ISSN:
1432-1912
Keywords:
Partial agonists
;
Dopamine receptors
;
Intrinsic activity
;
Ergolines
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary The partial dopamine receptor agonists SDZ 208-911 {N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamide|, and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (−80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (−32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ 208–912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208–912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208–911 and SDZ 208–912 also showed high affinities for central alpha2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208–911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208–911, SDZ 208-912 and terguride reduced the activity to 10–20% of controls with SDZ 208–912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called “jerking” behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208–911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208–912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses. SDZ 208–912 and SDZ 208–911 completely reversed the inhibition of firing rate produced by d-amphetamine, while SDZ 208–912 partially (81 %) reversed the inhibitory effects of apomorphine. It is concluded that all three amino-ergolines possess partial dopamine receptor agonistic effects with SDZ 208–911 and terguride displaying a similar intrinsic efficacy (in certain models approximately 50% of that of quinpirole or apomorphine). On the other hand, SDZ 208–912 displays a very low intrinsic efficacy, detectable only in the electrophysiological model and in reserpinized rats. The results are discussed in relation to the potential clinical utility of these compounds as antipsychotic agents.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00182999
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