Noradrenergic inputs from locus coeruleus to posterior ventral tegmental area are essential to support ethanol reinforcement

Abstract

Although dysregulation of the dopaminergic mesolimbic system is generally considered central to addiction, the involvement of other circuits is increasingly being appreciated. An interaction between locus coeruleus (LC) noradrenergic neurons and the posterior ventral tegmental area (pVTA) dopaminergic system, in the processing of drug‐triggered reward, has been suggested, but not demonstrated in behaving animals. Herein, we try to tease out the precise role of noradrenergic neurons in the LC–VTA circuit in mediating reward and reinforcement behavior associated with ethanol. In the standard two‐lever (active/inactive) operant paradigm, the rats were trained to self‐administer ethanol in pVTA and subjected to pharmacological intervention. Intra‐pVTA administration of phenylephrine (alpha‐1 adrenoceptor agonist) increased ethanol self‐administration, while prazosin and disulfiram (agents that reduce noradrenergic tone) produced opposite effects. While degeneration [N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine hydrochloride, DSP‐4, intraperitoneal route] or silencing (lidocaine or muscimol, both via intra‐LC route) of the LC noradrenergic neurons decreased, phenylephrine via the intra‐LC route reinstated ethanol self‐administration. Furthermore, lidocaine reduced ethanol self‐administration, but the effect was fully attenuated by noradrenaline given directly in the pVTA. This suggests that the feedback signals from LC to pVTA are necessary to sustain the ethanol self‐infusion activity. Ethanol self‐administration significantly increased tyrosine hydroxylase immunoreactivity in pVTA and LC; the response was blocked by DSP‐4 pre‐treatment. While dopamine D1, but not D2, receptors were localized on noradrenergic LC neurons, pre‐treatment with SCH‐23390 (intra‐LC) dampened the lever press activity. We suggest that two‐way communications between VTA and LC regions is essential for ethanol‐triggered reinforcement behavior.