Noradrenergic signaling in the VTA modulates cocaine craving

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 alpha₁ -adrenergic and alpha₂ -adrenergic receptors (α₁ -ARs and α₂ -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 α₁ -AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α₁ -AR agonist phenylephrine as well as α₂ -AR antagonist RX 821002, whereas the selective β-AR antagonist propranolol had no effects. In addition, blockade of α₁ -AR in the VTA prevented α₂ -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 α₁ -AR and α₂ -AR but not β-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.