Addiction biology

Bi-directional cannabinoid signalling in the basolateral amygdala controls rewarding and aversive emotional processing via functional regulation of the nucleus accumbens.

PMID 27230434


Functional connections between the basolateral amygdala (BLA) and nucleus accumbens (NAc) are involved critically in opiate-reward processing. In the BLA, inhibitory GABAergic substrates are inhibited by cannabinoid CB1 receptor (CB1R) activation and can modulate BLA projections to various limbic regions, including the NAc. However, the potential role of CB1R transmission in the regulation of opiate-related memory formation via the BLA → NAc circuit is not understood. Using an unbiased conditioned place preference paradigm in rats, we examined the effects of intra-BLA CB1R modulation by either direct pharmacological activation or blockade of CB1R transmission. We report that intra-BLA CB1R activation switches normally rewarding effects of morphine into strongly aversive effects. In contrast, CB1R blockade strongly potentiates normally subreward threshold effects of morphine. Next, using targeted microinfusions of an NMDA receptor antagonist to either the core or shell (NASh) subdivisions of the NAc, we found that selective blockade of NMDA transmission in the NA shell, but not core, prevented both intra-BLA CB1 blockade-mediated opiate reward potentiation and CB1 activation-mediated aversion effects. Finally, using multi-unit, in vivo electrophysiological recordings in the NASh, we report that the ability of intra-BLA CB1R modulation to control opiate reward salience and motivational valence is associated with distinct reward or aversion neuronal activity patterns and bi-directional regulation of intra-NASh fast-spiking interneurons versus medium spiny neurons. These findings identify a unique mechanism whereby bi-directional BLA CB1R transmission can regulate opiate-related motivational processing and control affective states through functional modulation of mesolimbic neuronal activity.