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Biomedical subjects

J E Moreton

Publications and source records attributed to J E Moreton.

11 recordsLinked to original sources
PubMed1979

Synthesis and preliminary biological studies of 4- and 5-[2-hydroxy-3-(isopropylamino)propoxy]benzimidazoles: selective beta2 adrenergic blocking agents.

Benzimidazoles carrying the 2-hydroxy-3-(isopropylamino)propoxy side chain at either the C-4 or C-5 ring positions were synthesized and investigated for beta-adrenergic blocking activity. Both compounds demonstrated beta2 selectivity when evaluated in guinea pig atrial and tracheal preparations. The C-4 isomer was 17 times more selective toward tracheal tissue, and its overall potency was roughly comparable to that of propranolol. beta2 selectivity of the C-5 isomer was minimal, with a potency about one-hundredth that of propranolol.

Adrenergic beta-Antagonists↗
PubMed1979

Electroencephalographic and behavioral tolerance to and cross-tolerance between D-Ala2-methionine-enkephalinamide and morphine in the rat.

Rats were given repeated intraventricular (i.vt.) injections of D-enkephalin (20 microgram/4 hr) or morphine (20 microgram/4 hr) for 72 to 96 hr during electroencephalograman(EEG) recording. Initial epileptiform EEG and associated wet-dog shakes occurred following D-enkephalin but not morphine. The epileptoid EEG progressed to a continous high-voltage EEG synchrony similar to morphine and was associated with behavioral stupor. Rapid eye movement sleep was also suppressed. Repeated administration of D-enkephalin or morphine produced tolerance to their effects. When challenged with i.vt. morphine, D-enkephalin-tolerant rats were cross-tolerant to morphine. Likewise, morphine-tolerant rats were cross-tolerant to D-enkephalin. While the morphine-tolerant rats demonstrated a marked abstinence syndrome when challenged with naloxone (10 mg/kg i.p.), no abstinence signs were observed in the D-enkephalin-tolerant rats. The demonstration of tolerance and cross-tolerance between morphine and D-enkephalin suggests a similar mechanism of action, but the differential development of physical dependence may entail different mechanisms or receptor sensitivities for this effect. These findings of similarities and differences in the acute and chronic effects of D-enkephalin and morphine support the contention that heterogenous opiate receptors may mediate their pharmacologic actions.

Animals↗
PubMed1978

Electroencephalographic and behavioral effects of D-ala2-methionine-enkephalinamide and morphine in the rat.

Rats were prepared with chronic cortical and temporalis muscle electrodes and bilateral intraventricular (i.vt.) cannulae. The direct and voltage integrated electroencephalogram (EEG) and integrated electromyogram as well as gross behavior were monitored after the i.vt. injection of D-enkephalin (10--240 microgram), morphine (2.5--40 microgram), naloxone (25--50 microgram) or sterile water (10 microliter). EEG high-amplitude slow-frequency waves (EEG slow bursts) occurred after i.vt. morphine or D-enkephalin and were associated with behavioral stupor. The behavioral depressant effect was followed by behavioral arousal and EEG activation. The EEG voltage output during morphine or D-enkephalin-induced EEG slow-wave activity was dose-dependent and was correlated with the behavioral state of the rat. D-Enkephalin was less potent and shorter-acting than morphine but produced a greater maximal response with respect to increasing the EEG voltage output. The effects of D-enkephalin and morphine were antagonized by pretreatment with naloxone (10 mg/kg s.c.). On the other hand, the i.vt. injection of naloxone alone or sterile water had no disruptive effect of the EEG or behavior of the rat. The results of this study established a dose-response relationship for the i.vt. administration of morphine and D-enkephalin using the direct and voltage integrated EEG. The demonstrated difference in maximal EEG response between morphine and D-enkephalin supports the contention that heterogenous opiate receptors in the brain may mediate their effects.

Animals↗
PubMed1977

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 level 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 self-injections. 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.

Animals↗
PubMed1977

1-alpha-acetylmethadol (LAAM), methadone and morphine abstinence in dependent rats: EEG and behavioral correlates.

Adult female Sprague-Dawley rats were prepared with chronic intravenous cannulas and cortical and muscle electrodes for recording electroencephalograms and electromyograms, respectively. They were made physically dependent on morphine by automatic intravenous injections and then trained to lever press in order to self-administer morphine on a FR-20 schedule of reinforcement. Upon stabilization of morphine self-administration, one group continued to self-administer morphine, while two other groups were switched to methadone or 1-alpha-acetylmethadol (LAAM) self-administration for an additional five to ten days. Continuous EEG and EMG recordings were collected. Initially, automatic injections of morphine suppressed rapid eye movement (REM) sleep time, then tolerance developed to this effect. REM sleep time in rats self-administering LAAM, methadone or morphine was within the lower limit of the normal range. Following withdrawal, REM sleep was severely suppressed during the first 24 h with morphine and methadone, but only moderately suppressed with LAAM. Increases in lever pressing during withdrawal from morphine and methadone occurred earlier and were more intense and prolonged than for LAAM. The incidence of head shakes peaked earlier and was higher for morphine and methadone during withdrawal than for LAAM. Irritability scores increased for morphine and methadone during the first day of withdrawal, but did not show any increase until the third day for LAAM. These findings suggest that in dependent rats withdrawal from LAAM is less severe than withdrawal from morphine or methadone.

Animals↗
PubMed1977

Ketamine self-administration by the rhesus monkey.

Intravenously administered ketamine served as a reinforcer of self-administration behavior in rhesus monkeys during daily 2-hour sessions. When the dose of ketamine was varied over a wide range at fixed-ratio schedules of reinforcement of 1, 8 and 64, the response rate was an inverted U-shaped function of the dose. Maximal response rates occurred at progressively higher doses as the fixed-ratio size was increased; drug intake per session was positively related to the dose. When the ketamine dose was held constant and the fixed-ratio was increased in a geometric series, the response rate increased as the fixed-ratio was increased to FR 128 or FR 256; additional increases in fixed-ratio size produced abrupt decreases in response rates. Since the response rate increased linearly as the fixed-ratio was increased geometrically, drug intake was a decreasing function of the response requirement. With respect to magnitude of reinforcement and fixed-ratio response requirement, the data show that ketamine maintains self-administration behavior in a manner similar to that of a number of other drugs and conventional reinforcers.

Animals↗
PubMed1976

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.

Animals↗
PubMed1975

REM sleep distributions in post-addict rats relapsing to morphine self-administration: effects of naloxone subcutaneous pellets.

Female Sprague-Dawley rats were prepared with chronic cortical and temporalis muscle electrodes and i.v. cannulas. They were administered i.v. injections of morphine to produce tolerance and physical dependence, then trained to lever press for i.v. self-injections of morphine (10 mg/kg) to maintain dependence. They were subsequently withdrawn for two weeks, implanted subcutaneously with one or two pellets of naloxone base, 100 mg each, or placebo pellets, returned to the experimental cages and allowed to relapse to self-administration of either saline or morphine. Rats with placebo pellets relapsed to morphine self-administration and reestablished the dependence state. However, rats implanted with naloxone and then permitted to self-administer morphine extinguished their lever pressing ("drug-seeking behavior"). Similar results were obtained with rats implanted with placebo pellets and self-administering saline. The self-injections of morphine by rats implanted with placebo pellets severely suppressed REM sleep and altered its normal distribution. Rats implanted with naloxone pellets and that subsequently extinguished their lever pressing, however, did not exhibit a change in REM sleep distributions. Similarly, self-injections of isotonic saline did not exert an effect on REM sleep distributions. These findings suggest that a correlation between REM sleep distributions, drug-seeking behavior, and morphine-naloxone interaction prevailed.

Animals↗