Cannabinoid receptors are localized to noradrenergic axon terminals in the rat frontal cortex

Abstract

Cannabinoid agonists exert complex actions on modulatory neurotransmitters involved in attention and cognition. Previous studies have demonstrated that acute systemic administration of the synthetic cannabinoid agonist, WIN 55,212-2, increases norepinephrine efflux in the rat frontal cortex. In an effort to elucidate whether cannabinoid (CB1) receptors are positioned to presynaptically modulate norepinephrine release in the frontal cortex, immunocytochemical detection of the CB1 receptor and the catecholamine-synthesizing enzyme dopamine-β-hydroxylase (DβH) was performed using confocal immunofluorescence microscopy and immunoelectron microscopy in rat brain. Fluorescence microscopy analysis of dually-labeled tissue sections from the frontal cortex indicated that individual axonal processes exhibited both CB1 receptor and DßH immunoreactivities. Ultrastructural analysis confirmed that one-third of axon terminals containing CB1 immunolabeling also exhibited DβH labeling. Cortical neurons were also found to be targeted by separately labeled CB1-and DβH-containing axon terminals. In conclusion, the present neuroanatomical data suggest that cortical norepinephrine release may be modulated, in part, by CB1 receptors that are presynaptically distributed on noradrenergic axon terminals.

Neurobiological Interactions Between Stress and the Endocannabinoid System

“…CB1 receptors not only represent the most abundant class of G-protein-coupled receptors in the central nervous system (Herkenham et al, 1990) but are also present in a variety of peripheral tissues (Howlett et al, 2002). Within the brain, CB1 receptors are expressed on GABAergic, glutamatergic, serotonergic, noradrenergic, and dopaminergic terminals (Azad et al, 2008;Haring et al, 2007;Hermann et al, 2002;Kano et al, 2009;Morozov et al, 2009;Oropeza et al, 2007), but given the relative abundance of excitatory and inhibitory neurons in the brain, and the high levels of CB1 receptor expression on these terminals, the predominant effects of eCB signaling occur at GABAergic and glutamatergic synapses (Katona and Freund, 2012). CB2 receptors are mostly located in immune cells and, when activated, can modulate immune cell migration and cytokine release both outside and within the brain (Pertwee, 2005).…”

Adolescent Exposure of JWH-018 “Spice” Produces Subtle Effects on Learning and Memory Performance in Adulthood

“…To repeat, during adolescence a number of areas of the brain are undergoing developmental changes with higher levels of novelty and sensation-seeking considered a common feature of adolescence [74]. Because presynaptic CB1 cannabinoid receptors have been discovered at serotoninergic, noradrenergic, glutamatergic, and GABAergic synapses in many areas of the brain [68,[70][71][72][73][75][76][77][78][79] including those critical for accurate responses and memory processes [5], these abused synthetic cannabinoids should be examined in greater detail. Doing so may further define the specific consequences associated with adolescent use.…”

Role of Prefrontal Cortex Dopamine and Noradrenaline Circuitry in Addiction

“…It has been found that posterior VTA dopamine neurons projecting to the ventral pallidum and mPFC are stimulated by local administration of ethanol and that these stimulating effects are mediated, at least in part, by 5-HT(3)receptors (Ding et al, 2011). The presence of cannabinoid receptors in the PFC has been shown by neuroanatomical data suggesting that cortical norepinephrine release may be modulated, in part, by CB1 receptors that are presynaptically distributed on noradrenergic axon terminals (Oropeza et al, 2006). Moreover, repeated treatment with delta-9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, or WIN 55,212-2 (WIN), a synthetic cannabinoid receptor agonist caused a persistent and selective reduction in mPFC dopamine turnover (Verrico et al, 2003).…”