Noradrenergic circuits and signaling in substance use disorders

Abstract

The central noradrenergic system innervates almost all regions of the brain and, as such, is well positioned to modulate many neural circuits implicated in behaviors and physiology underlying substance use disorders. Ample pharmacological evidence demonstrates that α₁, α₂, and β adrenergic receptors may serve as therapeutic targets to reduce drug -seeking behavior and drug withdrawal symptoms. Further, norepinephrine is a key modulator of the stress response, and stress has been heavily implicated in reinstatement of drug taking. In this review, we discuss recent advances in our understanding of noradrenergic circuitry and noradrenergic receptor signaling in the context of opioid, alcohol, and psychostimulant use disorders.

Keywords: Alcohol; Locus coeruleus; Norepinephrine; Nucleus of the tractus solitarius; Opioids; Psychostimulants.

Fig 1.

Plasticity in LC neuron following opioid dependence and tolerance. In the non-opioid dependent LC, activation of μ ORs normally decreases cAMP/PKA signaling and depresses LC excitability. The LC also receives glutamatergic input from the paragigantocellularis nucleus, lateral habenula, and prefrontal cortex and GABA/CRF input from the CeA. Under normal conditions, glutamatergic and CRF inputs enhance LC neuron activity. In the opioid dependent LC, the valence of μ OR activity changes, whereby activation of μ ORs enhances cAMP/PKA and CREB signaling. Glutamatergic inputs to the LC are also enhanced and drive increased LC excitability. There is also an increase in CRFR1 receptors which may potentiate the activity on CRF on LC excitability.

Figure 2.

LC and CeA circuitry in stress and alcohol use disorder. The LC sends noradrenergic projections to the CeA, while the CeA sends GABAergic and CRF-positive projections to the LC. During stress or alcohol withdrawal, LC activity increases and sends enhanced noradrenergic input to the CeA. This in turn increases GABA/CRF neuron activity in the CeA resulting in a feedforward-loop causing enhanced LC and CeA activity in stress and alcohol withdrawal. This enhanced activity contributes to an increase in both anxiety-like behaviors and alcohol consumption in rodents.

Figure 3.

vBNST to VTA circuitry in cocaine use disorder. In CUD, noradrenergic innervation of the vBNST is increased, which leads to increased activity of CRF-expressing GABAergic BNST neurons via activation of β₂ ARs. These BNST neurons project to the VTA and release elevated amounts of CRF. CRFR1 is activated which stimulates dopaminergic VTA neurons and results in increased DA release in the NAcc and mPFC which contributes to stress-induced reinstatement. This pathway is inhibited following β₂ AR antagonist treatment. CRF innervation from the vBNST to VTA is inhibited which decreases dopaminergic VTA neuron activity. This ultimately results in reduced DA release in the NAcc and mPFC and opposes stress-induced reinstatement of cocaine seeking.