Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

Abstract

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).

Interrogating the Spatiotemporal Landscape of Neuromodulatory GPCR Signaling by Real-Time Imaging of cAMP in Intact Neurons and Circuits

“…PKA, CREB, DARPP32, FosB) with direct roles in shaping the activity of MSN neurons (Gerfen and Surmeier, 2011; Kreitzer, 2009; Tritsch and Sabatini, 2012). In addition to dopamine, the activity of MSNs is substantially shaped by a variety of other neuromodulatory inputs including adenosine, acetylcholine, and neuropeptides, whose receptors are differentially segregated across neuronal populations and subcellular compartments (Johnson and Lovinger, 2016; Kreitzer, 2009). The scarcity of appropriate tools and approaches makes it also unclear how individual neurotransmitter GPCRs converging on cAMP modulation interact and what the signaling decoding logic is.…”

Arrestin-2 and arrestin-3 differentially modulate locomotor responses and sensitization to amphetamine

“…There is ample evidence of the critical, albeit distinct, roles of the D1 and D2 dopamine receptors expressed on postsynaptic medium spiny striatal neurons in the behavioral effects of psychostimulant drugs [reviewed in (Baik, 2013, Johnson and Lovinger 2016)]. Earlier studies suggested that striatal D1 and D2 receptors were dispensable for the induction of locomotor sensitization to psychostimulants (Baik, 2013, Johnson and Lovinger 2016, Vanderschuren and Kalivas, 2000) while emphasizing the role of the ventral tegmental area in that process (Vanderschuren and Kalivas, 2000). However, recent experiments highlighted the role of the striatal dopaminergic mechanisms, particularly those mediated by D1 receptors, in the induction of sensitization (Ferguson et al, 2011, Gore and Zweifel, 2013, Hikida et al, 2010).…”

<strong>Creating a valid <em>in silico</em> Dopamine D2-receptor model for small molecular docking studies</strong>

“…D2R, along with D3R, are believed to have a more complex function within the dopamine receptor family as they are present in post-and pre-synaptic termina (3). In addition they exert a negative feedback loop in the presynaptic terminal to control firing rate of neurons (4). Along with this functional complexity, it has been shown that alterations in dopaminergic transmission in the brain are correlated to several dysfunctions such as Parkinson's disease and Schizophrenia (5).…”