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).