Effect of DN-1417, a thyrotropin releasing hormone analog, on dopaminergic neurons in rat brain.
Acute and chronic effects of gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide (DN-1417) were investigated on motor activity, dopamine (DA) metabolites and DA receptors in various brain regions of rats. The motor activity, as measured with Automex recorder, was enhanced after a single injection with DN-1417 (20 mg/kg, IP), and the motor stimulating action persisted during 21 daily injections. Acute DN-1417 elevated both homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in 7 brain regions, prefrontal cortex polar, medial and lateral fields, nucleus accumbens, olfactory tubercles, amygdala and striatum. After chronic treatment for 7 days, the acute effect of DN-1417 on DA metabolites disappeared in all regions except for the striatum in which DN-1417 still increased HVA and DOPAC. The response of striatal DA metabolites was also observed after chronic treatment for 21 days. Chronic DN-1417 produced no significant change in 3H-spiperone binding in the prefrontal cortex, nucleus accumbens, olfactory tubercles and striatum, while striatal 3H-DA binding displaced by 30 nM spiperone was enhanced after chronic treatment. These results indicate that DN-1417 interacts with mesocortical, mesolimbic and nigrostriatal DA systems in the different modes of action. The lack of tolerance to motor hyperactivity, however, raises the question as to whether DN-1417-induced hyperactivity may be mediated by the activation of mesolimbic DA neurons. The involvement of nigrostriatal neurons in DN-1417-induced motor hyperactivity is suggested.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D006728:Hormones / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D006728:Hormones; D011954:Receptors, Dopamine; D014284:Triiodothyronine; D013134:Spiperone; D013973:Thyrotropin-Releasing Hormone; C029762:DN 1417; D013974:Thyroxine; D004298:Dopamine