Noradrenergic signaling in the VTA modulates cocaine craving

Abstract

Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha -adrenergic and alpha -adrenergic receptors (α -ARs and α -ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague-Dawley rats was attenuated by intra-VTA prazosin or terazosin-two selective α -AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α -AR agonist phenylephrine as well as α -AR antagonist RX 821002, whereas the selective β-AR antagonist propranolol had no effects. In addition, blockade of α -AR in the VTA prevented α -AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA α -AR and α -AR but not β-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

“…Previously, we demonstrated no behavioral effects of intra‐VTA infusion of propranolol (at a dose of 0.6 μg per infusion) on cocaine seeking under extinction conditions (Solecki et al . ). Here, we sought to confirm that phasic DA release is not under the control of β‐AR signaling in the VTA by testing the dose shown previously to have no effect, followed by a twofold higher dose.…”

“…Accordingly, intra‐VTA α 1 ‐AR blockade attenuates stress responses during fear conditioning and cocaine seeking in cocaine‐abstinent rats (Solecki et al . , ).…”

“…The doses used were derived from our previous experiments in which intra‐VTA administration was shown to modulate behavior (Solecki et al . , ).…”

“…) and reactions to conditional cues in the context of drug craving (Solecki et al . ) or fear memories (Solecki et al . ).…”

“…Here, we hypothesized that, given the heterogeneity of VTA-forebrain circuitry and evidence for the involvement of ARs as modulators of conditioned behaviors requiring phasic DA release (Schmidt and Weinshenker 2014;Solecki et al 2017Solecki et al , 2018, intra-VTA blockade of a 1 -and a 2 -ARs would preferentially affect phasic, rather than tonic, DA release. Furthermore, we hypothesized that different forebrain targets of the VTA would undergo different levels of adrenergic modulation in terms of phasic DA release, with structures such as the NAc core, recognized as key players in conditioned behavior (Brown et al 2011;Saddoris et al 2013;Solecki et al 2013;Saunders et al 2018), being potentially prime spots for such modulation.…”