Tomoji Yanagita

Relationship between minimum reinforcing doses and injection speed in cocaine and pentobarbital self-administration in crab-eating monkeys

The relationship between minimum reinforcing doses and injection speed was investigated by using 2 levels of speeds in experiments on self-administration of cocaine or pentobarbital in 2 crab-eating monkeys each. The experiments were conducted under a fixed ratio (FR) 1 schedule with 30-min time-out after each drug injection, wherein the drugs and saline were made available for alternate 5-day periods. The minimum reinforcing doses at each injection speed were determined by the titration procedure in which the presence or absence of reinforcing effect at a particular drug dose was judged based on comparison of the self-administration rate at that dose with the rate in the preceding saline period. The results showed that the minimum reinforcing doses of cocaine and pentobarbital tended to be higher in inverse proportion to the injection speed of the drugs.

Cigarette smoking in rhesus monkeys

In the present pilot study, an attempt was made to shape and maintain cigarette smoking behavior in rhesus monkeys both with and without the simultaneous use of other reinforcers. Initially, 14 monkeys were trained to suck air and puff on cigarettes using sweetened liquid reinforcer. After smoking had been established, the sweetened liquid reinforcement was removed. Smoking without this reinforcement, referred to as ‘voluntary smoking,’ was then observed during 20-h daily sessions. Of 14 monkeys studied, 2 have engaged in voluntary smoking for 2 years or longer. The maximum figures recorded for any single 20-h session were 3,271 puffs (20 cigarettes) in one monkey and 16,384 puffs (47 cigarettes) in the other. Although the baseline variability of smoking by these monkeys was quite high, low-nicotine and nicotine-free cigarettes seemed to lead to clear decreases in smoking. In 2 other monkeys that did not perform voluntary smoking, smoking was reestablished under a randomtime or a tandem schedule for sweetened liquid reinforcement. Within this situation (‘schedule-controlled smoking’) schedule manipulations also led to changes in intake of cigarrette smoke. The voluntary smoking model described in the present paper should be useful for studying the factors involved in initiating and maintaining smoking behavior and for studying the psychopharmacological effects of smoking, while the schedule-controlled smoking model should be useful for studying the physiological effects of smoking and for studying the relationship of smoking with various disease entities.

Intravenous self-administration of (−)-cathinone and 2-amino-1-(2,5-dimethoxy-4-methyl)phenylpropane in rhesus monkeys

The reinforcing effects of (-)-cathinone, a pharmacologically active ingredient of khat, and 2-amino-1-(2,5-dimethoxy-4-methyl)phenylpropane ((STP) (DOM)), a hallucinogenic psychotomimetic, were studied by intravenous self-administration experiments in rhesus monkeys. Among the experiments described in this paper, the result of continuous self-administration of (-)-cathinone was briefly reported elsewhere. T. Yanagita, Studies on Cathinones, NIDA Research Monograph 27, Proceedings of 41st Annual Scientific Meeting of the Committee on Problems of Drug Dependence, 1979, pp. 326-327.

Drug dependence potential of viloxazine hydrochloride tested in rhesus monkeys

The drug dependence potential of viloxazine was tested in 5 experiments on rhesus monkeys. In gross behavioral observation of normal monkeys the acute CNS effects of the drug were found to be very weak. Decrement of spontaneous motor activity and occasional eye-closing were observed with single doses higher than 16 mg/kg IV, IM and 128 mg/kg PO, while convulsions and death occured at 64 mg/kg IV and IM. Viloxazine did not suppress the morphine and barbital withdrawal signs in monkeys that had been made physically dependent on these drugs and withdrawal. In the test for physical dependence by repeated administration of the drug at 16 mg/kg IM twice daily for 31 days in normal monkeys, no observable withdrawal sign was developed in the naloxone precipitation and natural withdrawal tests. In intravenous self-administration experiments, a weak reinforcing effect was demonstrated in some monkeys, but the effect was extremely weak. Thus, viloxazine was found to be physical dependence-free and its overall dependence potential was regarded as very low.

Dependence Potential of Zopiclone Studied in Monkeys

In gross behavioral observation the minimum effective dose of zopiclone was intravenously 0.06-0.25 mg/kg and intragastrically 1-4 mg/kg in rhesus monkeys. Zopiclone suppressed barbital withdrawal signs of rhesus monkeys at a single dose of 16 mg/kg or more. The suppressing effect of zopiclone 32 mg/kg i.g. was comparable to diazepam 8 mg/kg. Crab-eating monkeys treated with zopiclone at doses up to 32 mg/kg twice daily for up to 8 weeks manifested intermediate-grade signs upon withdrawal (i.e., less severe than after treatment with diazepam and similar to nitrazepam). Zopiclone was self-administered by rhesus monkeys relatively frequently by the intravenous route; the infrequent intragastric rate was similar to or slightly higher than with diazepam.

Effects of an antitussive mixture and its constituents in rats discriminating methamphetamine from saline

The discriminative effects of over-the-counter antitussive syrup containing dihydrocodeine (DHC), methylephedrine (MEP), caffeine (CAF), and chlorpheniramine (CPA) were compared with those of methamphetamine (MA) in a drug discrimination experiment using rats. Rats were trained to discriminate the effects of MA at 0.5 mg/kg SC and saline for food reinforcement under the fixed-ratio 10 schedule in a two-lever operant chamber situation. In substitution testing using a cumulative dose procedure by the subcutaneous route, DHC (4 and 8 mg/kg, expressed hereafter as referred to cumulative dose) or CPA (16-64 mg/kg) individually did not produce MA lever selection. On the other hand, MEP (128 mg/kg) and CAF (64 mg/kg) produced MA lever selection 41.5 and 57.2% of the time, respectively. The complete mixture (16 mg/kg DHC + 32 mg/kg MEP + 33.2 mg/kg CAF + 6.4 mg/kg CPA) produced MA level selection 65.8% of the time. The partial mixture containing only MEP + CAF at the above doses produced MA lever selection 95.6% of the time. Thus, the complete mixture only partially substituted for MA in rats while the partial mixture containing MEP and CAF completely substituted for MA.

Nalfurafine hydrochloride, a selective κ opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys

Nalfurafine hydrochloride [(E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at μ opioid receptors. Opioids, especially those acting at μ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 μg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion). These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.

Behavioral and Biochemical Analysis of the Dependence Properties of Nicotine

Our recent studies on the reinforcing properties and psychotoxicity of nicotine in rats and rhesus monkeys are introduced. In drug discrimination experiments in rats, the discriminative effects of subcutaneous nicotine were generalized by the nicotine injected into nucleus accumbens or medical prefrontal cortex. In microdialysis in rats, nicotine increased dopamine (DA) and DOPAC at nucleus accumbens and striatum. In self-administration experiments in monkeys, faster infusion speeds resulted in higher intake rates of nicotine and possible development of physical dependence attenuated monkey’s nicotine-seeking behavior. The threshold dose for reinforcing effect of nicotine was found to be 2.5-10 µg/kg.

Dependence characteristics and risk assessment of agonist-antagonist analgesics.

Risk assessment of dependence-producing drugs comprises assessment of two major risks: the risk that a drug is likely to be abused (abuse liability) and the harm that is likely to occur as a consequence of abuse (termed here as harm liability). Important determinants of these risks are the dependence-related pharmacological and toxicological properties of a drug. In this paper, the relationships of the drug properties to the abuse and harm liabilities are described. Next, a scoring system to assess the abuse and harm liabilities is introduced. Finally, an attempt to actually apply this system to several prototypic drugs of abuse and some agonist-antagonist analgesics is explained.

Nicotine-Seeking Behavior in Rhesus Monkeys

Nicotine-seeking behavior was studied in rhesus monkeys mainly in intravenous self-administration experiments on nicotine and partly in cigarette-smoking experiments. As a result, the nicotine-seeking behavior by the intravenous route was observed mostly in the daytime with a relatively stable daily pattern, but by the smoking route such behavior was unstable from day to day. The intensity of the intravenous drug-seeking behavior for nicotine observed in a progressive ratio experiment was found to be quite strong but weaker than that for morphine or cocaine. Pretreatment with frequent intravenous doses of nicotine for 4 weeks did not enhance the intensity. This result demonstrates marked difference between physical dependence on opiates such as morphine or codeine and on nicotine. For analysis of nicotine-seeking behavior, serum nicotine level at the time of lever pressing for nicotine was determined. The result may indicate that the nicotine- seeking behavior is triggered by lowering of the serum nicotine level, which is proportional to the maintained dose level. Also analyzed were the intravenous threshold doses of nicotine in self-administration experiments and in drug discrimination experiments. The threshold dose for reinforcement in the former experiments and that for discrimination in the latter were quite close each other. This result may support the observation that nicotine-seeking behavior is developed as a consequence of its subjective effects.