Cannabinoid modulation of noradrenergic circuits: Implications for psychiatric disorders

Abstract

The interaction between the endocannabinoid system and catecholaminergic circuits has gained increasing attention as it is recognized that the development of synthetic cannabinoid receptor agonists/antagonists or compounds targeting endocannabinoid synthesis/metabolism may hold some therapeutic potential for the treatment of psychiatric disorders. The noradrenergic system plays a critical role in the modulation of emotional state, primarily related to anxiety, arousal, and stress. Recent evidence suggests that the endocannabinoid system mediates stress responses and emotional homeostasis, in part, by targeting noradrenergic circuits. This review summarizes our current knowledge regarding the anatomical substrates underlying regulation of noradrenergic circuitry by the endocannabinoid system. It then presents biochemical evidence showing an important effect of cannabinoid modulation on adrenergic receptor signaling. Finally, new evidence from behavioral pharmacology studies is provided demonstrating that norepinephrine is a critical determinant of cannabinoid-induced aversion, adding another dimension to how central noradrenergic circuitry is regulated by the cannabinoid system.

Involvement of medial prefrontal cortex alpha-2 adrenoceptors on memory acquisition deficit induced by arachidonylcyclopropylamide, a cannabinoid CB1 receptor agonist, in rats; possible involvement of Ca2+ channels

“…***p<0.001 compared with saline, +p<0.05, and +++p<0.001 compared with their respective groups. cannabinoid tone controls LC activity (Carvalho and Van Bockstaele, 2012). Unfortunately, few studies have focused on the interaction of cannabinoids and norepinephrine on the cellular level, although there are abundant data about the action of cannabinoids on complex changes of behavior mediated by the monoaminergic system.…”

Cannabis Abusers Show Hypofrontality and Blunted Brain Responses to a Stimulant Challenge in Females but not in Males

“…Moreover, the cerebellum has minimal DA innervation, which suggests that reduced metabolic increases to MP in CA could also reflect attenuated reactivity to MP-induced noradrenergic stimulation (Tilley and Gu, 2008). The cannabinoid system is an important regulator of noradrenergic systems in part via CB1 receptors (Reyes et al, 2009;Carvalho and Van Bockstaele, 2012;Cathel et al, 2014) and downregulation of CB1 receptors in CA (Hirvonen et al, 2012) could underlie the attenuated responses to MP-induced changes in metabolism observed in these brain regions. A prior study in CA showed that co-administration of Δ-9-tetrahydrocannabinol (THC) with ecstasy, which like MP is a monoamine transporter blocker, enhanced its cardiovascular effects and the increases in epinephrine and norepinephrine in plasma (Dumont et al, 2009).…”

Endocannabinoid Regulation of Neuroendocrine Systems

“…Both of the known cannabinoid receptors are coupled to Gα i/o , which is negatively coupled to adenylyl cyclase activity and downregulates cAMP production. CB 1 receptors are localized primarily on the presynaptic terminals of glutamatergic and GABAergic synapses, where they reduce the release probabilities of glutamate and GABA and modulate excitatory and inhibitory neurotransmission (Di, Malcher-Lopes, Halmos, & Tasker, 2003;Hirasawa et al, 2004;Melis et al, 2004;Ohno-Shosaku et al, 2002;, although they have also been reported to modulate the release of other neurotransmitters, such as norepinephrine (Carvalho & Van Bockstaele, 2012). Activation of presynaptic CB 1 receptors has been shown to suppress calcium influx via presynaptic voltage-gated calcium channels (Wilson, Kunos, & Nicoll, 2001), and to facilitate the opening of presynaptic voltage-gated potassium channels (Mackie, Lai, Westenbroek, & Mitchell, 1995), which lead in both cases to a decrease in the probability of neurotransmitter release.…”