Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors. A behavioral, biochemical and electrophysiological study.
The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-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 SDZ208-912, 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 alpha 2 (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.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Pharmacology, University of Göteborg, Sweden.
K
K
Svensson
A
A
Ekman
M F
MF
Piercey
W E
WE
Hoffmann
J T
JT
Lum
A
A
Carlsson
D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis; D015259:Dopamine Agents / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology*; D008090:Lisuride / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D019257:Quinpirole; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000502:physiology*; D011985:Receptors, Serotonin / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000096:biosynthesis; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D015259:Dopamine Agents; D004873:Ergolines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C062737:N-(2,6-dimethylergoline-8-yl)-2,2-dimethylpropanamide; C059362:N-(2-chloro-6-methylergoline-8-yl)-2,2-dimethylpropanamide; D019257:Quinpirole; C006208:dironyl; D012701:Serotonin; D012110:Reserpine; D008090:Lisuride; D015107:4-Butyrolactone; D004298:Dopamine