Dopamine D2 receptors bypass canonical signaling to directly tune NMDA receptor function and aversive learning

Dopamine D2-like receptors differentially shape GABAergic plasticity in distinct subtypes of hippocampal VIP interneurons.

Dopamine regulates diverse brain functions, including learning and memory, primarily through two receptor types, D1R and D2R, which activate and inhibit adenylate cyclase, respectively. Dopaminergic system critically modulates glutamatergic transmission, but less is known about its impact on GABAergic plasticity, in which the role of the D2R remains practically unexplored. Vasoactive intestinal polypeptide-expressing (VIP) interneurons (INs) represent an important subset, comprising those innervating other inhibitory cells, mediating disinhibition, and others contacting various neurons, including pyramidal cells. Herein, we addressed the role of D2Rs in GABAergic plasticity in two classes of VIP INs: interneuron-specific (IS) and non-interneuron specific (non-IS). We show that D2Rs activation with quinpirole upregulated the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in IS, while analogous result was observed in non-IS VIP INs upon D2Rs blockade with sulpiride and these effects were accompanied by prolongation of mIPSC decay. Brief NMDA application, known to evoke heterosynaptic inhibitory long-term plasticity, induced inhibitory LTP (iLTP) at GABAergic synapses onto IS VIP INs and iLTD in non-IS VIP INs. Notably, D2R agonism, but not antagonism, impaired NMDA-evoked iLTP in IS VIP INs, consistent with occlusion. Collectively, these findings reveal cell-specific and D2R-dependent GABAergic plasticity phenomena in IS and non-IS VIP INs.

Antipsychotic-like effects of TAAR1 agonists and D2 receptor blockers are mediated through distinct modulation of striatal neuronal dynamics.

The Cellular and Synaptic Actions of Dopamine During Behavior

Dopamine signaling in the striatum is essential for a wide range of functions, from reward learning to motor vigor and behavioral flexibility. Although dopamine signals fluctuate on sub-second timescales, how these signals are translated into lasting changes in striatal circuit function remains unknown. Resolving this requires cell-type-specific measurements of synaptic and intrinsic properties during behavior, a longstanding technical challenge. Here, we combined in vivo whole-cell membrane potential recordings, simultaneous monitoring and bidirectional manipulation of dopamine signaling in awake, behaving mice to examine how dopamine shapes corticostriatal circuits. Acute manipulations of dopamine over seconds to minutes produced only modest effects on corticostriatal synaptic transmission and no detectable changes in membrane potential dynamics or intrinsic excitability. By contrast, associative learning robustly strengthened identified corticostriatal synapses onto both D1- and D2-expressing spiny projection neurons, yet only D1-SPN plasticity required dopamine signaling. These findings challenge models in which dopamine acts rapidly to tune striatal excitability and identify learning related plasticity as its principal mechanism for shaping striatal circuits in vivo.

Distinct properties of glutamate-dopamine, nonglutamate-dopamine, and glutamate-only ventral tegmental area neurons.

Dopamine neurons in the ventral tegmental area (VTA) have roles in motivation, learning, and psychiatric disorders. We found that genetically defined VTA dopamine neuron subtypes had distinct electrophysiological properties, neuronal signaling dynamics in response to reward- and aversion-related stimuli, and roles in somatic optogenetically induced reward dependent on the neurotransmitters they released. Nonglutamate-dopamine neurons increased activity after reward-related stimuli and decreased activity after the omission of an expected reward (negative reward prediction error) and aversion-related stimuli. Glutamate-dopamine and glutamate-only (nonGABAergic and nondopaminergic) neurons were activated by both rewarding and aversive events, but only glutamate-dopamine neurons had sustained cue-induced reward signaling. Recordings of all dopamine neurons without considering glutamate cotransmission showed mixed population responses during prediction error and aversive stimuli that obscured the distinct signaling patterns of its constituent subpopulations. Although the examined cell types largely differ in mediolateral location, cell-type identity better accounted for functional differences than mediolateral location. Glutamate-dopamine neurons were more excitable than nonglutamate-dopamine neurons. Glutamate-dopamine and nonglutamate-dopamine axons had similar but not identical dopamine release dynamics in the nucleus accumbens. Only nonglutamate-dopamine neurons supported somatic optogenetically induced reward and reinforcement. In glutamate-dopamine neurons, the dopamine synthetic enzyme TH contributed to associative learning of aversive or less-beneficial outcomes, whereas the vesicular glutamate transporter VGLUT2 contributed to reward- and exploration-related vigor. Our results suggest that glutamate cotransmission is a distinguishing feature of VTA dopamine neuron signaling patterns and roles in natural reward- or aversion-motivated behavior.

A cholinergic hub in the nucleus accumbens gates opioid-reward learning

Beneficial and maladaptive opioid effects are difficult to dissociate, partly because dopamine signaling contributes to both. Here we show that associative opioid-reward learning can be blocked even under conditions that elevate dopamine in the nucleus accumbens. We developed naloxoneDART, a cell-type-specific analogue of the clinical opioid-receptor antagonist, and delivered it to genetically defined accumbal cholinergic interneurons (CINs), selectively rendering these cells morphine-insensitive. Acquisition of morphine conditioned place preference was abolished in a target-engagement-dependent manner, without evidence of contextual or locomotor impairment: saline habituation was enhanced between sessions and unchanged within sessions, while morphine-evoked hyperlocomotion, sensitization, and acute analgesia remained intact. Microdialysis revealed that CIN-specific naloxoneDART prevented morphine-induced acetylcholine reductions without detectably altering dopamine elevations in the accumbens. These findings identify a cholinergic gate for associative opioid-reward learning, support an emerging dopamine-acetylcholine plasticity theory, and motivate exploration of opioid-cholinergic strategies that may preserve acute analgesia while limiting early associative reward learning.

Metabotropic glutamate receptor internalization and synaptic AMPA receptor endocytosis by dopamine.

Group I metabotropic glutamate receptors (mGluRs) play important roles in synaptic function, plasticity and in many neuropsychiatric disorders. Trafficking plays crucial roles in proper targeting of these receptors in specific region of the neuron and also regulating the activity of these receptors. Group I mGluRs encounter dopamine in various regions of the brain and multiple evidences suggest that dopamine might regulate these receptors in the hippocampus. We show here, dopamine induces internalization of both members of the group I mGluR family, mGluR1 and mGluR5 in hippocampal neurons derived from mice through clathrin-dependent, but dynamin-independent pathway. Dopamine increases the mGluR-mediated Gαq activity and phosphorylation of MAP kinases. Subsequent to the dopamine-mediated internalization receptors recycle to the cell surface faster than agonist-mediated internalized receptors. Recycling of the dopamine-mediated internalized mGluR1 is protein phosphatase 2B-dependent. Finally, we report that dopamine also induces the mGluR-mediated synaptic AMPA receptor endocytosis, the cellular correlate of mGluR-dependent synaptic plasticity. Thus, this study unravels a novel role for dopamine in the internalization of mGluRs and mGluR-mediated AMPA receptor endocytosis.