R. James Collins

Prediction of abuse liability of drugs using IV self-administration by rats

A total 31 psychoactive drugs were offered to groups of naive rats for IV self-administration and an injection rate greater than that for rats offered only saline indicated reinforcement. Two protocols were used: in the first, rats were offered drug at a selected dose for 5 days, then the dose was reduced by 1 log unit (to 0.1 the original dose) for an additional 4 days; in the second, rats were offered saline for 3 days as a ‘prescreen’ to eliminate rats with high or low operant-injection rates. Drug was offered to acceptable rats for 5 days, then the dose was reduced 0.5 log unit (to 0.32 the original dose) for 5 more days. A scoring system, based upon the injection rates during the last 3 days of each period, describes the reinforcing action. Scores were dose-related. Tests on both protocols gave similar results. Data from monkey studies have been reported for 27 of the drugs tested. Of these drugs, 18 were reinforcers and six were nonreinforcers in both species, nalorphine and ethylketazocine were reinforcers only in rats, and ethanol was a reinforcer only in monkeys.

Factors affecting voluntary morphine intake in self-maintained addicted rats

SummarySelf-maintained morphine addicted rats were prepared by implanting chronic venous cannulas and fitting the rats with a device permitting relatively free movement and also enabling them to obtain morphine injections at will by pressing a lever. Three factors modifying voluntary morphine intake were studied. 1. Using a continuous reinforcement schedule, progressively decreasing the size of the morphine dose led to a greater number of doses daily. Compensation was incomplete in that the total daily morphine intake decreased. 2. Progressively increasing a fixed ratio reinforcement schedule up to about FR-75, caused rats to continue responding on the lever until the dose was obtained. Above FR-75 responding became intermittent and daily morphine decreased as the time interval between doses increased. 3. Continuous intravenous infusion of a second drug, leaving voluntary access to morphine at FR-10, led to decreased morphine intake following infusion of morphine itself, codeine and meperidine. Nalorphine infusion increased morphine intake. Effectiveness of infusions varied with the infusion rate.

Changes in morphine self-administration in rats induced by prostaglandin E1 and naloxone.

Interactions of prostaglandin E1 (PGE1) with morphine have been reported in several test systems and an hypothesis has been advanced for a role of prostaglandins in morphine analgesia and physical dependence. In rats self-administering morphine intravenously, a simultaneous and continuous infusion of naloxone hydrochloride at 56 to 560 mug/kg/day caused the expected increase in injection rate for morphine. Infusion of PGE1 by itself at 56 or 180 mug/kg/day had no effect on the rate of morphine intake. Likewise the addition of PGE1 at 180 mug/kg/day did not potentiate the increase caused by naloxone (56 or 180 mug/kg/day) when it was added to the naloxone infusion. These results do not support a role for prostaglandins in the behavioral aspects of morphine addiction. However, larger doses of PGE1 (1 and 1.8 mg/kg/day), which were without overt effects in normal rats, caused severe and incapacitating prostration in morphinized rats.

Dose and physical dependence as factors in the self-administration of morphine by rats

Groups of naive rats were offered morphine sulfate for self-administration in doses of 0.0032–10 mg/kg for 6 days. On day 7 saline was substituted for morphine. Loss of weight was taken as physiological evidence of dependence. Rats that did not lose weight formed a single population whose mean injection rate did not differe from control rats receiving only saline injections. Injection rates for rats losing weight were log-normally distributed, and the mean of the logarithms of the injection rates was linearly related to the logarithm of the dose. Mean daily injection rates averaged 12 for controls, 23 at 10 mg/kg, and 411 at 0.01 mg/kg. A transient increase in morphine intake after an injection of nalorphine was taken as behavioral evidence of dependence. Nalorphine increased morphine intake when rats were self-injecting 0.32 and 1.0 mg/kg of morphine, but not 0.032 or 0.1 mg/kg. The reinforcing property of morphine may occur without behavioral evidence of dependence.

Determination of biological activity of adinazolam and its metabolites

Adinazolam and its metabolites inhibit [3H]flunitrazepam binding in-vitro. The binding affinities of these compounds is significantly enhanced in the presence of 10-5 M muscimol, indicating that both adinazolam and its metabolites are benzodiazepine agonists. In-vivo metabolism of adinazolam results in the formation of active metabolites.

Relative potency of codeine, methadone and dihydromorphinone to morphine in self-maintained addict rats

SummaryA method is described for obtaining potency estimates of narcotic analgesics to morphine in experimental addict rats. Drugs were administered through a chronic right heart cannula and intake was under the rats voluntary control. Animals were offered two doses of morphine (3.2 and 10 mg/kg/injection) and two doses of test compound on a fixed ratio reinforcement schedule of 10:1. Logarithm of the daily number of injections taken was used as the effect metameter. Each potency estimate was based on results in four rats. Rats averaged 137 mg/kg/day of morphine when offered 10 mg/kg/injection. A diurnal variation in opiate intake was observed, the nighttime rate being about one-third greater than the daytime rate. Morphine intake measured before and after the assay period was essentially unchanged. Potency estimates and the 95% fiducial interval were: dihydromorphinone = 10 (5.2−19) × morphine, methadone = 3.4 (2.7−4.6) × morphine and codeine = 0.67 (0.45−1.0) × morphine. Analgesic activity for codeine was not proportional to its ability to substitute for morphine in addict rats.

Screening for Drug Reinforcement Using Intravenous Self-Administration in the Rat

The reinforcing activity of 31 psychoactive drugs was evaluated. Drugs were offered by intravenous self-administration to groups of naive rats. Reinforcement is indicated by an injection rate greater than that for rats offered only saline. Two similar protocols were used. In the first protocol, rats were offered drug at a selected dose for 5 days, then the dose was reduced by one log unit (to 0.1 times the initial dose) for an additional 4 days. In the second protocol, saline only was offered the first 3 days to eliminate rats with high or low operant rates, and the dose was reduced 0.5 log unit (to 0.32 times the initial dose) instead of one log unit. An empirical score, based on the injection rates during the last 3 days of each period, describes the reinforcing activity. Replicate tests using both protocols gave similar scores. Literature data for reinforcing activity in monkeys was available for 27 of the drugs tested. Results for rats and monkeys agreed for 24 of the 27 drugs. Nalorphine and ethylketazocine were reinforcers only in rats, and ethanol was a reinforcer only in monkeys.

Inhibition of evoked potentials by caudate stimulation and its antagonism by centrally acting drugs

Abstract Caudate conditioning depressed responses evoked by leg stimulation in the centrum medianum (CM) nucleus of the thalamus, reticular formation and cuneate nucleus in cats deeply anesthetized with α-chloralose. Responses evoked in the amygdala by preoptic stimulation, in hippocampus by amygdaloid stimulation and in cingulate cortex by mammillary stimulation were also depressed by caudate stimulation. Conversely, potentials evoked in visual cortex by photic flashes, in auditory cortex by clicks and in hippocampus by stimulation of the fornix were not changed by caudate conditioning. Extracellular microelectrode recordings revealed that caudate conditioning inhibited unit discharges of many CM cells while others were either unaffected or fired by caudate stimulation. Strychnine antagonized the inhibitory effects of caudate stimulation on unit activity. Although strychnine was most effective, picrotoxin, pentylenetetrazol, bemegride, morphine and pentobarbital also antagonized CM inhibition as recorded with macroelectrodes. However, the action of pentobarbital on inhibition is questionable since this agent also greatly depressed the CM response. Amphetamine, caffeine, imipramine, chlorpromazine and mephenesin were without effect on inhibition. In contrast to CM inhibition, depression of each of the responses recorded in the limbic system by prior caudate stimulation was not antagonized by strychnine, even in doses as large as 0·4 mg/kg.

Self-administration of morphine in the rat: Relative influence of fixed ratio and time-out

Rats were offered 3.2 mg/kg of morphine sulfate on a continuous reinforcement schedule until the daily injection rate had stabilized. The effect of fixed ratio schedules of 4 and 8 were compared to imposing time-out periods of 5 and 10 sec immediately followed each injection. The fixed ratio schedules decreased the injection rate while the time-out schedules had no effect. The hypothesis that the effect of a fixed ratio schedule is a consequence of imposing a time-out period, allowing full effects of the injection to be sensed, is not supported.

Lack of effect of dexoxadrol in self-maintained morphine dependence in rats.

SummaryDexoxadrol, dextromethorphan and meperidine were given by continuous intravenous infusion to selfmaintained morphine dependent rats. Dexoxadrol and dextromethorphan did not significantly decrease the rate of morphine self-administration. Meperidine produced a dose related decrease in the rate of morphine injections. The failure of dexoxadrol to reduce morphine intake is evidence that it will probably not produce opioid-like addiction liability in man.