A possible mechanism of action of thyrotropin-releasing hormone (TRH) and its analog DN-1417 on the release of dopamine from the nucleus accumbens and striatum in rats.
Slices of the nucleus accumbens, the terminus of the mesolimbic dopaminergic system and the striatum, the terminus of the nigrostriatal dopaminergic system obtained from rats, were used for analyzing the dopamine releasing effects of TRH and its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate). (1) Dopamine release: The addition of DN-1417 (5 X 10(-5) M) or TRH (5 X 10(-4) M) stimulated the release of prelabelled [3H]-dopamine (DA) from the superfused nucleus accumbens slices, and 100 or 20 times higher concentrations of each compound stimulated DA release from the striatal slices. The omission of Ca2+ from the superfusion medium or the addition of ouabain (5 X 10(-3) M), a (Na+ + K+) stimulated adenosine triphosphate (ATP) phosphohydrolase [(Na+ + K+)-ATPase] inhibitor, almost completely abolished the DN-1417- or TRH-induced DA releasing effect. (2) 45Ca2+ uptake: The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) stimulated 45Ca2+ uptake into the nucleus accumbens slices in a time-dependent manner from 1 to 5 min at 30 degrees C. On the other hand, both drugs (10(-4) M) had no effect on 45Ca2+ uptake into the striatal slices. A Ca2+ ionophore, A-23187 (10(-6) M), stimulated 45Ca2+ uptake into slices of the nucleus accumbens and striatum. Ouabain abolished the DN-1417-, TRH- and A-23187-induced effects. (3) Cyclic AMP formation: The addition of DN-1417 (10(-4) M) or TRH (10(-4) and 10(-3) M) accelerated cyclic AMP formation in the nucleus accumbens, but not in the striatal slices. A Ca2+ antagonist, methoxyverapamil (D-600, 10(-6) M) almost completely abolished the DN-1417- and TRH-effects. (4) (Na+ + K+)-ATPase activity: The addition of DN-1417 (10(-5) and 10(-4) M) or TRH (10(-4) M) activated (Na+ + K+)-ATPase in the P1 fraction (cell debris, nuclei) of the nucleus accumbens, but had little effect on the same activity in the striatum. (5) [3H]-TRH binding: The addition of 10(-6) to 10(-4) M of DN-1417 and TRH inhibited concentration-dependently [3H]-TRH binding in the nucleus accumbens and striatal slices. Ouabain (5 X 10(-3) M) almost completely abolished [3H]-TRH binding in both types of slices.(ABSTRACT TRUNCATED AT 400 WORDS)
Narumi
S
S
Nagai
Y
Y
Saji
Y
Y
Nagawa
Y
Y
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism*; D005711:Gallopamil / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012686:Septal Nuclei / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
D014150:Antipsychotic Agents; D002132:Calcium Radioisotopes; D000001:Calcimycin; D005711:Gallopamil; D010042:Ouabain; D013973:Thyrotropin-Releasing Hormone; C029762:DN 1417; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium; D004298:Dopamine