Norepinephrine regulates cocaine-primed reinstatement via alpha 1-adrenergic receptors in the medial prefrontal cortex

作者：Schmidt Karl T; Schroeder Jason P; Foster Stephanie L; Squires Katherine; Smith Brilee M; Pitts Elizabeth G; Epstein Michael P; Weinshenker David^*

来源：Neuropharmacology, 2017, 119: 134-140.

DOI：10.1016/j.neuropharm.2017.04.005

• Alpha-1 adrenergic receptor
• Cocaine
• Norepinephrine
• Prefrontal cortex
• Rat
• Reinstatement

Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine l3-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by al-adrenergic receptor (al AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine seeking behavior by determining whether ot1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical ARs. We found that while intracerebroventricular infusion of the alAR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the alAR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that al AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that alAR antagonists merit further investigation as pharmacotherapies for cocaine dependence.

• 出版日期2017-6