Dopamine D4 Receptor-Mediated Presynaptic Inhibition of GABAergic Transmission in the Rat Supraoptic Nucleus

Abstract

. Dopamine D4 receptor-mediated presynaptic inhibition of GABAergic transmission in the rat supraoptic nucleus. J Neurophysiol 90: 559 -565, 2003; 10.1152/jn.00226.2003. The mechanism by which dopamine induces or facilitates neurohypophysial hormone release is not completely understood. Because oxytocin-and vasopressin-secreting supraoptic neurons are under the control of a prominent GABAergic inhibition, we investigated the possibility that dopamine exerts its action by modulating GABA-mediated transmission. Whole cell voltage-clamp recordings of supraoptic neurons were carried out in acute hypothalamic slices to determine the action of dopamine on inhibitory postsynaptic currents. Application of dopamine caused a consistent and reversible reduction in the frequency, but not the amplitude, of miniature synaptic events, indicating that dopamine was acting presynaptically to reduce GABAergic transmission. The subtype of dopamine receptor involved in this response was characterized pharmacologically. Dopamine inhibitory action was greatly reduced by two highly selective D4 receptor antagonists L745,870 and L750,667 and to a lower extent by the antipsychotic drug clozapine but was unaffected by SCH 23390 and sulpiride, D1/D5 and D2/D3 receptor antagonists, respectively. In agreement with these results, the action of dopamine was mimicked by the potent D4 receptor agonist PD168077 but not by SKF81297 and bromocriptine, D1/D5 and D2/D3 receptor agonists, respectively. Dopamine and PD168077 also reduced the amplitude of evoked inhibitory postsynaptic currents, an effect that was accompanied by an increase in paired-pulse facilitation. These data clearly indicate that D4 receptors are located on GABA terminals in the supraoptic nucleus and that their activation reduces GABA release in the supraoptic nucleus. Therefore dopaminergic facilitation of neurohypophysial hormone release appears to result, at least in part, from disinhibition of magnocellular neurons caused by the depression of GABAergic transmission.

Dopamine Modulates Use-Dependent Plasticity of Inhibitory Synapses

“…This is consistent with previous reports demonstrating a similar D 4 -mediated mechanism responsible for decreasing the release of both GABA (Azdad et al, 2003) and glutamate (Price and Pittman, 2001) at terminals in the SON. It is interesting that, although a specific agonist of the D 4 receptor inhibits both GABA and glutamate release, there is little effect of quinpirole, a nonselective agonist of the D 2 -like family (including D 4 ) of dopamine receptors in either the current study or previous work (Price and Pittman, 2001).…”

“…6C). Consistent with findings in the SON (Azdad et al, 2003), we also observed an inhibition of IPSCs by the D 4 receptor agonist PD168077 (30 M; 69.3 Ϯ 11.5% depression; n ϭ 7; data not shown) but not by quinpirole, an agonist for the D 2 -like receptor family (90 M; 5.2 Ϯ 9.3% depression; n ϭ 5; data not shown).…”

“…Dopamine decreases the release of GABA at inhibitory synapses onto MNCs in the SON by activating presynaptic D 4 receptors (Azdad et al, 2003). To determine whether inhibitory synapses onto MNCs in PVN were similarly affected, we bath applied dopamine and examined the effect on evoked and mIPSCs.…”

“…Dopamine augments the release of OT during lactation (Moos and Richard, 1982), facilitates the release of VP (Bridges et al, 1976;Forsling and Williams, 1984;Rossi, 1998), and increases the excitability of MNCs (Moos and Richard, 1982;Mason, 1983). Furthermore, in the supraoptic nucleus (SON), dopamine directly depolarizes MNCs (Yang et al, 1991) and decreases the release of both GABA (Azdad et al, 2003) and the excitatory neurotransmitter glutamate (Price and Pittman, 2001). In other brain regions, neurotransmitter release is also regulated dynamically by the rate at which the nerve terminal is activated (Tsodyks and Markram, 1997;Thomson and Bannister, 1999;Dittman et al, 2000;Kreitzer and Regehr, 2000;Hefft et al, 2002;Telgkamp and Raman, 2002).…”

Glia-Dependent Switch of Kainate Receptor Presynaptic Action

“…KARs are positively coupled to GABA release in the SON Earlier studies described the action of various presynaptic receptors on GABA terminals in the SON (Kabashima et al, 1997;Schrader and Tasker, 1997;Wang et al, 1998;Oliet and Poulain, 1999;Li et al, 2001;Stern and Ludwig, 2001;Azdad et al, 2003) but no particular attention was paid to that of KARs. For this purpose, we performed recordings on miniature IPSCs (mIPSCs) in slices from animals under basal, nonstimulated conditions of neurosecretion, i.e., normally hydrated male and virgin female rats.…”