Blockade of Intranigral and Systemic D3 Receptors Stimulates Motor Activity in the Rat Promoting a Reciprocal Interaction among Glutamate, Dopamine, and GABA

Abstract

In vivo activation of dopamine D3 receptors (D3Rs) depresses motor activity. D3Rs are widely expressed in subthalamic, striatal, and dendritic dopaminergic inputs into the substantia nigra pars reticulata (SNr). In vitro studies showed that nigral D3Rs modulate their neurotransmitter release; thus, it could be that these changes in neurotransmitter levels modify the discharge of nigro-thalamic neurons and, therefore, motor behavior. To determine how the in vitro responses correspond to the in vivo responses, we examined the effect of intra-nigral and systemic blockade of D3Rs in the interstitial content of glutamate, dopamine, and GABA within the SNr using microdialysis coupled to motor activity determinations in freely moving rats. Intranigral unilateral blockade of D3R with GR 103,691 increased glutamate, dopamine, and GABA. Increments correlated with increased ambulatory distance, non-ambulatory activity, and induced contralateral turning. Concomitant blockade of D3R with D1R by perfusion of SCH 23390 reduced the increase of glutamate; prevented the increment of GABA, but not of dopamine; and abolished behavioral effects. Glutamate stimulates dopamine release by NMDA receptors, while blockade with kynurenic acid prevented the increase in dopamine and, in turn, of GABA and glutamate. Finally, systemic administration of D3R selective antagonist U 99194A increased glutamate, dopamine, and GABA in SNr and stimulated motor activity. Blockade of intra-nigral D1R with SCH 23390 prior to systemic U 99194A diminished increases in neurotransmitter levels and locomotor activity. These data highlight the pivotal role of presynaptic nigral D3 and D1R in the control of motor activity and help to explain part of the effects of the in vivo administration of D3R agents.

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

“…Probably, dopamine receptors expressed in a high spiking neuron are more sensitive to dopamine or drugs and, consequently, in the modulation of spontaneous motor behavior. In this respect, activation of D 3 R by endogenous dopamine regulates glutamate released in the high spiking subthalamic‐nigral neurons and motor activity (Rodríguez‐Sánchez et al., 2019). A factor that can also contribute to this effect is pallido‐pallidal terminals at the soma and initial segment of the pallidal neuron (Kita & Kitai, 1994).…”

“…Thus, as indicated in our electrophysiological experiments (Figures 4 and 5), the antagonist perfusion in GP will increase GABA release at presynaptic D 4 R. On the contrary, perfusion of D 2 R selective antagonist did not modify basal motor activity indicating low or none stimulation by endogenous dopamine to receptors in these conditions. Last, it is similar to D 1 R in SNr, as perfusion of D 1 R selective antagonist SCH 23390 modifies neither GABA release nor spontaneous motor behavior (Rodríguez‐Sánchez et al., 2019).…”

Coexistence of D3R typical and atypical signaling in striatonigral neurons during dopaminergic denervation. Correlation with D3nf expression changes

“…The SNr represents the central output nucleus of basal ganglia and a final point of dopaminergic modulation of signals coming from the striatum modulating motor control (Robertson, 1992). In this regard, dopaminergic presynaptic control of GABA and glutamate release at the nigral level modifies GABAergic output neuron activity and motor control (Rodriguez‐Sanchez et al, 2019). Our experimental strategy was to evaluate the effect of activation of D 1 R and D 3 R, separately and by coactivation, through injecting selective agonists into SNr alone or in the presence of NEM to block Gi protein signaling.…”

“…On the contrary, the sense of turning, contralateral to the injection, indicates less activity of output neurons. Thus, most likely the effect of PD 128907 represents the control of glutamate release by D 3 R (Briones‐Lizardi et al, 2019; Rodriguez‐Sanchez et al, 2019), since during denervation a substantial increment of firing of subthalamic neurons exist (Kreiss, Mastropietro, Rawji, & Walters, 1997), which is translated into glutamate release, and presynaptic D 3 R that control glutamate release are also sensitized (Briones, Erlij, Aceves, & Floran, 2016). Contrariwise, the decrement in glutamate release produces a decrease in the activity of output neurons favoring motor activity.…”

“…These effects of local manipulations of intra‐nigral D 3 R interacting with D 1 R on motor behavior are in concordance with in vitro observations and reflect the complex interaction between receptors during denervation. Moreover, the effects indicate that nigral receptors are an essential site of action for drugs that modify the activity of the SNr, as occurs in a normal state (Rodriguez‐Sanchez et al, 2019). However, it should still make us ponder that the result of the administration of drugs with D 3 R activity in models of Parkinson's disease is diverse.…”