Withdrawal Intensity Research Articles

Conditioned morphine withdrawal in the hamster

Conditioned withdrawal among golden Syrian hamsters was studied in two experiments. In experiment 1, morphine-pelleted (75 mg) hamsters were observed for signs of withdrawal (wet-dog shakes, etc.) before and after a naloxone (1 mg/kg) injection that was administered in a distinctive environment. Withdrawal signs that occurred in the distinctive environment before the naloxone injection were defined as anticipatory conditioned withdrawal responses. Two, 9, and 30 days following pellet removal, retention of conditioned withdrawal responding was assessed in the distinctive environment before and after a saline injection. Results indicated that: a) withdrawal intensity was a direct function of the number of implanted pellets; b) conditioned withdrawal occurred among animals withdrawn in the distinctive environment, but not among those withdrawn in the home cage; c) conditioned withdrawal was a nonmonotonic function of precipitated withdrawal intensity; d) conditioned withdrawal was evident up to 30 days after pellet removal. In experiment 2, conditioned withdrawal was extinguished by repeated exposure to the distinctive environment in the absence of precipitated withdrawal. It was concluded that environmental stimuli associated with the absence of morphine (i.e., precipitated withdrawal) elicit conditioned withdrawal. The results are compared to similar findings in rats and humans.

Inter-relationship between serum potassium and plasma catecholamines and 3′:5′ cyclic monophosphate in alcohol withdrawal

Serial analyses of serum potassium and plasma epinephrine, norepinephrine and adenosine 3′:5′-cyclic monophosphate (cyclic AMP) concentrations were measured in 13 patients with alcohol withdrawal, six of whom presented delirium tremens. Patients with delirium showed at admission levels of potassium (3.45 ± 0.45 mmol/l) lower ( P < 0.02) than patients without delirium (3.81 ± 0.14 mmol/l). Three patients were hypokalemic, all of them with delirium. Serum potassium increased significantly in all the patients during evolution. A close negative correlation ( r = − 0.751) between the intensity of withdrawal and serum potassium was observed. Plasma epinephrine concentrations were increased at admission (623 ± 192 pmol/l), patients with delirium showing greater values (705 ± 137 pmol/l). As the alcohol withdrawal improved, plasma epinephrine concentration decreased. Plasma norepinephrine concentrations were also increased at admission (3422 ± 1451pmol/l), but did not change significantly during evolution, being similar in patients with and without delirium. Plasma cyclic AMP levels were high at admission (40.4 ± 24.3 nmol/l) and increased significantly ( P < 0.05) during evolution. The data obtained suggest that in patients with alcohol withdrawal, as symptomatology improves, plasma epinephrine decreases, while plasma norepinephrine remains increased. The combined actions of the two facts — less β-stimulus, maintaining of α-stimulus — would comprise a significant increase of kalemia, that in cases of initial hypokalemia would lead to normal values of serum potassium.

Alcohol Withdrawal Syndrome: Clinical and Hormonal Responses to α2‐Adrenergic Agonist Treatment

Lofexidine (L) was compared to placebo (P) in a random double blind placebo controlled study of 23 healthy alcoholics in withdrawal. In serial alcohol withdrawal syndrome (AWS) scales, P greater than L for first 18 hr. The major changes in AWS were in blood pressure and pulse, while restlessness or diaphoresis did not show faster normalization with L vs. P. Other ratings of withdrawal intensities and craving by patients were similar in both P and L. There were no differences in the rate of patient completion, or appearance of hallucinations by group. Plasma catecholamines were in the high ranges, similar in both groups at 0 and 3 hr, but after 5 hr P greater than L for norepinephrine (but not epinephrine or dopamine). The data suggest L has pharmacological effects on some objective, catecholamine related, components of alcohol withdrawal, with little effect on others. L type treatment of alcoholics in withdrawal is promising, modestly effective and warrants further study.

Convulsive and non-convulsive ethanol withdrawal behaviour in rats with lesions of the noradrenergic locus coeruleus system

The ascending noradrenergic pathways from the locus coerulus were lesionsed bilaterally in 10 rats by intracerebral 6-hydroxydopamine injections. Tem rats were sham-operated. All animals were subjected to a 4-day ethanol intoxication period using intrasgastric intubation. Intoxication and withdrawal assessments were performed blindly. The 6-hydroxydopamine lesions did not appear to affect tolerance to ethanol. During withdrawal, however, lesioned animals showed minor, but statistically significant changes in scores of certain non-convulsive withdrawal signs, but incidence and intensity of spontaneous and audiogenic convulsive seizures were not different between the groups.

Ethanol withdrawal in mice precipitated and exacerbated by hyperbaric exposure.

Mice were fed an ethanol-containing liquid diet for 9 days. On removal of the diet, exposure to 12 atmospheres absolute of a mixture of helium and oxygen precipitated earlier withdrawal, increased withdrawal scores for the first 6 hours, and increased the peak withdrawal intensity compared to dependent animals exposed to control conditions. The enhanced withdrawal did not appear to reflect alterations in ethanol elimination, oxygen or helium partial pressures, body temperature, or general excitability. These results extend to chronically treated animals the evidence that hyperbaric exposure antagonizes the membrane actions of ethanol.

Prostanoid modulation (mediation?) of certain behavioral effects of ethanol

Prostaglandin E1 (PGE1) and prostanoid precursor fatty acids enhance the acute sedative effects of ethanol in mice, and reduce the intensity of withdrawal after chronic exposure to ethanol. Aspirin, and other inhibitors of prostanoid synthesis, attenuate ethanol's sedative effects, and interfere with the beneficial effects of prostanoid precursors (but not of PGE1 itself) in withdrawal. Neither aspirin nor indomethacin administered alone effect withdrawal behavior. In contrast, ethanol impairment of rotorod behavior is not affected by prostanoid precursors nor by aspirin. These findings support a role for prostanoids as modulators (? mediators) of certain direct effects of ethanol and a role for prostanoid deficiency in the pathogenesis of withdrawal behavior.

Cyclosporine alters opiate withdrawal in rodents

Opiates exert numerous effects on all levels of the central nervous system with tolerance, physical dependence and withdrawal being characteristics of this drug class. The degree of dependence is directly correlated to the intensity of withdrawal. Therefore, success in modifying the withdrawal syndrome may shed light on the dynamics of opiate addiction. The present study demonstrates that cyclosporine, a widely used immunosuppressive drug, considerably modified the behavioral signs of a naloxone-induced abstinence syndrome in morphine-addicted rats. In previous experiments, α-interferon has shown similar results. The similarity in actions of these two immunomodulator drugs is discussed and we suggest that opiate addiction may involve the immune system.

Sleep patterns in cats during chronic low-dose barbiturate treatment and withdrawal.

Sleep patterns were recorded during 5 weeks of chronic treatment with sodium barbital and after abrupt cessation of drug administration. Sodium barbital was administered intragastrically to adult cats twice daily in doses to produce a peak response of gross ataxia ("low-dose" barbiturate treatment). Sleep stages were scored from EEG, EOG, and neck EMG recordings from chronically implanted electrodes. Sleep was monitored continuously for 48 h once each week during barbital administration and continuously for 7 to 10 days during withdrawal. Rapid eye movement (REM) sleep during barbital treatment was reduced to approximately half compared with control. At the end of the treatment, equivalent doses of pentobarbital were substituted for barbital. Cessation of pentobarbital administration produced withdrawal. Withdrawal intensity was moderate and spontaneous convulsions occurred in half the animals. The duration of withdrawal insomnia was 2 to 3 days. Return of the non-REM and REM sleep was associated with changes in withdrawal behaviors, notably the appearance of overly affectionate behavior. Furthermore, during return of sleep both non-REM and REM sleep increased to values greater than control.

Self-administration of ketocyclazocine and ethylketocyclazocine by the rat

The purpose of the study was to assess possible substitution of either ketocyclazocine or ethylketocyclazocine for morphine in rats maintaining their own dependence by self-administration. Rats were prepared with indwelling IV cannulae, made tolerant to and physically dependent on morphine, then trained to lever press for morphine self-injections on a fixed ratio (FR) schedule of reinforcement. When either ketocyclazocine or ethylketocyclazocine was substituted for morphine, rats self-administered single injections of these kappa opioid agonists at relatively evenly spaced intervals over a 24-hr period. These self-injection patterns continued for up to at least 15 consecutive days. Substitution of saline for the kappa opioid agonists did not result in the emergence of a morphine-like abstinence syndrome. Differences in extent and intensity of withdrawal between morphine and these kappa opioid agonists indicate the involvement of separate receptor populations in the process of dependence on morphine and these kappa opioid agonists.

Self-administration of dynorphin-[1–13] and D-ala 2-dynorphin-[1–11] (kappa opioid agonists) in morphine (mu opioid agonist)-dependent rats

Adult female Sprague-Dawley rats were prepared with permanent cortical EEG and temporalis EMG electrodes and i.v. cannulae. They were made tolerant to and physically dependent on morphine by automatic, hourly injections. These physically dependent rats were then trained to lever press for 10 mg/kg injections of morphine on a fixed ratio (FR) schedule of reinforcement. Upon stabilization of morphine self-administration at a FR-10, dynorphin-[1–13] (DYN) or D-ala 2-dynorphin-[1–11] (D-ala 2-DYN) at doses of 125 or 250 ug/kg/inj was substituted for morphine. Rats self-administered these opioid-like peptides at both dose levels. As expected, self-injections were more numerous at the lower dose. No signs of morphine withdrawal were seen during the peptide substitutions. Following DYN or D-ala 2-DYN abstinence, no withdrawal symptoms were noted. The question is raised as to whether DYN or D-ala 2-DYN and morphine are producing their reinforcing effects in sustaining self-administration via the same receptor populations. Since morphine abstinence is associated with severe withdrawal symptoms and the peptides studied are not, the involvement of separate receptor populations in the process of dependence on morphine and these opioid-like peptides is indicated. In conclusion, both a mu and two kappa agonists exhibited an analogous reinforcing property in the rat. However, the degree of physical dependence and the intensity of withdrawal differed; being higher with the mu agonist and lower with the kappa agonists.

Buprenorphine: Demonstration of physical dependence liability

This study was designed to assess the dependence-producing capacity of the opiate partial agonist, buprenorphine. Rats chronically treated with buprenorphine for 4 days showed only very weak signs of withdrawal upon cessation of buprenorphine treatment of upon challenge with naloxone, although complete tolerance had developed to the drug at this time. However, more intense withdrawal could be induced when buprenorphine treatment was followed by substitution treatment with morphine. Even one injection of morphine given 12 h after the last buprenorphine treatment enabled the precipitation of withdrawal with naloxone. Naloxone could not precipitate signs of withdrawal in naive rats treated with this dose of morphine. Thus, contrary to some claims in the literature, buprenorphine, like other opiate agonists and partial agonists, induces dependence. The fact that only few signs of withdrawal are seen in direct dependence tests, probably reflects the slow dissociation of the drug from the receptor—which probably limits the intensity of withdrawal by preventing the rapid uncovery of the receptor upon discontinuance of treatment with the drug or upon injection of an antagonist. In addition, the maximum degree of dependence induced by buprenorphine—in comparison to pure agonists— is limited, like that of other partial agonists.

Reciprocal inhibition between feeding and withdrawal behaviors inPleurobranchaea

1. The interaction between two discrete behavioral acts, feeding and withdrawal from tactile stimulation, was examined in 32 specimens of the marine molluskPleurobranchaea. The experimental paradigm (Fig. 2) incorporated gradation of the intensity of the respective sensory stimuli for both behaviors over a wide range. 2. Withdrawal amplitude was suppressed during simultaneous feeding in individual animals (Figs. 5 and 7) and in grouped data from all 32 subjects (Fig. 9). The suppression of withdrawal was greater with increased feeding intensity (Fig. 9). 3. Feeding intensity declined during simultaneous withdrawal in individual animals (Figs. 6 and 8) and in grouped data from all subjects (Fig. 10). The suppression of feeding during withdrawal was greater with increased withdrawal intensity, and less with increased feeding intensity (Fig. 10). 4. It is concluded that feeding and withdrawal interact reciprocally rather than hierarchically, and a modified scheme for the overall organization ofPleurobranchaea's behavioral hierarchy is presented (Fig. 11). The findings are discussed from an evolutionary, ethological and neurophysiological view point.

Increased fear reactions in cats after carbachol administered intraventricularly

The effects upon normal defensive behavior of carbachol administered intraventricularly have been studied in the cat. The dose of carbachol (7 – 9 μg) elicited no observable behavioral response. The defense reaction in the animal receiving carbachol was evoked by the presence of a second cat which was impelled to emit threatening behavior by concurrent hypothalamic electrical stimulation. The intensity of withdrawal, backward flattening of the ears, and hissing induced by threat, increased significantly as a consequence of otherwise non-behaviorally active doses of intraventricular carbachol. Rage or attack behavior were not observed at these doses of carbachol. The conclusion drawn from these experiments is that doses of carbachol which are below the threshold for elicitation of overt behavior increase a form of behavior which is thought to be motivated or accompanied by fright or fear.

Preparation and evaluation of a sustained morphine delivery system in rats

A new drug delivery system to induce physical dependence to morphine in rats is described. The device consists of a silicone polymer containing a water soluble “carrier” material, sodium alginate, which swells on contact with moisture to release the drug. The silicone or silastic ® pellets formulated to contain morphine sulfate are very easily prepared and the advantages over existing methods to induce physical dependence to morphine are discussed. In addition, a comparison of the percent of drug released and withdrawal intensities in rats was made with a silastic-morphine sulfate pellet, silastic-morphine base pellet and a microcrystalline cellulose-morphine base pellet.

Ethanol dependence in the rat: A parametric analysis

Rats were maintained on liquid diets as their sole source of calories and fluid for 10, 15, 20 and 30 days. The diets consisted of 35–40% of total calories in the form of ethanol. This procedure resulted in substantial ethanol intake leading to behavioral intoxication. Blood ethanol concentrations were found to be elevated throughout the day with a peak during the dark phase of the light cycle. The removal of ethanol resulted in evidence of physiological dependence, including behavioral manifestation of autonomic and somatic dysfunction and an increased susceptibility to audiogenic convulsions. Ten days of ethanol exposure was found to be sufficient for the reliable induction of ethanol dependence. Further increases in ethanol exposure resulted in increased hyperexcitability as measured by susceptibility to audiogenic convulsions. The severity of withdrawal behavior was found to be correlated with the blood ethanol concentration measured upon ethanol removal. A behavioral rating scale for the evaluation of alcohol withdrawal intensity in rats is described.

Effects of depletion of brain catecholamines during the development of morphine dependence on precipitated withdrawal in rats

The significance of long term depletion of brain catecholamines (CSs) for the development of morphine dependence and for the expression of morphine withdrawal was studied in rats which were implanted with morphine pellets for 10 days. CAs were depleted by inhibition of tyrosine-hydroxylase with alpha-methyl-tyrosine (AMT) or by destruction of catecholaminergic nerve terminals wit6-hydroxydopamine (6-OHDA). In the "acute" experiments these drugs were applied within 24 hrs before precipitation of withdrawal; in the "chronic" experiments drug administration was started before the first implantation and in the case of AMT, continued repeatedly thereafter. With either method, "acute" depletion of brain CAs resulted in reduced intensity of withdrawal. When CAs were kept low through the whole time of morphine exposure and also at the time of withdrawal, the intensity of withdrawal was normal in the case of 6-OHDA administration and only slightly decreased in the case of AMT. When AMT administration was discontinued 40 hrs before precipitation of withdrawal the withdrawal pattern occurred with unchanged intensity. Our experimental data are compatible with the assumption that long lasting depletion of brain CAs is compensated for by induction of neuronal supersensitivity for noradrenaline (NA) and dopamine (DA). While both CAs play an important role in the full expression of the withdrawal syndrome their possible involvement in mechanisms leading to dependence seems to be unlikely although final statements cannot be made by the presented experiments.

Ambivalence in rats using single-lever Skinner boxes.

Ambivalent behavior or ambivalence in rats was observed in a single-lever Skinner box situation. The behavioral features associated with ambivalence were filmed and described, and their intensities were graded. It was found that different behavioral patterns, depending on the site of stimulation, are involved in ambivalence. Moreover, the intensity of self-stimulation and withdrawal was found to be higher in subjects implanted in posterior brain areas than in rats implanted in anterior areas, suggesting the existence of a gradient of ambivalence. At a theoretical level, it was suggested that complex mechanisms, possibly involving an autonomous ambivalent system, could be responsible for ambivalence.