Abstract
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.
Highlights
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
Using a combination of behavioral assays and in vivo neuronal electrophysiology, we report that THC infused into the anterior NASh produces μ-opioid receptor dependent reward, potentiates morphine reward salience, decreases medium spiny neuron activity and increases the power of high frequency γ-oscillations
The nucleus accumbens serves as a critical nexus point for the integration of affective information from numerous inputs, including the ventral tegmental area (VTA), amygdala, ventral hippocampus and prefrontal cortex (PFC)
Summary
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. We report that the rewarding vs aversive stimulus properties of THC are both anatomically and pharmacologically dissociable within distinct anterior vs posterior subregions 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. 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. Given that THC serves as a partial CB1 receptor agonist, this evidence may suggest that the differential affective stimulus effects of THC might depends upon differential activation of anatomically distinct OR subtypes, within the mammalian NAc
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