G protein-coupled receptor modulation of striatal dopamine transmission: Implications for psychoactive drug effects.

Dopamine transmission in the striatum is a critical mediator of the rewarding and reinforcing effects of commonly misused psychoactive drugs. G protein-coupled receptors (GPCRs) that bind a variety of neuromodulators including dopamine, endocannabinoids, acetylcholine and endogenous opioid peptides regulate dopamine release by acting on several components of dopaminergic circuitry. Striatal dopamine release can be driven by both somatic action potential firing and local mechanisms that depend on acetylcholine released from striatal cholinergic interneurons. GPCRs that primarily regulate somatic firing of dopamine neurons via direct effects or modulation of synaptic inputs are likely to affect distinct aspects of behaviour and psychoactive drug actions compared with those GPCRs that primarily regulate local acetylcholine-dependent dopamine release in striatal regions. This review will highlight mechanisms by which GPCRs modulate dopaminergic transmission and the relevance of these findings to psychoactive drug effects on physiology and behaviour.

Local modulation by presynaptic receptors controls neuronal communication and behaviour.

Central nervous system neurons communicate via fast synaptic transmission mediated by ligand-gated ion channel (LGIC) receptors and slower neuromodulation mediated by G protein-coupled receptors (GPCRs). These receptors influence many neuronal functions, including presynaptic neurotransmitter release. Presynaptic LGIC and GPCR activation by locally released neurotransmitters influences neuronal communication in ways that modify effects of somatic action potentials. Although much is known about presynaptic receptors and their mechanisms of action, less is known about when and where these receptor actions alter release, especially in vivo. This Review focuses on emerging evidence for important local presynaptic receptor actions and ideas for future studies in this area.

Prefrontal cortex parvalbumin interneurons exhibit decreased excitability and potentiated synaptic strength after ethanol reward learning.

The prefrontal cortex (PFC) is intimately associated with behavioral characteristics of alcohol use disorders, including high motivation to drink and difficulty with moderation. Thus, continued mechanistic research investigating PFC cells and targets altered by ethanol experiences should inform translational efforts to craft new, efficacious treatments. Inhibitory interneurons expressing parvalbumin (PV-INs) comprise only a minor fraction of cells within the PFC, yet these cells are indispensable for coordinating PFC ensemble function, oscillatory activity, and subcortical output. Based on this, PV-INs represent an exciting target for the rational design of breakthrough treatments for alcohol use disorders. Here, we assessed experience-dependent physiological adaptations via ethanol place conditioning. By manipulating the timing of administration relative to conditioning sessions, equivalent ethanol exposure can form either rewarding or aversive memories in different individuals. Here, we found that female mice and male mice on a C57BL/6J background display conditioned place preference (CPP) or aversion (CPA) to an intoxicating dose of ethanol (2 g/kg, intraperitoneal [i.p.]) without overt differences between sexes. Ethanol reward learning was associated with decreased PV-IN excitability in deep layer prelimbic PFC, whereas PV-INs from CPA mice were not different from controls. Furthermore, PV-INs from mice in the CPP group, but not the CPA group, displayed potentiated excitatory synaptic strength that emerged during 1 week of abstinence. Taken together, these findings illustrate that synaptic and intrinsic adaptations associated with ethanol can depend on an individual's experience. These studies provide further context and support for PFC PV-INs as intriguing targets for modulating alcohol associations.

Allosteric modulation of metabotropic glutamate receptors in alcohol use disorder: Insights from preclinical investigations.

Metabotropic glutamate (mGlu) receptors are family C G protein-coupled receptors (GPCRs) that modulate neuronal excitability and synaptic transmission throughout the nervous system. Owing to recent advances in development of subtype-selective allosteric modulators of mGlu receptors, individual members of the mGlu receptor family have been proposed as targets for treating a variety of neurological and psychiatric disorders, including substance use disorders. In this chapter, we highlight preclinical evidence that allosteric modulators of mGlu receptors could be useful for reducing alcohol consumption and preventing relapse in alcohol use disorder (AUD). We begin with an overview of the preclinical models that are used to study mGlu receptor involvement in alcohol-related behaviors. Alcohol exposure causes adaptations in both expression and function of various mGlu receptor subtypes, and pharmacotherapies aimed at reversing these adaptations have the potential to reduce alcohol consumption and seeking. Positive allosteric modulators (PAMs) of mGlu2 and negative allosteric modulators of mGlu5 show particular promise for reducing alcohol intake and/or preventing relapse. Finally, this chapter discusses important considerations for translating preclinical findings toward the development of clinically useful drugs, including the potential for PAMs to avoid tolerance issues that are frequently observed with repeated administration of GPCR agonists.

Operant self-stimulation of thalamic terminals in the dorsomedial striatum is constrained by metabotropic glutamate receptor 2.

Dorsal striatal manipulations including stimulation of dopamine release and activation of medium spiny neurons (MSNs) are sufficient to drive reinforcement-based learning. Glutamatergic innervation of the striatum by the cortex and thalamus is a critical determinant of MSN activity and local regulation of dopamine release. However, the relationship between striatal glutamatergic afferents and behavioral reinforcement is not well understood. We evaluated the reinforcing properties of optogenetic stimulation of thalamostriatal terminals, which are associated with vesicular glutamate transporter 2 (Vglut2) expression, in the dorsomedial striatum (DMS), a region implicated in goal-directed behaviors. In mice expressing channelrhodopsin-2 (ChR2) under control of the Vglut2 promoter, optical stimulation of the DMS reinforced operant lever-pressing behavior. Mice also acquired operant self-stimulation of thalamostriatal terminals when ChR2 expression was virally targeted to the intralaminar thalamus. Stimulation trains that supported operant responding evoked dopamine release in the DMS and excitatory postsynaptic currents in DMS MSNs. Our previous work demonstrated that the presynaptic G protein-coupled receptor metabotropic glutamate receptor 2 (mGlu2) robustly inhibits glutamate and dopamine release induced by activation of thalamostriatal afferents. Thus, we examined the regulation of thalamostriatal self-stimulation by mGlu2. Administration of an mGlu2/3 agonist or an mGlu2-selective positive allosteric modulator reduced self-stimulation. Conversely, blockade of these receptors increased thalamostriatal self-stimulation, suggesting that endogenous activation of these receptors negatively modulates the reinforcing properties of thalamostriatal activity. These findings demonstrate that stimulation of thalamic terminals in the DMS is sufficient to reinforce a self-initiated action, and that thalamostriatal reinforcement is constrained by mGlu2 activation.

Age-dependent impairment of metabotropic glutamate receptor 2-dependent long-term depression in the mouse striatum by chronic ethanol exposure.

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu2) is a Gi/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu2 function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu2 function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu2-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu2-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu2-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu2 fully rescues mGlu2-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu2-LTD. We did not observe a reduction of mGlu2 mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu2 occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu2 activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

Active Zone Proteins RIM1αß Are Required for Normal Corticostriatal Transmission and Action Control.

Dynamic regulation of synaptic transmission at cortical inputs to the dorsal striatum is considered critical for flexible and efficient action learning and control. Presynaptic mechanisms governing the properties and plasticity of glutamate release from these inputs are not fully understood, and the corticostriatal synaptic processes that support normal action learning and control remain unclear. Here we show in male and female mice that conditional deletion of presynaptic proteins RIM1αß (RIM1) from excitatory cortical neurons impairs corticostriatal synaptic transmission in the dorsolateral striatum. Key forms of presynaptic G-protein-coupled receptor-mediated short- and long-term striatal plasticity are spared following RIM1 deletion. Conditional RIM1 KO mice show heightened novelty-induced locomotion and impaired motor learning on the accelerating rotarod. They further show heightened self-paced instrumental responding for food and impaired learning of a habitual instrumental response strategy. Together, these findings reveal a selective role for presynaptic RIM1 in neurotransmitter release at prominent basal ganglia synapses, and provide evidence that RIM1-dependent processes help to promote the refinement of skilled actions, constrain goal-directed behaviors, and support the learning and use of habits.SIGNIFICANCE STATEMENT Our daily functioning hinges on the ability to flexibly and efficiently learn and control our actions. How the brain encodes these capacities is unclear. Here we identified a selective role for presynaptic proteins RIM1αß in controlling glutamate release from cortical inputs to the dorsolateral striatum, a brain structure critical for action learning and control. Behavioral analysis of mice with restricted genetic deletion of RIM1αß further revealed roles for RIM1αß-dependent processes in the learning and refinement of motor skills and the balanced expression of goal-directed and habitual actions.

Endocannabinoid Actions on Cortical Terminals Orchestrate Local Modulation of Dopamine Release in the Nucleus Accumbens.

Dopamine (DA) transmission mediates numerous aspects of behavior. Although DA release is strongly linked to firing of DA neurons, recent developments indicate the importance of presynaptic modulation at striatal dopaminergic terminals. The endocannabinoid (eCB) system regulates DA release and is a canonical gatekeeper of goal-directed behavior. Here we report that extracellular DA increases induced by selective optogenetic activation of cholinergic neurons in the nucleus accumbens (NAc) are inhibited by CB1 agonists and eCBs. This modulation requires CB1 receptors on cortical glutamatergic afferents. Dopamine increases driven by optogenetic activation of prefrontal cortex (PFC) terminals in the NAc are similarly modulated by activation of these CB1 receptors. We further demonstrate that this same population of CB1 receptors modulates optical self-stimulation sustained by activation of PFC afferents in the NAc. These results establish local eCB actions on PFC terminals within the NAc that inhibit mesolimbic DA release and constrain reward-driven behavior.

Parallel, but Dissociable, Processing in Discrete Corticostriatal Inputs Encodes Skill Learning.

Changes in cortical and striatal function underlie the transition from novel actions to refined motor skills. How discrete, anatomically defined corticostriatal projections function in vivo to encode skill learning remains unclear. Using novel fiber photometry approaches to assess real-time activity of associative inputs from medial prefrontal cortex to dorsomedial striatum and sensorimotor inputs from motor cortex to dorsolateral striatum, we show that associative and sensorimotor inputs co-engage early in action learning and disengage in a dissociable manner as actions are refined. Disengagement of associative, but not sensorimotor, inputs predicts individual differences in subsequent skill learning. Divergent somatic and presynaptic engagement in both projections during early action learning suggests potential learning-related in vivo modulation of presynaptic corticostriatal function. These findings reveal parallel processing within associative and sensorimotor circuits that challenges and refines existing views of corticostriatal function and expose neuronal projection- and compartment-specific activity dynamics that encode and predict action learning.

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum.

The striatum plays critical roles in action control and cognition, and activity of striatal neurons is driven by glutamatergic input. Inhibition of glutamatergic inputs to projection neurons and interneurons of the striatum by presynaptic G protein-coupled receptors (GPCRs) stands to modulate striatal output and striatum-dependent behaviors. Despite knowledge that a substantial number of glutamatergic inputs to striatal neurons originate in the thalamus, most electrophysiological studies assessing GPCR modulation do not differentiate between effects on corticostriatal and thalamostriatal transmission, and synaptic inhibition is frequently assumed to be mediated by activation of GPCRs on corticostriatal terminals. We used optogenetic techniques and recently-discovered pharmacological tools to dissect the effects of a prominent presynaptic GPCR, metabotropic glutamate receptor 2 (mGlu2), on corticostriatal vs. thalamostriatal transmission. We found that an agonist of mGlu2 and mGlu3 induces long-term depression (LTD) at synapses onto MSNs from both the cortex and the thalamus. Thalamostriatal LTD is selectively blocked by an mGlu2-selective negative allosteric modulator and reversed by application of an antagonist following LTD induction. Activation of mGlu2/3 also induces LTD of thalamostriatal transmission in striatal cholinergic interneurons (CINs), and pharmacological activation of mGlu2/3 or selective activation of mGlu2 inhibits CIN-mediated dopamine release evoked by selective stimulation of thalamostriatal inputs. Thus, mGlu2 activation exerts effects on striatal physiology that extend beyond modulation of corticostriatal synapses, and has the potential to influence cognition and striatum-related disorders via inhibition of thalamus-derived glutamate and dopamine release.

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the Gi/o class of G protein. There is increasing evidence that these presynaptic Gi/o-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, Dopamine (DA; D1- and D2-like receptors), Endocannabinoids (eCBs; CB1 receptors) and glutamate (group II metabotropic glutamate (mGlu) receptors). The focus is on recent evidence from laboratory animal models (and some evidence in humans) implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on development of mGlu2 positive allosteric modulators (PAMs).

Presynaptic Plasticity Found in Translation.

In this issue of Neuron, Younts et al. (2016) demonstrate that activation of presynaptic CB1 receptors by retrograde endocannabinoid signaling stimulates protein synthesis in axon terminals to induce long-term depression of hippocampal inhibitory transmission.

Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT.

Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS.

Metabotropic glutamate (mGlu) receptors play important roles in regulating CNS function and are known to function as obligatory dimers. Although recent studies have suggested heterodimeric assembly of mGlu receptors in vitro, the demonstration that distinct mGlu receptor proteins can form heterodimers or hetero-complexes with other mGlu subunits in native tissues, such as neurons, has not been shown. Using biochemical and pharmacological approaches, we demonstrate here that mGlu2 and mGlu4 form a hetero-complex in native rat and mouse tissues which exhibits a distinct pharmacological profile. These data greatly extend our current understanding of mGlu receptor interaction and function and provide compelling evidence that mGlu receptors can function as heteromers in intact brain circuits.

The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson's disease.

Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata.

Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) has been implicated as a potential therapeutic strategy for treating both motor symptoms and progressive neurodegeneration in Parkinson's disease (PD). Modulation of excitatory transmission in the basal ganglia represents a possible mechanism by which group II mGlu agonists could exert antiparkinsonian effects. Previous studies have identified reversible effects of mGlu2/3 activation on excitatory transmission at various synapses in the basal ganglia, including the excitatory synapse between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Using whole-cell patch clamp studies of GABAergic SNr neurons in rat midbrain slices, we have found that a prolonged activation of group II mGlus by the selective agonist LY379268 induces a long-term depression (LTD) of evoked excitatory postsynaptic current (EPSC) amplitude. Bath application of LY379268 (100nM, 10min) induced a marked reduction in EPSC amplitude, and excitatory transmission remained depressed for at least 40min after agonist washout. The effect of LY379268 was concentration-dependent and was completely blocked by the group II mGlu-preferring antagonist LY341495 (500nM). To determine the relative contributions of mGlu2 and mGlu3 to the LTD induced by LY379268, we tested the ability of LY379268 (100nM) to induce LTD in wild type mice and mice lacking mGlu2 or mGlu3. LY379268 induced similar LTD in wild type mice and mGlu3 knockout mice, whereas LTD was absent in mGlu2 knockout mice, indicating that mGlu2 activation is necessary for the induction of LTD in the SNr. These studies suggest a novel role for mGlu2 in the long-term regulation of excitatory transmission in the SNr and invite further exploration of mGlu2 as a therapeutic target for treating the motor symptoms of PD.

Context-dependent pharmacology exhibited by negative allosteric modulators of metabotropic glutamate receptor 7.

Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323:147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[ 4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G alpha(15). Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative cooperativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G(i/o)-coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G(i/o) signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.

Glutamate receptors as therapeutic targets for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia. The primary pathophysiology underlying PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta. Loss of these neurons causes pathological changes in neurotransmission in the basal ganglia motor circuit. The ability of ionotropic and metabotropic glutamate receptors to modulate neurotransmission throughout the basal ganglia suggests that these receptors may be targets for reversing the effects of altered neurotransmission in PD. Studies in animal models suggest that modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy. Moreover, glutamate receptor ligands may slow disease progression by delaying progressive dopamine neuron degeneration. Antagonists of NMDA receptors have shown promise in reversing motor symptoms, levodopa-induced dyskinesias, and neurodegeneration in preclinical PD models. The effects of drugs targeting AMPA receptors are more complex; while antagonists of these receptors exhibit utility in the treatment of levodopa-induced dyskinesias, AMPA receptor potentiators show promise for neuroprotection. Pharmacological modulation of metabotropic glutamate receptors (mGluRs) may hold even more promise for PD treatment due to the ability of mGluRs to fine-tune neurotransmission. Antagonists of mGluR5, as well as activators of group II mGluRs and mGluR4, have shown promise in several animal models of PD. These drugs reverse motor deficits in addition to providing protection against neurodegeneration. Glutamate receptors therefore represent exciting targets for the development of novel pharmacological therapies for PD.