Gerald A. Young

Differential neuropharmacological effects of MU, kappa and sigma opioid agonists on cortical EEG power spectra in the rat: stereospecificity and naloxone antagonism

The study was designed to determine and compare the acute effects of the enantiomers of mu, kappa and sigma opioid agonists on the cortical EEG with the spectral analysis technique. The relative ability of naloxone to antagonize such effects was also assessed. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG and temporalis muscle EMG recording electrodes, and with permanent indwelling external jugular cannulae. (-)-Methadone(mu agonist) produced increases in spectral power over the zero to 10Hz range, while (-)-ketocyclazocine (kappa agonist) produced increases in the 5-8 Hz band as a predominant peak. The(+) enantiomers of methadone and ketocyclazocine were inactive. The drug (+)-SK-10,047 (sigma agonist), produced a predominant spectral peak in the 7-9 HZ band that was associated with behavior that suggested psychotomimetic effects. The effects of morphine (mu agonist) on EEG and EEG power spectra were more sensitive to antagonism by naloxone than those produced by ketocyclazocine. The effects of (+/-)-SKF-10,047 and (+)-SKF-10,047 were not antagonized by 10 mg/kg of naloxone, while the effects of (-)-SKF-10,047 were partially antagonized by 10 mg/kg of naloxone. These findings further delineate the specificity of the differential effects of mu, kappa and sigma opioid agonists on the EEG and EEg power spectra in the rat.

Effects of acute δ9-THC administration on EEG and EEG power spectra in the rat

Abstract This study was designed to determine the acute effects of Δ 9 -THC on the cortical EEG with the spectral analysis technique. Adult female Sprague-Dawley rats were implanted with chronic cortical and temporalis muscle electrodes. Intraperitoneally administered Δ 9 -THC (5 and 10 mg/kgmg/kg) produced a reduction in peak-to-peak voltage of the desynchronized cortical EEG during wakefulness. Associated spectral power was reduced to about 50% of control during the first hour after injection of Δ 9 -THC and gradually returned toward the control value over an 8-hr period. Occurrences of Δ 9 -THC-induced high-voltage EEG bursts, overriding the reduced EEG tracing, were associated with an EEG spectral peak at 6 Hz. The first few slow-wave sleep (SWS) episodes appearing after Δ 9 -THC administration were associated with more slow-frequency waveforms and more slow-frequency spectral power than with control slow-wave sleep episodes. During control rapid eye movement (REM) sleep episodes, an EEG theta wave pattern, with an associated spectral peak at about 8 Hz, was characteristic. Conversely, the first few REM sleep episodes emerging after Δ 9 -THC administration contained overriding high-voltage bursts, the related power spectra of which had two peaks at about 7 and 11 Hz.

Cortical EEG power spectra associated with sleep-awake behavior in the rat

Power spectral analyses were used to study cortical EEG activities during sleep-awake behavior in the rat. EEG spectra, both long-time and sequential short-time, derived from EEG during the states of wakefulness, sleep, and REM sleep were qualitatively and quantitatively different. The degree of inter- and intrasubject variability between these spectra was minimal. This experimental model with the rat should allow quantitative delineation of cortical EEG changes produced by psychotropic drugs.

Sigma receptors mediate the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties

Our present findings suggest that SKF-10,047, the prototype sigma agonist, has its opioid entity residing with its (-) isomer, while both its (+) and (-) isomers possess psychotogenic properties similar to those produced by PCP. We found that (-)-SKF-10,047 blocks EEG and behavioral effects of morphine in the naive rat, precipitates withdrawal in morphine-dependent rats, produces physical dependence as evidenced by naloxone-induced withdrawal, and displaces [3H]dihydromorphine from brain homogenates. (+)-SKF-10,047 did not produce dependence upon chronic treatment, and it did not displace [3H]dihydromorphine from brain homogenates. Such pharmacodynamic dissociation with SKF-10,047 suggests an association of sigma receptors with psychogenic, but not opioid effects. The latter are most likely mediated by mu or kappa receptors.

Self-administration of dynorphin-[1–13] and D-ala2-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-ala2-dynorphin-[1-11] (D-ala2-DYN) at doses of 125 or 250 micrograms/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-ala2-DYN abstinence, no withdrawal symptoms were noted. The question is raised as to whether DYN or D-ala2-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.

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.

Self-administration of nalbuphine, butorphanol and pentazocine by morphine post-addict rats.

The purpose of the study was to define possible self-administration of nalbuphine, butorphanol and pentazocine by morphine post-addict rats. Rats were prepared with permanent EEG and EMG electrodes and indwelling IV cannulae, made tolerant to and physically dependent on morphine, then trained to lever press for morphine IV self-injections on a fixed ratio (FR) 20 schedule of reinforcement. Rats were then spontaneously withdrawn from morphine. When these morphine post-addict rats were returned to the experimental cages three to four weeks later, they were found to reestablish self-administration of morphine as well as to establish self-administration of nalbuphine, butorphanol and pentazocine. Suppression of REM sleep for at least 30 min was apparent following self-injections of these agents. After the stabilization of self-injection patterns, withdrawal from nalbuphine and pentazocine was found to be associated with intense abstinence symptoms. However, withdrawal from morphine and butorphanol was not. It can be concluded that while drug-seeking behavior for the above narcotics in morphine post-addict rats was analogous as measured by self-administration, nalbuphine and butorphanol appeared to produce lower levels of physical dependence.

Genetic profiles of morphine-induced EEG, EEG power spectra, and behavior in two inbred rat strains

The purpose of the present study was to examine and compare the effects of morphine at doses of 3, 10, and 30 mg/kg, IV, on EEG, EEG power spectra, and behavior in two inbred rat strains, Lewis and Fischer 344. Duration of morphine-induced EEG slow-wave bursts and associated behavioral stupor was greater in Lewis rats. Latency to slow-wave sleep increased in a dose-related manner for both strains; differences were not significant between the two groups. The analog EEG signal was transformed by fast Fourier analysis; six power spectral quantities were examined: peak frequency, complexity, mobility, mean frequency, edge frequency, and total power. With the exception of peak frequency and edge frequency, all differed as a function of inbred rat strain. Regarding morphine dose, all spectral parameters differed except peak frequency. Factor analysis on morphine-induced EEG revealed a unique factor for each strain that was bipolar in nature and may be associated with the burst and interburst periods that occur in EEG after opiate administration. Genetic variability appears to play a role in the behavioral, EEG, and derived power spectral responses of both LEW and F344 inbred rat strains following acute morphine administration. These results may reflect differences in neurosensitivity and/or opioid receptor populations between Lewis and Fischer 344 inbred rat strains.

Modulation of morphine-induced EEG and behavioral effects by dynorphin A-(1-13) in non-tolerant and morphine-tolerant rats

The purpose of the present study was to assess effects of dynorphin A-(1-13) on morphine-induced changes in electroencephalographic (EEG) spectral power and morphine-induced suppression of slow-wave sleep in non-tolerant and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG electrodes, electromyographic electrodes in the temporalis muscle and with intracerebroventricular (i.c.v.) cannulae and, in some cases, additional intravenous (i.v.) cannulae. Injections of morphine (i.c.v., 20 micrograms/rat) produced a biphasic EEG and behavioral response, composed of 2-3 hr of slow-wave bursts and increased spectral power (0-4 Hz) in the EEG, associated with behavioral stupor, followed by 2-3 hr of EEG and behavioral arousal. Dynorphin (i.c.v., 20 micrograms/rat), administered 10 min before injections of morphine in non-tolerant rats, antagonized morphine-induced increases in spectral power of the EEG and morphine-induced suppression of slow-wave sleep. In addition, EEG power spectra obtained after intraventricular administration of morphine from rats, treated with dynorphin and morphine intraventricularly 24 hr earlier, were qualitatively similar to those previously found after acute administration of kappa opioid agonists. In morphine-tolerant rats, pretreatment with dynorphin given intraventricularly, 10 min prior to intraventricular administration of morphine, restored morphine-induced increases in EEG spectral power and suppression of slow-wave sleep. The results suggest that dynorphin may modulate the characteristics of opioid receptors.

Comparison of abstinence syndromes following chronic administration of mu and kappa opioid agonists in the rat

Abstinent states were compared following chronic administration of mu and kappa opioid agonists, morphine and ethylketocyclazocine, respectively. Rats were prepared with chronic EEG and EMG electrodes and indwelling IV cannulae. One group of rats was chronically administered IV morphine, while a second group received chronic injections of IV ethylketocyclazocine. Morphine abstinence was associated with suppression of REM sleep occurrences, increases in number of wet-dog shakes, and a decline in EEG spectral power during slow-wave sleep episodes. In contrast, the ethylketocyclazocine abstinence syndrome included minor abstinence signs. Differences in abstinent states between morphine and ethylketocyclazocine indicate the involvement of separate receptor populations in the process of dependence on morphine and ethylketocyclazocine.