LAUSR

ABSTRACT A neurochemical target at which cannabinoids interact to have global effects on behavior is brain noradrenergic circuitry. Acute and repeated administration of a cannabinoid receptor synthetic agonist is capable of increasing multiple indices of noradrenergic activity. This includes cannabinoid‐induced 1) increases in norepinephrine (NE) release in the medial prefrontal cortex (mPFC); 2) desensitization of cortical &agr;2‐adrenoceptor‐mediated effects; 3) activation of c‐Fos in brainstem locus coeruleus (LC) noradrenergic neurons; and 4) increases in anxiety‐like behaviors. In the present study, we sought to examine adaptations in adrenoceptor expression and function under conditions of cannabinoid receptor type 1 (CB1r) deletion using knockout (KO) mice and compare these to wild type (WT) controls. Electrophysiological analysis of &agr;2‐adrenoceptor‐mediated responses in mPFC slices in WT mice showed a clonidine‐induced &agr;2‐adrenoceptor‐mediated increase in mPFC cell excitability coupled with an increase in input resistance. In contrast, CB1r KO mice showed an &agr;2‐adrenoceptor‐mediated decrease in mPFC cell excitability. We then examined protein expression levels of &agr;2‐ and &bgr;1‐adrenoceptor subtypes in the mPFC as well as TH expression in the locus coeruleus (LC) of mice deficient in CB1r. Both &agr;2‐ and &bgr;1‐adrenoceptors exhibited a significant decrease in expression levels in CB1r KO mice when compared to WT in the mPFC, while a significant increase in TH was observed in the LC. To better define whether the same cortical neurons express &agr;2A‐adrenoceptor and CB1r in mPFC, we utilized high‐resolution immunoelectron microscopy. We localized &agr;2A‐adrenoceptors in a knock‐in mouse that expressed a hemoagglutinin (HA) tag downstream of the &agr;2A‐adrenoceptor promoter. Although the &agr;2A‐adrenoceptor was often identified pre‐synaptically, we observed co‐localization of CB1r with &agr;2‐adrenoceptors post‐synaptically in the same mPFC neurons. Finally, using receptor binding, we confirmed prior results showing that &agr;2A‐adrenoceptor is unchanged in mPFC following acute or chronic exposure to the synthetic cannabinoid receptor agonist, WIN 55,212–2, but is increased, following chronic treatment followed by a period of abstinence. Taken together, these data provide convergent lines of evidence indicating cannabinoid regulation of the cortical adrenergic system. HIGHLIGHTSCB1r KO mice showed an &agr;2‐adrenoceptor‐mediated decrease in mPFC cell excitability.&agr;2‐ and &bgr;1‐adrenoceptor levels decreased in mPFC while TH increased in LC in CB1r KO mice.CB1r and &agr;2‐adrenoceptors are co‐localized post‐synaptically in the same mPFC neurons.&agr;2A‐adrenoceptor binding is unchanged in mPFC following acute or chronic WIN 55,212–2 but increased following withdrawal.These data provide convergent lines of evidence indicating cannabinoid regulation of the cortical adrenergic system.