Behavioral evidence for dopaminergic supersensitivity following chronic treatment with methadone or chlorpromazine in the guinea pig

This study demonstrated the enhancement, as a consequence of prior chronic drug treatment, of two behaviors (stereotyped oral behaviors and open field locomotion) which are thought to depend primarily on the striatel dopamine system. Following a 5-week treatment with methadone (MD), chlorpromazine (CPZ), or saline, the dopamine agonist methamphetamine (MA) elicited more intense stereotypies in the MD and CPZ animals. After chronic treatment with MD, the MA-elicited stereotypies were reduced by an acute dose of MD. Stereotyped oral behaviors elicited by a stressful stimulus (foot shock) were enhanced in the MD animals both during and following chronic drug treatment. MA-elicited open field locomotion, measured 2 weeks following termination of chronic drug treatment, was enhanced in the MD and CPZ animals.     

The effect of p-chlorophenylalanine on the pethidine- or methadone-induced decrease in locomotor activity of rats.

Either pethidine HCl (50 mg/kg s.c.) or methadone HCl (8 mg/kg s.c.) produced a prominent decrease in locomotor activity of rats. Pretreatment of rats with p-chlorophenylalanine (p-CPA, 320 mg/kg i.p.) 48 h before the narcotic injection significantly antagonized the activity-decreasing effects of narcotics. When rats pretreated with p-CPA were given 5-hydroxytryptophan (75 mg/kg s.c.) 30 min before narcotic administration, the activity-decreasing response to narcotics was restored. Thus, a decrease in locomotor activity induced in rats by either pethidine or methadone is probably mediated by serotonergic mechanisms.     

Head-Shake distributions during self-maintained dependence on morphine,methadone, and l-alpha-acetylmethadol (LAAM) in the rat

Adult female Sprague-Dawley rats were prepared with chronic cortical and muscle electrodes and i.v. cannulas, made tolerant to and physically dependent on morphine, and trained to lever press for i.v. morphine self-injections to maintain dependence. Methadone or l-alpha-acetylmethadol (LAAM) was then substituted for morphine in some of these rats. During self-maintained dependence on either morphine or methadone, head shakes appeared and increased in frequency before lever pressing for selfinjections. In contrast, there were fewer head shakes during LAAM dependence, which were evenly distributed over the entire duration of the interinjection interval. These findings suggest a relationship between head-shake distributions, drug-seeking behavior, and the pharmacodynamics of these three narcotics.     

Enhancement of memory by a cholinesterase inhibitor associated with muscarinic receptor down-regulation

Rats trained on a passive avoidance task 24 hours following a single intraperitoneal injection of diisopropyl fluorophosphate (DFP, 1.2 mg/kg) showed enhanced retention when tested 7 days later. In a parallel group of rats, reduced cortical [3H] quinuclidinyl benzilate binding was demonstrable 24 hours following DFP administration. The association of reduced muscarinic receptor binding and enhanced performance on a memory task contradicts previous reports which suggested that retention was impaired by treatments which down-regulate muscarinic receptors. This contradiction may be reconciled if pre-synaptic factors such as agonist availability are considered in conjunction with post-synaptic receptor effects.     

Barbital-induced changes in sensitivity to the behavioral effects of narcotics

Twelve male (Sprague-Dawley) rats were trained to respond under a variable-interval 15 sec schedule of sweetened-milk reinforcement. Rats were tested with doses of morphine and methadone, both before and after the development of tolerance to barbital (100 mg/kg, IP). Barbital-tolerant rats were tolerant to the effects of methadone on VI responding but were not tolerant to the effects of morphine. These data demonstrate that tolerance to some narcotics can develop after chronic exposure to drugs other than those of the same pharmacologic class. Furthermore, this investigation demonstrates the necessity of considering changes in the pharmacokinetics of a narcotic as a possible explanation for the development of tolerance to the behavioral effects of the drug.     

Opiates, endorphins and the developing organism: A comprehensive bibliography

A comprehensive bibliography of the literature concerned with opiates, endorphins, and the developing organism is presented. A total of 1378 clinical and laboratory references, with citations beginning in 1875, are recorded. A series of indexes accompanies the citations in order to make the literature more accessible. These indexes are divided into clinical and laboratory topics. The clinical section is subdivided into: age of subject examined; maternal aspects; effects on the fetus; pharmacology, physiology, and the withdrawal syndrome; and “other” effects on the offspring. The laboratory section is subdivided into: type of opiate/endorphin studied; species utilized; and major subject areas explored.     

Morphine- and methadone-tolerant mice differ in cross-tolerance to other opiates

Summary Mice were rendered tolerant to morphine or l-methadone by subcutaneous injections for 4 days. The antinociceptive activities of morphine, codeine, l-methadone and d-propoxyphene were determined in tolerant and control mice using the hot-plate test, and the respective ED₅₀'s were calculated by the up-and-down procedure of Dixon. An asymmetry in cross-tolerance patterns was found: While morphine-pretreated mice were tolerant to morphine only (with a dose-ratio tolerant: control of 5.2), methadonepretreated mice were tolerant to all analgesics tested, and more so to morphine than to methadone itself (dose-ratios: morphine 5.2; l-methadone 3.0; codeine 2.7 and d-propoxyphene 1.9).The results are discussed in terms of heterogeneity in opioid receptor mechanisms.     

Drug effects on distress-evoked behavior in mice: Methodology and drug class comparisons

Methodologic studies were undertaken to establish the optimal conditions of continuous foot shock stimulation (3 min at 0.08 mA) for investigating drug effects on distress-evoked behavior, e.g., vocalizing, leaping, running, fighting and recovery latencies. The drugs subsequently studied under these conditions (imipramine, methamphetamine, methadone, perphenazine, pentobarbital, ethyl alcohol and chlordiazepoxide) could be distinguished and classified from the profiles of action obtained. Greatest overall reduction of the distress-evoked behaviors in diminishing order were produced by perphenazine, methadone, ethyl alcohol and chlordiazepoxide. Methadone most selectively reduced leaping responses; perphenazine most selectively prolonged recovery time latencies. None of the agents reduced fighting at doses that did not also modify the other modes of responding.     

Effect of the antiepileptic di-n-propylacetamide on 5-hydroxytryptamine turnover in the brain and 5-hydroxyindoleacetic acid level in the cerebrospinal fluid

The effect of antiepileptic drug di-n-propylacetamide (DPM) on 5-hydroxytryptamine (5-HT) turnover in rat brain and 5-hydroxyindoleacetic acid (5-HIAA) in cat cerebrospinal fluid (CSF) was investigated. DPM (200 mg/kg) increased brain 5-HIAA without altering the 5-HT level. DPM augmented the accumulation of 5-HT induced by monoamine oxidase inhibition with pargyline (80 mg/kg) and enhanced the accumulation of 5-HIAA in the brain following blockade of transport of this metabolite by probenecid (200 mg/kg). Prior inhibition of 5-HT synthesis by p-chlorophenylalanine (300 mg/kg) abolished the DPM-induced increase in cerebral 5-HIAA. DPM (100 mg/kg) given daily for 5 days considerably elevated 5-HIAA in the CSF of cat during the treatment period. We conclude that DPM increases the turnover of 5-HT in brain and that this can be observed by monitoring the 5-HIAA content of CSF.     

Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence

AIMS: To evaluate slow-release oral morphine (SROM) as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. DESIGN: Open-label crossover study. SETTING: Out-patient methadone maintenance programme. PARTICIPANTS: Eighteen methadone maintenance patients. Intervention Participants were transferred from methadone to SROM (once-daily Kapanol trade mark ) for approximately 6 weeks before resuming methadone maintenance. MEASUREMENTS: Patient outcomes were assessed (1) during the transition between medications (dose requirements, withdrawal severity) and (2) after at least 4 weeks on a stable dose of each drug (treatment preference, patient ratings of treatment efficacy and acceptability, drug use, health, depression and sleep). FINDINGS: Transfer from methadone to SROM was associated with relatively mild withdrawal for the first 5 days; the final mean SROM : methadone dose ratio was 4.6 : 1. Compared to methadone, SROM was associated with improved social functioning, weight loss, fewer and less troublesome side-effects, greater drug liking, reduced heroin craving, an enhanced sense of feeling 'normal' and similar outcomes for unsanctioned drug use, depression and health. The majority of subjects preferred SROM (78%) over methadone (22%). CONCLUSIONS: These findings provide justification for further evaluation of SROM as a maintenance pharmacotherapy for opioid dependence.