The Bivalent Rewarding and Aversive properties of Δ9-tetrahydrocannabinol are Mediated Through Dissociable Opioid Receptor Substrates and Neuronal Modulation Mechanisms in Distinct Striatal Sub-Regions

Abstract

The primary psychoactive compound in cannabis, Δ 9 -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.

Effects of pituitary adenylate cyclase‐activating polypeptide isoforms in nucleus accumbens subregions on ethanol drinking

“…Within the NAc shell, recent literature demonstrates that there exist further subdivisions, such that there are differences along the rostro‐caudal axis in the hedonic impact of specific neurochemicals 13,34 . In particular, hedonic hotspots have been identified in the rostral medial NAc shell and coldspots in the caudal medial shell 13,34 . While most of the PACAP injections in the present experiment targeted the rostral two thirds of the medial NAc shell, the region generally examined in studies involving the shell, injections in the caudal third of the NAc shell led to the opposite effect on ethanol drinking.…”

“…Thus, our results suggest that PACAP‐27 could affect ethanol drinking by altering the hedonic value of ethanol. Within the NAc shell, recent literature demonstrates that there exist further subdivisions, such that there are differences along the rostro‐caudal axis in the hedonic impact of specific neurochemicals 13,34 . In particular, hedonic hotspots have been identified in the rostral medial NAc shell and coldspots in the caudal medial shell 13,34 .…”

Effects of intrathecal and intracerebroventricular microinjection of kaempferol on pain: possible mechanisms of action

“…Normal saline was applied for dilution of Dic and morphine as positive controls. The selected concentrations of drugs were based on the previous literature and the outcomes of our initial experiments ( 10 16 17 18 19 20 21 ). Furthermore, because normal saline or DMSO administrations have shown the same results without any acute or chronic toxicity, we decided to use DMSO as a control or vehicle in all experiments.…”

Possible Involvement of Serotonergic Mechanism(s) in the Antinociceptive Effects of kaempferol

“…The solutions were prepared immediately prior to testing. The selected concentrations of KM and all drugs were based on previous studies and outcomes of the initial experiments of the authors of the present study [9,[15][16][17][18][19][20]. Furthermore, since NS or DMSO administration has shown the same results without any acute or chronic toxicity, it was decided to use DMSO as a control or vehicle (Veh) group in all the experiments.…”