RESUMEN
Transmission in the "direct" pathway through the basal ganglia, which has an important role in the control of motor movement, is markedly facilitated by the concurrent activation of dopamine D(1) receptors. Consistent with this, Ca(2+)-dependent, depolarization-induced release of [(3)H]-GABA from striatal slices from rats pretreated with reserpine was greatly increased in the presence of 1 microM SKF 38393, a dopamine D(1)-like receptor agonist. The effect of SKF 38393 was mimicked by 1 mM 8-bromo-cyclic AMP (Br-cAMP) and inhibited by the protein kinase A (PKA) inhibitor H-89, mean inhibition 92% +/- 4% with 10 microM H-89 (n = 3). The effects of SKF 38393 and Br-cAMP were not additive. The stimulatory effects of SKF 38393 and Br-cAMP were practically abolished in the presence of the histamine H(3) receptor agonist immepip (1 microM). The depolarization-induced release of [(3)H]-GABA in the presence of SKF 38393 was not significantly inhibited by 5 microM nimodipine, an L-type Ca(2+) channel blocker, or by 0.3 microM omega-conotoxin MVIIA, a selective blocker of N-type channels. However, preincubation of the slices with 0.95 microM omega-agatoxin TK, a P/Q-type channel blocker, followed by washing before changing to a depolarizing medium containing SKF 38393, resulted in a marked inhibition of the stimulated release of [(3)H]-GABA, mean 68% +/- 4% (n = 3). These observations provide evidence that dopamine D(1) agonist facilitation of the depolarization-induced release of GABA from striatal terminals is mediated by the cAMP/PKA pathway and involves mainly P/Q-type Ca(2+) channels.
Asunto(s)
Canales de Calcio/metabolismo , Cuerpo Estriado/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Receptores de Dopamina D1/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Canales de Calcio Tipo P/efectos de los fármacos , Canales de Calcio Tipo P/metabolismo , Canales de Calcio Tipo Q/efectos de los fármacos , Canales de Calcio Tipo Q/metabolismo , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Inhibidores Enzimáticos/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Cultivo de Órganos , Ratas , Ratas Wistar , Receptores de Dopamina D1/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/efectos de los fármacosRESUMEN
Abnormalities in dopaminergic control of basal ganglia function play a key role in Parkinson's disease. Adenosine appears to modulate the dopaminergic control in striatum, where an inhibitory interaction between adenosine and dopamine receptors has been demonstrated. However the interaction has not been established in substantia nigra pars reticulata (SNr) where density of both receptors is high. Here we have explored the interaction between A1/D1 receptors in SNr. In SNr slices, SKF 38393, a selective D1 receptor agonist, produced a stimulation of depolarization-induced Ca(2+)-dependent [(3)H]GABA release that was inhibited by adenosine. The adenosine inhibition was abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist. DPCPX per se enhanced GABA release, indicating inhibition of the release by endogenous adenosine. When D1 receptors were blocked with SCH 23390 or the slices were depleted of dopamine, the effect of DPCPX was suppressed, showing that activation of dopamine receptors was necessary for the adenosine inhibition. In normal slices, 2-chloro-n(6)-cyclopentyladenosine (CCPA), a selective A1 agonist, inhibited GABA release, but the inhibition was prevented by the blockade of D1 receptors with SCH 23390. Superperfusion with 8-bromo-cAMP produced a stimulation of GABA release that was not blocked by CCPA: this finding indicates that the blockade of D1 effects caused by activation of A1 receptors is specific. To see if these actions on GABA release were correlated with changes in motor behavior we studied the effect of unilateral intranigral injections of modifiers of adenosine A1 and dopamine D1 receptors in rats challenged with systemic methamphetamine. Both the A1 agonist CCPA and the D1 antagonist SCH 23390 produced ipsilateral turning whereas the A1 antagonist DPCPX caused contralateral turning. These motor effects are consistent with the findings on GABA release. The results indicate the presence of an inhibitory A1/D1 receptor interaction in SNr. The inhibition exerted by A1 adenosine receptors on GABAergic striatonigral transmission would be due exclusively to blockade of the facilitation resulting from activation of D1 dopamine receptors. The data permit to better understand the action of adenosine antagonists in the treatment of Parkinson's disease.
Asunto(s)
Actividad Motora/fisiología , Inhibición Neural/fisiología , Enfermedad de Parkinson/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores Purinérgicos P1/metabolismo , Sustancia Negra/metabolismo , Ácido gamma-Aminobutírico/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Adenosina/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Cultivo de Órganos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Potasio/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D1/efectos de los fármacos , Receptores Purinérgicos P1/efectos de los fármacos , Sustancia Negra/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Tritio , Xantinas/farmacologíaRESUMEN
1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.
Asunto(s)
Neostriado/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores Histamínicos H3/metabolismo , Tiourea/análogos & derivados , Ácido gamma-Aminobutírico/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Calcio/farmacología , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2 , Histamina/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/antagonistas & inhibidores , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Potenciales de la Membrana/efectos de los fármacos , Neostriado/efectos de los fármacos , Piperidinas/antagonistas & inhibidores , Piperidinas/farmacología , Potasio/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D2/metabolismo , Reserpina/farmacología , Sulpirida/antagonistas & inhibidores , Sulpirida/farmacología , Tiourea/farmacologíaRESUMEN
Attempting to better understand the role of the dopaminergic innervation in the rat globus pallidus, we examined here whether or not endogenous dopamine modulates the release of [3H]GABA in superfused pallidal slices. The superfusion medium contained elevated (15 mM) potassium. The release of endogenous dopamine was induced by the dopamine releaser drug, methamphetamine. Methamphetamine (100 microM) inhibited by 46% the release of [3H]GABA. Methamphetamine inhibition was completely blocked by reserpinization of the rats. It was also completely blocked by the D2 dopamine receptor antagonist sulpiride (10 microM). Sulpiride alone caused a 105% increase in GABA release. The increase was not observed in slices from reserpinized rats. Quinpirole (10 microM), a D2 dopamine receptor agonist, inhibited (43%) [3H]GABA release. The results suggest that endogenous dopamine exerts an inhibitory effect on GABA release in the rat globus pallidus. The effect is mediated by D2 receptors presumably located on striatopallidal axon terminals.
Asunto(s)
Dopamina/fisiología , Globo Pálido/metabolismo , Receptores de Dopamina D2/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Globo Pálido/efectos de los fármacos , Técnicas In Vitro , Masculino , Metanfetamina/farmacología , Quinpirol/farmacología , Ratas , Ratas Wistar , Sulpirida/farmacologíaRESUMEN
D1 dopamine receptors are present on terminals of striatal neurons to the pars reticulata of the substantia nigra in the rat. Here we have studied the effect of the activation of these receptors on the synthesis of gamma-aminobutyric acid (GABA) in slices of the pars reticulata of the substantia nigra isolated from 6-hydroxydopamine-lesioned rats. The synthesis was judged by the accumulation of GABA after inhibiting GABA transaminase with aminooxyacetic acid. Both dopamine and SCH 23390, a D1 agonist, stimulated the synthesis. The effect of both compounds was blocked by SCH 23390, a D1 antagonist, but not by sulpiride, a D2 antagonist. In the absence of receptor activation, the synthesis was very slow. The results suggest a trophic influence of dopamine upon the synthesis of GABA via D1 receptors.