Date of Award

1986

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacy and Toxicology

First Advisor

John J. DeFeo

Abstract

The purpose of this research was to examine the effects of mu (μ), kappa (κ) and sigma (o) agents namely, morphine (μ), ethylketocyclazocine (κ), SKF 10,047 (σ), pentazocine (κ, o), cyclazocine (κ, σ) and the mu antagonists, naloxone and naltrexone on dopamine mediated behaviors and the development of haloperidol-induced dopaminergic supersensitivity (DA-SS) in the mouse. Three behavioral paradigms were utilized which are predictive of mesolimbic and/or striatal dopaminergic effects: locomotor activity (mesolimbic); apomorphine-induced stereotyped behavior (striatal) and apomorphineinduced climbing behavior (mesolimbic/striatal). Morphine, SKF 10,047, pentazocine and cyclazocine produced increases in locomotor activity suggesting increased dopaminergic activity, while naloxone and naltrexone had no effect on locomotion. Ethylketocyclazocine (EKC) induced a biphasic effect of sedation followed by an increase in locomotor activity at three hours post administration. EKC and SKF 10,047 antagonized apomorphine-induced climbing because of motor deficits, sedation and ataxia, respectively, while the other opiates had no effect. Only EKC inhibited apomorphine-induced stereotypy, due to initial motor deficits and sedation. Thus, these compounds were not dopamine antagonists, insofar as apomorphine-induced behaviors were only antagonized at debilitating doses which incapacitated mice. Furthermore, both EKC and SKF 10,047 increased locomotion, unlike neuroleptics which generally cause motor depression.

The stimulant properties of the κ and α opiates warranted further investigation. EKC at 5 mg/kg sc produced a biphasic effect over time with a peak effect from 180 to 210 minutes. EKC (5 mg/kg) hyperactivity was dependent upon catecholamine synthesis and transmission since a -MPT (300 mg/kg), reserpine (5 mg/kg), tetrabenazine (5, 40 mg/kg), haloperidol (1 mg/kg), apomorphine (0.1 mg/kg), muscimol (1 mg/kg) and prazosin (2.5 mg/kg) blocked EKC-induced locomotor activity. SKF 10,047 at 40 mg/kg sc not only increased locomotor activity but also induced stereotypy and climbing behavior with an ED50 for climbing at 90 minutes equal to 14.6 mg/kg sc. SKF 10,047 (40 mg/kg) -induced climbing was dependent on catecholamine transmission and a direct serotonin receptor interaction since α -MPT (300 mg/kg), tetrabenazine (5, 40 mg/kg), haloperidol (1 mg/kg), apomorphine (0.1 mg/kg), muscimol (1 mg/kg), prazosin (2.5 mg/kg) and methysergide (10 mg/kg) antagonized this behavior. Both EKC-induced hyperactivity and SKF 10,047-induced climbing were not antagonized by naloxone (10, 100 mg/kg). Furthermore, naloxone, EKC and SKF 10,047 potentiated apomorphine-induced climbing.

The μ, κ, σ and mixed K, σ agents all produced effects suggesting dopaminergic activity, i.e., locomotion, stereotypy, climbing and potentiation of apomorphine effects. Therefore, each was tested for its ability to attenuate haloperidol-induced DA-SS in the climbing and stereotyped behavior paradigms. In the acute climbing paradigm, haloperidol-induced DA-SS was dose-dependently attenuated by SKF 10,047, EKC, cyclazocine, pentazocine, naloxone and naltrexone, with morphine inactive. In the chronic (5-day) climbing and stereotypy models, only the concomitant administration of either SKF 10,047 or cyclazocine and haloperidol inhibited the development of DA-SS, while morphine alone produced DA-SS. These results suggest differential opiate modulation of DA-SS in the acute vs. chronic paradigms. Furthermore, sigma agonists were most effective in attenuating haloperidol-induced DA-SS, presumably through dopamine agonist properties.

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