The Neuroscience of Drug Reward and Addiction

Abstract

Drug consumption is driven by a drug's pharmacological effects, which are experienced as rewarding, and is influenced by genetic, developmental, and psychosocial factors that mediate drug accessibility, norms, and social support systems or lack thereof. The reinforcing effects of drugs mostly depend on dopamine signaling in the nucleus accumbens, and chronic drug exposure triggers glutamatergic-mediated neuroadaptations in dopamine striato-thalamo-cortical (predominantly in prefrontal cortical regions including orbitofrontal cortex and anterior cingulate cortex) and limbic pathways (amygdala and hippocampus) that, in vulnerable individuals, can result in addiction. In parallel, changes in the extended amygdala result in negative emotional states that perpetuate drug taking as an attempt to temporarily alleviate them. Counterintuitively, in the addicted person, the actual drug consumption is associated with an attenuated dopamine increase in brain reward regions, which might contribute to drug-taking behavior to compensate for the difference between the magnitude of the expected reward triggered by the conditioning to drug cues and the actual experience of it. Combined, these effects result in an enhanced motivation to "seek the drug" (energized by dopamine increases triggered by drug cues) and an impaired prefrontal top-down self-regulation that favors compulsive drug-taking against the backdrop of negative emotionality and an enhanced interoceptive awareness of "drug hunger." Treatment interventions intended to reverse these neuroadaptations show promise as therapeutic approaches for addiction.

Keywords: cannabis; dopamine; glutamate; nucleus accumbens; opioids; substance use disorders.

Conflict of interest statement

M. Michaelides is a cofounder and owns stock in Metis Laboratories, Inc. No conflicts of interest, financial or otherwise, are declared by the other authors.

Figures

Graphical abstract

FIGURE 1.

Schematic representation of key target sites for various drugs of abuse across the reward circuitry. Ventral tegmental area (VTA) dopamine (DA)ergic neurons project to forebrain targets such as the basolateral amygdala (BLA), medial prefrontal area of the cortex (CTX) or mPFC, and nucleus accumbens (NAc). These neurons receive excitatory synaptic inputs from the mPFC (but also from lateral hypothalamus and pedunculopontine tegmental nucleus/dorsolateral tegmental nucleus; not shown). GABAergic neurons in the VTA target neighboring DAergic neurons as well as projecting to the mPFC and NAc (other inhibitory inputs to these DAergic neurons are likely to arise from extended amygdala output structures; not shown). GABAergic medium spiny neurons (MSNs) in the NAc, which project to either the globus pallidus externus/ventral pallidum (VP) predominantly via D2R-expressing but also D1R-expressing neurons or to the VTA/SN via D1R-expressing neurons, receive dopaminergic input from the VTA. They also receive excitatory inputs from the mPFC and the basolateral amygdala (BLA) (but also from the hippocampus and thalamus). The activity of MSNs is modulated by both cholinergic and fast-spiking GABAergic interneurons (not shown) (312). Drugs of abuse, despite diverse initial actions, produce some common effects on the VTA and NAc. Stimulants directly increase dopaminergic transmission in the NAc. Opiates increase DA indirectly by inhibiting GABAergic interneurons in the VTA, disinhibiting them and by stimulating mu opioid receptors (MOR) on NAc neurons (244). Nicotine stimulates DA neuron firing by its effects on ionotropic (nicotinic) acetylcholine receptors (314). Alcohol, among other effects, increases the firing of VTA DA neurons projecting to NAc via their disinhibition through the inhibition of GABA neurons (238). Cannabinoids (CBs) disrupt the normal endocannabinoid (ECB) signaling–from DAergic neurons on nearby glutamatergic (via retrograde suppression of excitation) and GABAergic (via retrograde suppression of inhibition) terminals–that is responsible for fine-tuning the activity of mesolimbic dopamine projections (31). [Modified from Nestler (244), with permission from Springer Nature.]

FIGURE 2.

Schematic simplified cartoon showing some of the indirect modulatory effects of midbrain (ventral tegmental area, VTA) opioid and endocannabinoid signals on dopaminergic transmission in nucleus accumbens (NAc). Reward-related stimuli conveyed through glutamatergic afferents (green) promote burst firing of dopamine (DA) neurons (yellow) mainly driven by ionotropic glutamate receptor (iGluR) binding activation at the dopaminergic cell. The level of activation is normally kept in check by GABAergic counterbalancing inputs (pink), but also by direct inhibitory GABAergic input inhibiting presynaptic glutamate release (66). Endogenous [released from opioidergic neurons (light blue), mostly projecting from the hypothalamus] or exogenous (natural or synthetic opioid like molecules) opioids activate endogenous mu opioid receptors (MOR) on GABAergic interneurons. The MOR is coupled to inhibitory G proteins, whose activation (by an endogenous peptide like endorphin or exogenous agonists like morphine and fentanyl) leads to a dissociation between the Gα and Gβγ subunits and the activation of intracellular effector pathways. One such pathway leads to the inhibition of GABA release as a result of increased conduction of potassium ions, which hyperpolarizes the cell making it less responsive to depolarizing inputs and inhibiting calcium influx (123). In addition, activation of MOR increases mitogen-activated protein kinase (MAPK) signaling while their phosphorylation activates the arrestin pathway (5), which has the ability to desensitize, activate, and control the trafficking of G protein-coupled receptors (GPCR) (140). A drop in GABAergic tone causes a net disinhibition of the neighboring dopaminergic neuron and the release of excess dopamine (black dots) onto direct and indirect medium spiny neurons [pink medium spiny neuron (MSN)], which reinforces the euphorigenic effects of opioids. Ionotropic GluR-mediated activation of the DA neuron leads to Ca2+ influx (via voltage-gated calcium channels), which is either facilitated or hampered in D1R vs D2R expressing MSN populations, respectively (317) (inset), leading to their differential roles in plasticity. At the same time, the Ca2+ influx, combined with activation of mGluA1/5, triggers the “on demand” production of 2-arachidonoylglycerol (2-AG) from diacylglycerol (DAG) [or anandamide (AEA) from N-acyl-phosphatidylethanolamines (NAPE)]. Retrograde 2-AG transmission through CB1 receptor binding on monoacylglycerol lipase (MAGL) containing afferent (GABA and Glu) neurons has the net effect of disinhibiting dopamine neurons and facilitating phasic DA release (63). This is because cannabinoids (e.g., tetrahydrocannabinol, 2-AG) operate as full agonists at GABA terminals [that display a high CB1R to vesicles ratio (188)] but as partial agonists at Glu terminals [where the CB1R-to-vesicles ratio is much lower (295, 296)]. As shown, AEA is assumed to be retrograde in spite of data showing that FAAH is predominately postsynaptic while NAPE PLD is presynaptic. The true nature of AEA neurotransmission remains unclear partly because there are other pathways for AEA synthesis. In the NAc, GABAergic projections, sent by the VTA, also synapse onto cholinergic interneurons (dark gray), thus inhibiting their excitatory input onto DA terminals. Activation of either CB1 or MOR on these GABA neurons can stimulate DA terminals (independently of VTA DA neuron activation) by disinhibiting ACh release while activation of these receptors, which are also expressed on ACh interneurons, could in theory have the opposite effect on DA levels in the accumbens (351). GABAergic and glutamatergic terminals in the NAc also have the capacity to modulate accumbal DA activity onto MSNs directly. Since these neurons also express MOR [but some also CB1R (226, 361)], their activation on GABA inputs could enhance DA release, while their inhibitory effects on glutamatergic inputs could reduce accumbal release of DA.

FIGURE 3.

Leading hypothesis of how a temporally coordinated cascade of drug-induced changes in synaptic activity hijack multipurpose learning processes to engender maladaptive and persistent addictive behaviors. VTA, ventral tegmental area; DA, dopamine; PFC, prefrontal cortex; Amy, amygdala; Hipp, hippocampus. Bottom figures depict (from left to right) a heat map of genes upregulated (*) in the nucleus accumbens (NAc) 1 h after acute cocaine administration to naive animals (275); examples of such transient transcription and epigenetic modulatory events include regulatory and signaling genes like fosB, ΔFosB, NFκB, CdK5, and MEF2. [From Robison and Nestler (275), with permission from Springer Nature.] Drug-induced changes in neuronal activity (e.g., changes in NMDA/AMPA receptor balance) lead to synaptic plasticity (e.g., LTP) in the reward circuitry (169). [From Jones and Bonci (169), with permission from Elsevier.] Morphological and functional changes, like increased dendritic spine density, which, if sustained, can lead to cytoskeletal and circuit remodeling, a phenomenon that correlates with synaptic strength and the strength of drug-associated memories in vivo, which, over a period of months and years, contributes to the orchestration and cementing of stereotypical addictive behaviors. [From Nestler. Dialogues Clin Neurosci 15: 431–443, 2013.]