Modification of dopaminergic transmission by thyrotropin-releasing hormone.

TRH may act on the brain independently of its effects on the pituitary, and some of the CNS actions of TRH are probably closely related to brain catecholamines. TRH enhanced SMA by systemic injection (20 mg/kg, i.p.) or direct microinjection (10 micrograms) of TRH into the nucleus accumbens (ACB), one of the nerve terminal sites of the mesolimbic dopaminergic system, in rats. Prevention of this TRH effect by pretreatment with haloperidol or pimozide, a DA receptor blocker, or alpha-MT, an inhibitor of tyrosine hydroxylase, indicated that the SMA stimulatory action of TRH was the result of an enhancement of the release of DA from the nerve terminals. In rats lesioned unilaterally in the nigrostriatal DA pathway by 6-OHDA, high doses of TRH given i.p. (100 mg/kg) or into the nonlesioned caudate nucleus (50 micrograms) produced a circling toward the lesioned side which was suppressed by haloperidol or alpha-MT. The in vitro study demonstrated that TRH (5 X 10(-4)M) enhanced the release of preloaded [3H]DA from the slices of ACB after stable spontaneous DA release was established under superfusion, while a higher concentration (10(-2)M) was required to enhance the DA release from striatal slices. These in vitro studies supported the findings in investigation in vivo. In addition, TRH (2.5-20 mg/kg) markedly enhanced the circling behavior induced by L-DOPA or apomorphine in mice with unilateral caudate nucleus lesions induced by injection of 6-OHDA. In the 6-OHDA lesioned mice treated with TRH, DA-induced cyclic AMP formation was clearly enhanced in the striatal slices taken from the lesioned side but not from the intact side. In conclusion, TRH in low doses facilitates the DA presynaptic transmission by increasing the release of this amine from the ACB and also the DA postsynaptic transmission by increasing DA-stimulated cyclic AMP formation in striatum supersensitized with 6-OHDA. Endogenous TRH may play a physiological role as a modulator on DA transmission in CNS.