Journal Article•
Antagonism of the behavioral effects of morphine and methadone by narcotic antagonists in the pigeon
01 Nov 1970-Journal of Pharmacology and Experimental Therapeutics (American Society for Pharmacology and Experimental Therapeutics)-Vol. 175, Iss: 2, pp 443-458
TL;DR: Naloxone, which has been considered to be a relatively pure narcotic antagonist, affected the schedule-controlled behavior of the pigeon in the same way as other narcotic antagonists and with a greater potency than some.
Abstract: The effects of narcotics and narcotic antagonists, alone and in combination, were studied on the schedule-controlled behavior of the pigeon. Morphine and methadone increased the rate of responding under the fixed-interval component of a multiple fixed-interval, fixed-ratio schedule at low dose levels in some birds, and at higher dose levels they decreased the rates of responding under both components in all birds. The effects of narcotic antagonists were much like the effects of morphine and methadone. Naloxone, which has been considered to be a relatively pure narcotic antagonist, affected the schedule-controlled behavior of the pigeon in the same way as other narcotic antagonists and with a greater potency than some. Narcotic antagonists blocked both the rate-increasing and rate-decreasing effects of morphine. The order of potency of the narcotic antagonists for blocking the rate-decreasing effects of morphine was: naloxone = cyclasocine > nalorphine > pentazocine. This antagonism of the rate-decreasing effect of morphine seemed to be specific for narcotic analgesics, since naloxone and cyclazocine blocked the effects of methadone as well as morphine, but naloxone did not block the rate-decreasing effects of chlorpromazine and cyclazocine. Although d -amphetamine could reverse the rate-decreasing effects of morphine, the degree of reversal was proportional to the rate-increasing effects of d -amphetamine, which was unlike the antagonism of the rate-decreasing effects of morphine by narcotic antagonists. The rate-increasing effects of morphine and d -amphetamine were additive, rather than antagonistic.
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TL;DR: If it is to be shown unequivocally that it is rate of operant responding which determines the behavioral effects of drugs, procedures are needed in which other varibles such as reinforcement frequency are more adequately controlled.
Abstract: It has been claimed that the effects of amphetamines on schedule-controlled behavior depend to a large extent on the rate of responding in control conditions. A review of the literature shows that there is considerable support for this hypothesis if the behavior is not suppressed by aversive procedures, is not under the control of powerful external stimuli or is not occurring very infrequently. The extension of a rate-dependency hypothesis to the effects of other drugs has less empirical support, however. It is argued that many of the procedures used for studying rate-dependent drug effects do not provide critical tests of the hypothesis. If it is to be shown unequivocally that it is rate of operant responding which determines the behavioral effects of drugs, procedures are needed in which other varibles such as reinforcement frequency are more adequately controlled.
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TL;DR: This work has attempted to minimize problems in demonstrating tolerance to marijuana and its active constituents by using only those constituents of marijuana that have been shown to have activity in man and are available in relatively pure form and by using standardized procedures for measuring the development of tolerance in several species.
Abstract: Tolerance to a drug is said to have developed “when, after repeated administration, a given dose of a drug produces a decreasing effect, or conversely when increasingly larger doses must be administered to obtain the effects observed with the original dose.”’ There is evidenv that tolerance develops to the effects of marijuana and its active constituents in animaW6 and in man.7 However, many investigators have not observed tolerance to marijuana or its active constituents in animalss and in mang-lls or have suggested that the repeated administration of marijuana may result in an increased sensitivity to the subjective effects of marijuana in man.12 There are many factors that might have contributed to the conflicting findings concerning the development of tolerance to marijuana. Among the most serious of these factors has been the difficulty in controlling the dose level of the active constituents in marijuana, due to the varying purity of the preparations from the plant material.I3 Since tolerance to a drug is defined either in terms of a diminishing response to a constant dose or in terms of a constant response to graded increases in the dose, failure to control the dose adequately makes the demonstration of tolerance difficult. Other problems in demonstrating tolerance to marijuana and its active constituents may arise from differences in the methods used to assess tolerance and from species differences. We have attempted to minimize these problems by using only those constituents of marijuana that have been shown to have activity in man14-17 and are available in relatively pure form,ls and by using standardized procedures for measuring the development of tolerance in several species. Recently, schedule-controlled behavior has been used as a sensitive and stable baseline for assessing the development of tolerance to a number of d r ~ g s ~ * ~ J ~ ~ ~ in several species. The basic techniques for studying schedule-controlled behavior are well known.22 In our experiments, pigeons are trained to peck a translucent plastic response key in order to obtain a four-second access to mixed grain. Each peck breaks an electrical circuit, which permits the peck to be counted and recorded. Occasionally, depending on the schedule of food reward, pecks produce access to grain. The reward schedule for pigeons that has been used most often in tolerance s t ~ d i e s ~ ~ J ~ is the multiple fixed-ratio 30-response, fixed-interval fiveminute (mult FR 30 FI 5) schedule of food presentation. Under this schedule, when a blue light behind the translucent key is on, 30 key pecks are required to produce food (FR 30 component), and when a red light behind the key is on, the first key peck after five minutes produces food (FI 5 component). The two schedule components alternate throughout a session, with a 40-second time limit applying to both components of the schedule, so that the schedule can change automatically from one component to the other component if the pigeon is not responding at the time food is available. At these schedule parameters, pigeons usually respond at a high steady rate under the FR component, while responding under the FI 5 component is characterized by a pause early in the interval, followed by an increasing rate of responding as the availability of food appr0aches.2~
132 citations
TL;DR: Research directed at identifying mechanisms whereby drugs exert their therapeutic actions is inherently difficult, and even for effects which correlate with the relative pharmacological potency of various opiates, one cannot readily ascertain whether the effects are primary or are simply secondary consequences of some other, more fundamental drug action.
Abstract: Research directed at identifying mechanisms whereby drugs exert their therapeutic actions is inherently difficult. It is easy for pharmacologists to describe many “effects” of drugs on physiological and biochemical processes. Uncertainties crop up when one endeavors to conclude that a particular effect represents the mechanism of action of the drug. Opiates, like most other drugs, produce myriad effects on biological organisms, on energy metabolism, protein synthesis, nucleic acid disposition, neuronal firing patterns, and neurotransmitter disposition. Some of these effects are clearly irrelevant pharmacologically, because they are elicited by drugs that have no opiate-like pharmacological actions. However, even for effects which correlate with the relative pharmacological potency of various opiates, one cannot readily ascertain whether the effects are primary or are simply secondary consequences of some other, more fundamental drug action.
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TL;DR: It was suggested that there may be common pharmacological mechanisms involved in both positive reinforcement and aversive conditioning by drugs of the opiate class.
Abstract: In Experiment 1, 4 doses of morphine and 4 doses of naloxone were tested for their ability to induce a conditioned aversion to saccharin in rats. Morphine was much more potent than naloxone which had only weak effects at the highest dose (12.96 mg/kg). Based on the determinations of Experiment 1, doses of 0.096, 0.96 and 0.6 mg/kg of morphine in a second experiment. The highest dose of naloxone was an effective antagonist of morphine-induced aversion. The antagonism was incomplete, but this may have reflected the particular dose combinations that were employed. Although 12.96 mg/kg of naloxone induced only a weak conditioned aversion to saccharin in Experiment 1, 9.6 mg/kg had a substantial effect in Experiment 2. Thus naloxone was itself an agent of aversive conditioning at a dose which significantly antagonized the aversive effects of morphine. Because of the successful demonstraion of antagonism, it was suggested that there may be common pharmacological mechanisms involved in both positive reinforcement and aversive conditioning by drugs of the opiate class.
96 citations