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.
Highlights
IntroductionActivation of dopamine D3 receptors (D3Rs) depresses motor activity in rodents, as pharmacologically selective antagonists increase spontaneous motor behavior, whereas agonists decrease it [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15].Messenger RNA (mRNA), protein, and in vitro neurochemical and electrophysiological studies indicate that D3 and receptor (D3R) are widely expressed in projections into the substantia nigra pars reticulata (SNr) of the rat, in striato–nigral [16,17,18,19,20] and subthalamo–nigral projections [21,22,23,24,25,26]
D3 receptors (D3Rs) effects in the different intra-nigral afferents modify neurotransmitter release, we have examined the responses to blockading D3R activity by systemic and intra-nigral antagonist administration using microdialysis and motor activity determinations in freely moving animals
Our results revealed that blockade of NMDA receptors (NMDARs) did not modify basal glutamate release (Figure 4A, glutamate dialysate number three: 103% ± 4% vs. dialysate number six: 109% ± 4%, mean difference 6, ns, p = 0.99, F(12,60) = 33.7, two-way analyzed by two-way analysis if variance (ANOVA) following Tukey, n = six rats)
Summary
Activation of dopamine D3 receptors (D3Rs) depresses motor activity in rodents, as pharmacologically selective antagonists increase spontaneous motor behavior, whereas agonists decrease it [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15].Messenger RNA (mRNA), protein, and in vitro neurochemical and electrophysiological studies indicate that D3Rs are widely expressed in projections into the substantia nigra pars reticulata (SNr) of the rat, in striato–nigral [16,17,18,19,20] and subthalamo–nigral projections [21,22,23,24,25,26]. Dopaminergic neurons that release dopamine from their dendrites within the SNr express D3R [21,27,28,29,30,31,32]. The functional effects of these presynaptic D3Rs modulating neurotransmitter release have been described elsewhere [19,20,23,25,26]. Because discharges of nigro-thalamic neurons control the flow of impulses through the thalamic relay nucleus to the motor cortex [33], the activation of D3R in the SNr may play a major role in the modulation of motor behavior.
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