4. Modulation of dopamine transmission by metabotropic glutamate receptor 2
mGlu2 receptors are primarily expressed at presynaptic sites of glutamatergic synapses, where they reduce neurotransmitter release by inhibiting voltage-gated calcium channels (Kupferschmidt & Lovinger, 2015; Niswender & Conn, 2010). Activation of mGlu2 reduces dopamine release in the dorsal striatum and NAc (reviewed in Johnson, 2021). However, mGlu2expression is not detected in midbrain dopamine neurons, and mGlu2 agonists do not reduce dopamine release or associated behavioral effects produced by direct stimulation of midbrain dopamine neurons (Pehrson & Moghaddam, 2010); these findings indicate that mGlu2 modulates dopamine release indirectly. Inex vivo preparations, activation of mGlu2 induces long-term depression of both cortical and thalamic glutamatergic inputs to the dorsal striatum, and also inhibits dopamine release driven by optogenetic stimulation of thalamostriatal afferents (Johnson et al., 2017; Johnson et al., 2020). mGlu2 modulation of dopamine transmission in the dorsal striatum is occluded by nicotinic receptor blockade, supporting the idea that mGlu2modulation of dopamine release is exclusively mediated by indirect, ACh-dependent mechanisms (Johnson et al., 2020). This mechanism appears to be engaged in vivo as well, as mGlu2activation reduces operant responding for optogenetic stimulation of thalamostriatal neurons, while mGlu2 blockade increases response rates for thalamostriatal self-stimulation. Although mGlu2 effects on cortically-driven dopamine release have not been directly evaluated, mGlu2-mediated inhibition of cortical inputs to CINs in both the dorsal striatum and NAc represents another possible mechanism for modulation of dopamine transmission.
In addition to effects on basal dopamine transmission, mGlu2 activation can reduce dopamine evoked by psychoactive drugs including amphetamine, nicotine, and cocaine, and likewise reduces associated behavioral effects including drug-induced locomotor activity (Arndt et al., 2014; Bauzo et al., 2009; D’Souza et al., 2011; Johnson & Lovinger, 2016; Pehrson & Moghaddam, 2010). Moreover, some effects of psychoactive drugs are altered in mice or rats lacking mGlu2, including increased vulnerability to excessive drug consumption (reviewed in Jordan & Xi, 2021). mGlu2 activation could therefore decrease the reinforcing properties of a variety of psychoactive drugs, and this is supported by observations that mGlu2 activation reduces operant self-administration of drugs including alcohol (Augier et al., 2016), cocaine (Bauzo et al., 2009; Jin et al., 2010), methamphetamine (Crawford et al., 2013), and nicotine (Justinova et al., 2015; Li et al., 2016; Liechti et al., 2007). Interestingly, mGlu2activation can also reduce cue-induced reinstatement of drug seeking, though it is unclear whether inhibition of cue-associated dopamine responses are attenuated by mGlu2. Based on these findings, mGlu2 positive allosteric modulators are currently being developed to treat several substance use disorders (reviewed in Caprioli et al., 2018; Johnson & Lovinger, 2020).