Endocannabinoid modulation of dopamine neurotransmission

Abstract

Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".

Keywords: Cannabinoids; Dopamine; Endocannabinoids; Nucleus accumbens; Striatum.

Figure 1

Modulation of DA release at striatal axon terminals. (A) Striatal medium spiny neurons (MSNs) receive afferent input from the prefrontal cortex (PFC), cholinergic interneurons (CIN), and midbrain DA neurons. Output from each site influences terminal DA release. (B) Acetylcholine released from CINs targets nicotinic acetylcholine receptors (nACh-Rs) and metabotropic acetylcholine receptors (mACh-Rs) at each afferent input site and on MSNs. For simplicity, ACh is depicted as influencing glutamate release via receptor binding on glutamatergic terminals from the PFC. However, the source of glutamate targeted by ACh may also arise from DA or CIN terminals (Shin et al., 2015; Higley et al., 2011; Nelson et al., 2014). (C) Glutamate release from the PFC targets metabotropic glutamate receptors (mGlu-Rs) at each neuronal site and ionotropic glutamate receptors (iGlu-Rs) on CINs and MSNs. (D) Endocannabinoid release from striatal MSNs can be elicited by glutamatergic and cholinergic inputs. Increased calcium (Ca²⁺) flux through voltage-gated Ca²⁺ channels (VGCCs) following nACh-R or iGlu-R binding, and G_g/11-coupled mACh-R or mGlu-R binding both target intracellular phospholipase C (PLC) signaling. Activation of PLC promotes synthesis of diacylglycerol (DAG), which is hydrolyzed by diacylglycerol lipase alpha (DGLα) to form 2-arachidonoylglycerol (2-AG) that is released onto presynaptic cannabinoid type 1 (CB1) receptors on PFC terminals. CB1 receptors are not found on DA terminals (Julian et al., 2003) or CINs (Hohmann and Herkenham, 2000; Uchigashima et al., 2007), but are expressed on glutamate terminals (Uchigashima et al., 2007), where their activation inhibits glutamate release onto output targets.

Figure 2

Endocannabinoid control of midbrain DA neurons. The endocannabinoid 2-AG is synthesized by DA neurons via DGLα and released onto presynaptic CB1 receptors of GABAergic (GABA) and glutamatergic (GLUT) terminals. Several signaling mechanisms target PLC to trigger DGLα activity, including increased Ca²⁺ flux (e.g., following iGluR signaling) and G_g/11 GPCR binding. A number of identified G_g/11 GPCRs drive 2-AG synthesis and CB1 receptor-mediated inhibition of presynaptic input, including type 1 orexin receptors (OX1R; Tung et al., 2016), alpha1 adrenergic receptors (α1R; Wang et al., 2015), mGluR5 glutamate receptors (Wang et al., 2015), insulin receptors (IR; Labouèbe et al., 2013), and neurotensin receptors (NTSR; Kortleven et al., 2012).