Post-dependent Rats Research Articles

Previous treatment with morphine and sensitization to the excitatory actions of opiates: Dose-effect relationship

The stimulatory effect of morphine on locomotor activity has been shown to be largely modified in rats that have been formerly dependent on this drug. In the present study, the relationship between the chronic dose of morphine and the degree of sensitization to the excitatory effect of opiates was investigated. To this end, four groups of rats were treated daily for 30 days with 1.25, 5, 20 and 80 mg/kg of morphine (i.p.) and challenged with morphine (1.25 and 2.5 mg/kg) or fentanyl (40 and 80 μg/Kg) 1–4 months after ceasing the treatment. Drug-induced hypermotility in post-dependent rats appeared to be linearly related to the dose of the preceding chronic treatment after test doses of both morphine and fentanyl. The results are discussed in terms of a persistent dose-related modification of the neuronal mechanism subserving the excitatory component of the action of opiates; such a modification might offer a neurobiological basis for the fact that “relapse tendencies” for opiates persist for a long time after withdrawal.

Sensitivity to the narcotic cue in non-dependent, morphine-dependent and post-dependent rats

Using a food-reinforced two-lever operant procedure, 12 rats were trained to discriminate 10 mg/kg (i.p.) of morphine from saline. Five animals were given daily non-contingent exposure to morphine (20 mg/kg on saline, or no-test days, and 10 mg/kg on drug days) from the beginning of the experiment; the others received injections of saline. In the morphine generalization tests, the dependent rats showed an increased sensitivity to the narcotic cue as compared with non-dependent animals (ratio of the ED 50 values: 2.30). This increased sensitivity was still present 3 months after discontinuing the non-contingent treatment with morphine (ratio of the ED 50 values: 1.98). The results of the present study, together With other results reported in the literature, suggest that the experimental procedure plays a role in determining whether tolerance, no tolerance or enhanced sensitivity to the discriminative stimulus properties of narcotics is observed.

Cross-sensitization to the excitatory effect of morphine in post-dependent rats

Time-effects of morphine, methadone, meperidine and pentazocine upon locomotor activity were investigated in naive and in post-dependent rats. Dependence was induced by daily injection of 20 mg/kg (i.p.) of morphine for 30 days. Tests were run starting from 1 month after withdrawal from morphine. Morphine produced a greater increase in activity in post-dependent than in naive rats. Marked cross-sensitization to the excitatory effect occurred with methadone but not with pentazocine. The motility pattern of meperidine was similar in naive and in post-dependent animals. The findings presented here suggest that: (1) different mechanisms underlie the excitatory actions of opiates; (2) the narcotic character of a drug can be detected by challenging this drug in rats previously dependent on morphine.

Discriminative stimulus properties of morphine in non-dependent, dependent and post-dependent rats

Discriminative stimulus properties of morphine in non-dependent, dependent and post-dependent rats

Long-term sensitization to the excitatory effects of morphine: A motility study in post-dependent rats

Motility effects of excitatory and depressant doses of morphine were studied in naïve, dependent (20 mg/kg daily) and post-dependent (about 40 days after withdrawal) rats. Doses of 0.6 and 1.25 mg/kg of morphine produced a greater increase in activity in post-dependent than in naïve rats. A 20-mg/kg dose exerted an excitatory effect in dependent rats instead of the depressant one induced in naïve animals. This excitatory effect was still evident but less pronounced in post-dependent rats. The dose of 1.25 mg/kg was repeatedly challenged in post-dependent (80 mg/kg daily) rats. It was found that the increased excitatory effect of this dose persisted unchanged 160 days after ceasing treatment. The present results demonstrate that several months after the withdrawal of morphine, sensitization still exists to the excitatory effect of the drug while tolerance to the depressant action is slight or no longer present shortly after ceasing treatment.

Locomotor activity in morphine-dependent and post-dependent rats

The effects of morphine and naloxone were compared on the locomotor activity of nondependent, morphine-dependent, and post-dependent rats. Dependence was induced and maintained for 30 weeks by scheduled access to 0.05% morphine solution for 10 min every 6 hr. Locomotor activity in nondependent and dependent animals was increased by low doses of morphine and reduced by higher doses. Both components were antagonized by naloxone. Chronic morphine treatment produced marked tolerance to the depressant effect of high morphine doses, but not to the stimulant effect of low doses. Post-dependent animals remained tolerant to the depressant effect of high doses of morphine. The development of tolerance to the depressant but not to the stimulant effect of morphine in dependent and post-dependent animals suggests that different neuronal substrates mediate morphine-induced stimulation and depression of locomotor activity. Abrupt or naloxone-precipitated withdrawal generally disrupted locomotor activity in dependent rats. Naloxone alone also decreased activity in post-dependent animals. Thus, chronic morphine administration produces long-lasting changes in the sensitivity of dependent and post-dependent rats to the effects of morphine and naloxone on locomotor activity.

Sexual behaviour of morphine-dependent and abstinent male rats.

Morphine HCl (5–20 mg/kg) impaired the sexual behaviour of non-tolerant male rats in a doserelated way. Mounting responses and the amount of time spent in social and sexual interaction with a receptive female were reduced, while the frequency of contacts remained unchanged. Tolerant male rats which had been maintained on large daily doses of morphine HCl (100 mg/kg) also showed marked variations in sexual behaviour, depending upon whether they were tested in the drugged or the abstinent state. When tested 2.5 h after their usual dose of morphine, sexual behaviour was almost completely suppressed although the rats were active and, in one test, made bodily contact more frequently with the females than did the controls. The time spent in social and sexual interaction was markedly reduced and the drugged males appeared to respond inappropriately to the females. When tested after 23-h withdrawal or 1 h after the precipitation of abstinence by naloxone, the sexual behaviour of tolerant rats was indistinguishable from that of controls. Thus, disturbances of sexual behaviour appear to differ from patterns of change in eating and drinking in drugged and morphine-abstinent rats. Post-dependent rats, tested after 2 weeks of withdrawal, did not differ from controls, unless they were challenged with morphine (30 mg/kg), when their sexual responses and locomotor behaviour were less affected.

Drug self-administration and sleep-awake activity in rats dependent on morphine, methadone, or l-alpha-acetylmethadol.

Morphine post-dependent rats were prepared with chronic cortical EEG and temporalis muscle EMG electrodes and i.v. jugular cannulae and permitted to self-administer morphine (10 mg/kg/injection) on a fixed-ratio schedule of reinforcement to reestablish and maintain dependence. Morphine was then replaced by methadone or 1-alpha-acetyl-methadol (LAAM) at a dose of 2 and 1 mg/kg, respectively. The rats developed stable patterns of self-administration of each narcotic and maintained the dependent state. The mean (+/- S.E.) interinjection interval was 2.5 +/- 0.1 h for morphine, 1.4 +/- 0.1 h for methadone and 8.8 +- 0.8 H FOR LAAM. The distribution of sleep, REM sleep, and awake within the interinjection interval for the three narcotics was similar. A short phase of behavioral stupor concomitant with EEG slow bursts emerged following the self-injections. This phase was followed by arousal with EEG activation. Sleep and REM sleep then reappeared and predominated before the next injection. LAAM manifested a relatively slow onset of action in comparison with morphine and methadone.

Limbic system and opioid addiction in the rat

Statistical comparisons of means in groups of morphine-dependent (or post-dependent) rats with and without bilteral lesions in the cingulum, the dorsomedial thalamic nucleus, the anterior temporal lobe (amygdaloid complex and ventral hippocampus), or the septum, and in nondependent rats with and without such lesions, revealed no significant lesion effects on specific signs of the 24-hr primary morphine-abstinence syndrome in this species: decreased water intake; increased “no-choice” drinking of a 5-μg/ml aqueous solution of a potent opioid (etonitazene); increased “wet dog” shake frequency; fall in colonic temperature. Lesions in the cingulum attenuated one sign of the secondary (protracted) morphine-abstinence syndrome (increased 24-hr water consumption). None of the lesions altered the suppressive effects on the primary morphine-abstinence syndrome of “no-choice” etonitazene-drinking or of intraperitoneal injection of morphine. None of the lesions prevented “relapse” of postdependent rats, as measured by comparisons of mean volumes of etonitazene (5-μg/ml) and water consumed in “choice” trials 9–72 days after permanent withdrawal of morphine.