Yosef Sarne, Fadi Asaf, Miriam Fishbein, Mikhal Gafni, Ora Keren

British Journal of Pharmacology (2011)163 1391–1401

doi: 10.1111/j.1476-5381.2011.01280.x

Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of Δ9‐tetrahydrocannabinol (THC) (3–4 orders of magnitude lower than the conventional doses) to mice induced long‐lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre‐ or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long‐term cognitive neuroprotection. The future therapeutical potential of these findings is discussed

Abstract

Christopher Norris, Hanna J. Szkudlarek, Brian Pereira, Walter Rushlow & Steven R. Laviolette 

05 July, 2019 Scientific Reports

DOI: 10.1038/s41598-019-46215-7

The primary psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), is capable of producing bivalent rewarding and aversive affective states through interactions with the mesolimbic system. However, the precise mechanisms underlying the dissociable effects of THC are not currently understood. In the present study, we identify anatomically dissociable effects of THC within the rat nucleus accumbens (NAc), using an integrative combination of behavioral pharmacology and in vivo neuronal electrophysiology. We report that the rewarding vs. aversive stimulus properties of THC are both anatomically and pharmacologically dissociable within distinct anterior vs. posterior sub-regions of the NAc. While the rewarding effects of THC were dependent upon local μ-opioid receptor signaling, the aversive effects of THC were processed via a κ-opioid receptor substrate. Behaviorally, THC in the posterior NASh induced deficits in social reward and cognition whereas THC in the anterior NAc, potentiated opioid-related reward salience. In vivo neuronal recordings demonstrated that THC decreased medium spiny neuron (MSN) activity in the anterior NAc and increased the power of gamma (γ) oscillations. In contrast, THC increased MSN activity states in the posterior NASh and decreased γ-oscillation power. These findings reveal critical new insights into the bi-directional neuronal and pharmacological mechanisms controlling the dissociable effects of THC in mesolimbic-mediated affective processing.

Abstract

Linda A Parker, Erin M Rock 

British Journal of Pharmacology (2011) 163(7), 1411-1422

doi: 10.1111/j.1476-5381.2010.01176.x

Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti‐emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re‐exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ9‐THC, HU‐210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB‐597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non‐psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti‐nausea/anti‐emetic effects of CBD may be mediated by indirect activation of somatodendritic 5‐HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5‐HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.

Abstract