Chronic loss of noradrenergic tone produces β‐arrestin2‐mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens

Abstract

Cocaine blocks plasma membrane monoamine transporters and increases extracellular levels of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). The addictive properties of cocaine are mediated primarily by DA, while NE and 5-HT play modulatory roles. Chronic inhibition of dopamine β-hydroxylase (DBH), which converts dopamine (DA) to norepinephrine (NE), increases the aversive effects of cocaine and reduces cocaine use in humans, and produces behavioral hypersensitivity to cocaine and D2 agonism in rodents, but the underlying mechanism is unknown. We found a decrease in β-arrestin2 (βArr2) in the nucleus accumbens (NAc) following chronic genetic or pharmacological DBH inhibition, and overexpression of βArr2 in the NAc normalized cocaine-induced locomotion in DBH knockout (Dbh −/−) mice. The D2/3 agonist quinpirole decreased excitability in NAc medium spiny neurons (MSNs) from control, but not Dbh −/− animals, where instead there was a trend for an excitatory effect. The Gαi inhibitor NF023 abolished the quinpirole-induced decrease in excitability in control MSNs, but had no effect in Dbh −/− MSNs, whereas the Gαs inhibitor NF449 restored the ability of quinpirole to decrease excitability in Dbh −/− MSNs, but had no effect in control MSNs. These results suggest that chronic loss of noradrenergic tone alters behavioral responses to cocaine via decreases in βArr2 and cellular responses to D2/D3 activation, potentially via changes in D2-like receptor G protein coupling in NAc MSNs.

Arresting the Development of Addiction: The Role ofβ-Arrestin 2 in Drug Abuse

“…Mice that lack dopamine b-hydroxylase (Dbh2/2 mice) cannot synthesize norepinephrine and are hypersensitive to cocaine. Interestingly, these animals had reduced barr2 in the nucleus accumbens and altered D2 receptor function (Gaval-Cruz et al, 2016). Overexpressing barr2 in the nucleus accumbens of Dbh2/2 mice reversed the cocaine hypersensitivity (Gaval-Cruz et al, 2016), demonstrating the complex effects that barr2 can have in cocaine-induced locomotion.…”

Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine

“…D2R activation in iMSNs produces well-described changes in intracellular signaling, biochemical pathway and gene expression (Girault and Greengard, 2004; Tritsch and Sabatini, 2012; Walker et al, 2015). The electrophysiological consequences of D2R activation, however, are still controversial (Gaval-Cruz et al, 2014; Hernandez-Lopez et al, 2000; Lemos et al, under review; Nicola et al, 1996) in part because MSNs lack the G-protein inward-rectifying potassium (GIRK) channels that are responsible for generating the D2R-mediated currents in other neurons such as midbrain DA neurons (Beckstead et al, 2004). Adding to the complexity is the diverse expression pattern of D2Rs in the striatum, which has limited the interpretation of experiments relying on pharmacology to characterize the effect of D2R activation in iMSNs because D2Rs are also expressed in cholinergic interneurons (Maurice et al, 2004; Zhang et al, 2009), and in presynaptic terminals from midbrain DA neurons (Adrover et al, 2014; Ford, 2014) and corticostriatal glutamatergic neurons (Bamford et al, 2004a; Bamford et al, 2004b).…”

Loss of β-arrestin2 in D2 cells alters neuronal excitability in the nucleus accumbens and behavioral responses to psychostimulants and opioids

“…The underlying mechanisms that lead to DA-induced changes in cellular excitability are complex. Some have reported that the D2/D3 agonist quinpirole has no effect on excitability (Lemos, Friend, Kaplan et al, 2016), while others have reported that quinpirole causes a decrease in intrinsic excitability (Gaval-Cruz, Goertz, Puttick et al, 2014;Urs, Gee, Pack et al, 2016). While the D2 cell response is largely dose-dependent, D1 agonists can facilitate either an increase or decrease in firing rate depending on the resting membrane potential (Hernández-López, Bargas, Surmeier et al, 1997).…”

“…Alterations in βarr2 in the NAc affect cocaine-induced locomotion (Gaval-Cruz, Goertz, Puttick et al, 2014). Although the modulation of drug responses by barr2 are thought to occur within mesolimbic circuitry, the striatal cell-types have not been fully identified.…”

“…While mesolimbic βarr2 is implicated in the effects of drugs of abuse, there is little information regarding how barr2 regulates the activity of D1-and D2-MSNs, and the specific cell types that mediate the impact of barr2 on drug-induced locomotion and reward remain unclear (Gaval-Cruz, Goertz, Puttick et al, 2014;Rose, Pack, Peterson et al, 2018;Urs, Daigle & Caron, 2011;Urs, Gee, Pack et al, 2016). In the present study, we used conditional barr2-KO mice that lack βarr2 specifically in D1 or D2 receptor-containing cells (D1 βarr2-KO and D2 βarr2-KO ) (Urs, Gee, Pack et al, 2016) to investigate the contribution of endogenous βarr2 to (1) DAmediated changes in D1-and D2-MSN excitability, and (2) the locomotor-activating and rewarding effects of the psychostimulant cocaine and opioid morphine.…”