as the technical-grade product, resulted in no deaths following ip administration, whereas the po value resulted in 100% death. The data indicate an effect of the Pydrin formulation vehicle on fenvalerate toxicity, whereas the Ambush vehicle did not enhance permethrin toxicity. Technical-grade material in general was more toxic following po than ip administration suggesting the corn oil vehicle may have reduced ip absorption.