Alpha1-adrenergic receptor blockade in the ventral tegmental area modulates conditional stimulus-induced cocaine seeking

Exposure to drug-associated cues evokes drug-craving and upregulates noradrenaline (NA) and dopamine (DA) system activity. Importantly, conditional stimulus-induced drug-seeking behavior depends particularly on phasic DA signaling downstream from the ventral tegmental area (VTA), a midbrain structure key for the regulation of cocaine seeking. In particular, the activity of the alpha(1)- adrenergic receptor (alpha(1)-AR), which has recently been hypothesized to modulate salience encoding, is capable of bidirectional regulation of VTA dopaminergic activity. Thus, the impact of the conditional stimuli (CSs) on drug-seeking behavior might involve alpha(1)-AR signaling in the VTA. To date, the role of VTA alpha(1)-ARs in regulating CS-induced cocaine seeking has not been studied. In male Sprague-Dawley rats, we found that intra-VTA terazosin, a selective alpha(1)-AR antagonist, attenuated CS-induced cocaine seeking in a novel context and under extinction conditions, as well as CS-induced reinstatement of cocaine seeking. In contrast, terazosin microinfusion in a dose that attenuated CS-induced cocaine seeking had no effects on CS-induced food seeking or stress (2 mg/kg yohimbine)-evoked reinstatement of cocaine seeking. The potential nonspecific effects (sedative, anxiogenic) of alpha(1)-AR blockade of the VTA were also measured in the open-field test. Finally, using immunostaining, we demonstrated dopamine beta-hydroxylase (DBH)-positive afferents in the VTA of cocaine-abstinent rats, providing a neuroanatomical substrate for the alpha(1)-AR mechanism. These results demonstrated for the first time that NAergic signaling via VTA alpha(1)-ARs potently and selectively regulates CS-induced cocaine seeking. Our findings provide new neuronal mechanisms that regulate cocaine craving.