Dopamine D4 receptor modulates inhibitory transmission in pallido-pallidal terminals and regulates motor behavior.

Two major groups of terminals release GABA within the Globus pallidus; one group is constituted by projections from striatal neurons, while endings of the intranuclear collaterals form the other one. Each neurons' population expresses different subtypes of dopamine D2-like receptors: D2 R subtype is expressed by encephalin-positive MSNs, while pallidal neurons express the D4 R subtype. The D2 R modulates the firing rate of striatal neurons and GABA release at their projection areas, while the D4 R regulates Globus pallidus neurons excitability and GABA release at their projection areas. However, it is unknown if these receptors control GABA release at pallido-pallidal collaterals and regulate motor behavior. Here, we present neurochemical evidence of protein content and binding of D4 R in pallidal synaptosomes, control of [3 H] GABA release in pallidal slices of rat, electrophysiological evidence of the presence of D4 R on pallidal recurrent collaterals in mouse slices, and turning behavior induced by D4 R antagonist microinjected in amphetamine challenged rats. As in projection areas of pallidal neurons, GABAergic transmission in pallido-pallidal recurrent synapses is under modulation of D4 R, while the D2 R subtype, as known, modulates striato-pallidal projections. Also, as in projection areas, D4 R contributes to control the motor activity differently than D2 R. This study could help to understand the organization of intra-pallidal circuitry.

Cannabinoid-induced depression of synaptic transmission is switched to stimulation when dopaminergic tone is increased in the globus pallidus of the rodent.

Because activation of D2 receptors reverses the neurochemical effects of cannabinoids, we examined whether increasing dopaminergic tone in the globus pallidus (GPe) switches cannabinoid induced depression of synaptic transmission. GABAergic synaptic currents evoked in pallidal neurons by stimulation of striatal projections (IPSCs) were depressed by perfusion with the CB1R agonist ACEA. Coactivation of D2Rs with quinpirole converted the depression into stimulation. Pretreatment with pertussis toxin (PTX) to limit Gi/o protein coupling also switched the CB1R-induced depression of IPSCs. The stimulation of IPSCs was blocked by the selective PKA blocker H89. Changes in the paired pulse ratio during both inhibitory and stimulatory responses indicate that the effects are due to changes in transmitter release. Postsynaptic depolarization induces endocannabinoid release that inhibits transmitter release (DSI). When D2Rs were activated with quinpirole, depolarization increased transmission instead of depressing it. This increase was blocked by AM251. We also examined the effects of CB1R/D2R coactivation on cAMP accumulation in the GPe to further verify that the AC/PKA cascade is involved. CB1R/D2R coactivation converted the inhibition of cAMP seen when each receptor is stimulated alone into a stimulation. We also determined the effects on turning behavior of unilateral injection of ACEA into the GPe of awake animals and its modification by dopamine antagonists. Blockade of D2 family receptors with sulpiride antagonized the motor effects of ACEA. We show, for the first time, that cannabinoid-inhibition of synaptic transmission in the GPe becomes a stimulation after D2Rs or PTX treatment and that the switch is probably relevant for the control of motor behavior.