Edgar T. Iwamoto

Circling behavior in rats with 6-hydroxydopamine or electrolytic nigral lesions☆

Unilateral destruction of dopaminergic cell bodies in the substantia nigra zona compacta (SNC) was performed in rats using either electrocoagulation or chemical lesioning (6-hydroxydopamine, 6-OHDA). Neostriatal dopamine concentration ipsilateral to an electrolytic lesion was 34% of the contralateral side 2-3 weeks after operation; serotonin and noradrenaline brain levels were not altered. In contrast, dopamine and noradrenaline forebrain concentrations ipsilateral to a 6-OHDA lesion were 20 and 31%, respectively, of the contralateral side. After 6-OHDA, dopamine concentrations in the ipsilateral neostriatum were reduced to levels below the sensitivity of the fluorometric assay; cortical, brainstem and neostriatal serotonin levels, on the other hand, were not altered after 6-OHDA. Ipsilateral circling behavior was elicited by d-amphetamine after electrolytic and chemical lesioning. In contrast, the direction of circling produced after apomorphine differed between the two lesion models: contralateral circling behavior was exhibited by 6-OHDA-lesioned rats, whereas ipsilateral circling was produced in animals with electrolytic lesions. Contralateral circling was induced in both lesion-type models by haloperidol or pimozide. S.c. atropine administration induced ipsilateral circling in rats with 6-OHDA lesions, whereas contralateral circling was observed after arecoline. Animals with electrolytic SNC lesions turn ipsilaterally after s.c. administrations of either arecoline or atropine. The data indicate that the electrolytic and 6-OHDA circling behavior models represent two different neuropharmacological states and it is, therefore, suggested that comparisons of data obtained from models using different methods of lesioning be made with caution.

Dopaminergic-cholinergic interactions in naloxone-induced circling in morphine-dependent rats with nigral lesions

3-4 weeks after placement of a unilateral, electrolytic lesion of the substantia nigra zona compacta, rats were highly dependent on morphine by the s.c. morphine pellet implantation technique. Following challenge with a supramaximal naloxone dose of 20 mg/kg i.p., both continuous contralateral circling behavior and severe withdrawal signs in morphine-dependent, lesioned rats were elicited. After various drug pretreatments, the contralaeral circling behavior precipitated by naloxone was: (a) reversed to ipsilateral circling by i.p. apomorphine or d-amphetamine, (b) unaltered by i.p. haloperidol or intraneostriatal arecoline administered into the intact neostriatum, and (c) reversed to ipsilateral circling by the administration of atropine into the intact neostriatum. Atropine, apomorphine and amphetamine all interfered with the manifestation of naloxone-precipitated abstinence. These data suggest that a diminution of dopaminergic or an enhancement of cholinergic activities, or both, occur at the level of the neostriatum during naloxone-precipitated withdrawal in morphine-dependent rats.

Effect of pargyline on morphine tolerance and physical dependence development in mice

The effects of single and repeated pargyline administration on morphine antinociception in both naive and morphine-tolerant mice and on naloxone-precipitated withdrawal in morphine tolerant-dependent animals were investigated. Adult, male Swiss-Webster mice were rendered tolerant to and dependent on morphine by the s.c. pellet implantion technique. Morphine analgesia, as assessed by the tail-flick antinociceptive test, was potentiated in tolerant animals by acute adminstration of pargyline but antagonized by repeated pargyline administration; pargyline produced similar effects in non-tolerant mice and to the same relative degree. Repeated pargyline treatment during morphine pellet implantation enhanced the withdrawal jumping response precipitated by naloxone in dependent mice. Pargyline also, after a single injection, exacerbated jumping in mice undergoing abrupt withdrawal. Neither acute nor chronic pargyline administration altered the brain distribution of injected morphine in non-tolerant mice. It was concluded that pargyline may modify acute morphine actions and withdrawal without materially altering the process(es) involved in the development of tolerance and physical dependence.

EFFECT OF CALCIUM AND LANTHANUM IN MORPHINE ANALGESIA AND TOLERANCE

Abstract A series of experiments were initiated to study the influence of calcium on morphine action. The analgetic effect of morphine in non-tolerant and tolerant mice was found to be antagonized by intraventricular calcium and enhanced by the cation chelator EGTA. Elevation of brain bioamines by monoamine oxidase inhibition (pargyline) or reducing brain catecholamine by chemical sympathectomy (6-hydroxydopamine) failed to alter the calcium effect. Enhancing calcium influx with the ionophore X537A also decreased morphine analgesia while inhibition of calcium binding to and movement across cell membrane by lanthanum greatly augmented morphine analgesia. Interestingly, lanthanum per se produced analgesia in both mice and rats and the action was inhibited by the narcotic antagonist, naloxone. Moreover, the analgetic sensitive sites in the CNS to lanthanum and morphine were both found to be in the periventricular and periaqueductal gray areas. Cross tolerance between lanthanum and morphine was noted and lanthanum attenuated the withdrawal syndrome in morphine-dependent mice. The development of tolerance to morphine was accompanied by an increased level of calcium in synaptosomes and a decrease in high affinity calcium binding to the synaptosomal plasma membrane fraction but not to the other membrane fractions studied. The effects suggest that chronic morphine treatment decreases the availability of calcium binding sites on the inner surface of the synaptosomal membrane.