Dopamine modulation of excitatory currents in the striatum is dictated by the expression of D1 or D2 receptors and modified by endocannabinoids

Abstract

Striatal medium-sized spiny neurons (MSSNs) receive glutamatergic inputs modulated presynaptically and postsynaptically by dopamine. Mice expressing the gene for enhanced green fluorescent protein as a reporter gene to identify MSSNs containing D1 or D2 receptor subtypes were used to examine dopamine modulation of spontaneous excitatory postsynaptic currents (sEPSCs) in slices and postsynaptic N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents in acutely isolated cells. The results demonstrated dopamine receptor-specific modulation of sEPSCs. Dopamine and D1 agonists increased sEPSC frequency in D1 receptor-expressing MSSNs (D1 cells), whereas dopamine and D2 agonists decreased sEPSC frequency in D2 receptor-expressing MSSNs (D2 cells). These effects were fully (D1 cells) or partially (D2 cells) mediated through retrograde signaling via endocannabinoids. A cannabinoid 1 receptor (CB1R) agonist and a blocker of anandamide transporter prevented the D1 receptor-mediated increase in sEPSC frequency in D1 cells, whereas a CB1R antagonist partially blocked the decrease in sEPSC frequency in D2 cells. At the postsynaptic level, low concentrations of a D1 receptor agonist consistently increased NMDA and AMPA currents in acutely isolated D1 cells, whereas a D2 receptor agonist decreased these currents in acutely isolated D2 cells. These results show that both glutamate release and postsynaptic excitatory currents are regulated in opposite directions by activation of D1 or D2 receptors. The direction of this regulation is also specific to D1 and D2 cells. We suggest that activation of postsynaptic dopamine receptors controls endocannabinoid mobilization, acting on presynaptic CB1Rs, thus modulating glutamate release differently in glutamate terminals projecting to D1 and D2 cells.

Cue-Evoked Dopamine Release Rapidly Modulates D2 Neurons in the Nucleus Accumbens During Motivated Behavior

“…Furthermore, this finding likely extends to other reward-based behaviors because similar changes in extracellular dopamine and firing rate occur in the NAc during a behavioral paradigm in which a cue signals the impending lever availability for food (Cacciapaglia et al, 2011). Understanding the specific circuits associated with dopamine's regulation of reward-mediated behaviors is necessary to determine the mechanisms that influence reward learning, which becomes hijacked by drugs of abuse (Koob and Volkow, 2010;Bock et al, 2013). This work establishes that the responses in the NAc are quite different from those measured previously in the dorsal striatum, where studies using optogenetic monitoring of dopamine neurons have shown that D1Rs and D2Rs work simultaneously (Cui et al, 2013).…”

“…Therefore, our results demonstrate, for the first time during behavior, that this D2-mediated suppression is a consequence of dopamine release triggered by the cue. The synaptic architecture at MSNs containing D2Rs allows dopaminergic modulation of cannabinoids and adenosine that promote high-pass filtering of glutamatergic afferents (André et al, 2010;Wang et al, 2012;Wong et al, 2015). Indeed, activation of D2Rs on MSNs has been suggested to promote switching from ongoing behavior to lever approach (van den Bos et al, 1991;Nicola, 2010).…”

Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

“…The input of this neural network consists of glutamatergic cortical afferents that excite D1-class (D1R) and D2-class dopamine receptor (D2R)-expressing striatal medium-sized spiny neurons (MSNs), which form distinct direct and indirect pathways that promote and suppress competing motor movements, respectively (Pennartz et al, 1994; Nicola et al, 2000). Modulation of these excitatory corticostriatal synapses is determined by the availability of dopamine and acetylcholine, which are necessary for the establishment of reward, attention, and motor learning (Kalivas and Volkow, 2005;Cepeda et al, 2010). Emerging evidence suggests that abnormalities in the availability of these neuromodulators may promote an imbalance between direct and indirect striatal pathways (Beutler et al, 2011;Kozorovitskiy et al, 2012; to produce the motor and neuropsychological symptoms of Parkinsonism and drug dependence Bamford and Cepeda, 2009).…”

Dopamine-Dependent Long-Term Depression Is Expressed in Striatal Spiny Neurons of Both Direct and Indirect Pathways: Implications for Parkinson's Disease

“…Direct confirmation of these hypotheses has been hindered by difficulty in selectively targeting direct and indirect pathway neurons with traditional techniques. Thus, bacterial artificial chromosome (BAC) transgenic mice conferring cell type-specific expression of enhanced green fluorescent protein (eGFP) in distinct neuronal subpopulations, including MSNs of the direct and indirect pathways, have been used in the last years (Kreitzer and Malenka, 2007;Ade et al, 2008;Shen et al, 2008;André et al, 2010). Utilizing BAC transgenic mice in which direct and indirect pathway neurons were labeled with GFP, Kreitzer and Malenka (2007) found that DA-dependent plasticity was selectively expressed in MSNs of the indirect pathway, while MSNs of the direct pathway did not express this form of synaptic plasticity.…”