Cannabinoid receptor 1-expressing neurons in the nucleus accumbens

Endocannabinoid signaling critically regulates emotional and motivational states via activation of cannabinoid receptor 1 (CB1) in the brain. The nucleus accumbens (NAc) functions to gate emotional and motivational responses. Although expression of CB1 in the NAc is low, manipulation of CB1 signaling within the NAc triggers robust emotional/motivational alterations related to drug addiction and other psychiatric disorders, and these effects cannot be exclusively attributed to CB1 located at afferents to the NAc. Rather, CB1-expressing neurons in the NAc, although sparse, appear to be critical for emotional and motivational responses. However, the cellular properties of these neurons remain largely unknown. Here, we generated a knock-in mouse line in which CB1-expressing neurons expressed the fluorescent protein td-Tomato (tdT). Using these mice, we demonstrated that tdT-positive neurons within the NAc were exclusively fast-spiking interneurons (FSIs). These FSIs were electrically coupled with each other, and thus may help synchronize populations/ensembles of NAc neurons. CB1-expressing FSIs also form GABAergic synapses on adjacent medium spiny neurons (MSNs), providing feed-forward inhibition of NAc output. Furthermore, the membrane excitability of tdT-positive FSIs in the NAc was up-regulated after withdrawal from cocaine exposure, an effect that might increase FSI-to-MSN inhibition. Taken together with our previous findings that the membrane excitability of NAc MSNs is decreased during cocaine withdrawal, the present findings suggest that the basal functional output of the NAc is inhibited during cocaine withdrawal by multiple mechanisms. As such, CB1-expressing FSIs are targeted by cocaine exposure to influence the overall functional output of the NAc.Cannabinoid receptor type 1 (CB1) has been extensively implicated in a variety of psychological and psychiatric disorders, including drug addiction (1, 2). Recent studies suggest that CB1 within the nucleus accumbens (NAc), a key component of the brain reward circuit, plays a particularly important role in the development and maintenance of cocaine-induced behavioral alterations (3). Compared with the extensive expression of CB1 in the striatum, the mRNA and protein levels of CB1 within the NAc are sparse, leading to the notion that CB1 at afferent terminals projecting to the NAc are largely responsible for intra-NAc, CB1-dependent, cocaine-induced behaviors (4–6). However, a recent study primarily targeting CB1-expressing neurons demonstrates that inhibiting the expression of CB1 within the NAc antagonizes cocaine-induced reward responses (7). This and other results (8) suggest that CB1-expressing neurons in the NAc, although sparse, are critical for cellular and behavioral alterations induced by cocaine and other drugs of abuse.To examine these putative CB1-expressing neurons within the NAc, we generated a knock-in mouse line in which CB1-expressing neurons expressed the fluorescent protein td-Tomato (tdT). Our results show that tdT-positive neurons within the NAc were exclusively fast-spiking interneurons (FSIs). These FSIs were not only electrically connected with each other but exerted extensive inhibitory control on nearby medium spiny neurons (MSNs), the principal neurons in the NAc, via monosynaptic connections. Furthermore, the membrane excitability of these neurons became significantly up-regulated throughout short- and long-term withdrawal from repeated exposure to cocaine. These results suggest that CB1-expressing FSIs within the NAc are neural substrates targeted by cocaine exposure and influence the overall functional output of the NAc.