Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism

ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity

“…Unlike the dorsal striatum, which features prominent CB1R expression on MSN terminals to modulate MSN-to-MSN lateral inhibition 42,106 , parvalbumin-expressing FSIs represent the exclusive known source of local CB1R expression on inhibitory terminals to MSNs in the murine NAc 38,40,52 . While NAc FSIs are additionally themselves capable of regulating synaptic transmission onto their pre-synaptic cortical and thalamic CB1R-expressing glutamatergic inputs via endocannabinoid synthesis/release, these effects are most likely mediated by anandamide rather than 2-AG 107,108 . Dorsal striatal FSIs may be dispensable for the expression of normal locomotion 109 , however numerous studies have linked striatal FSI activity to control of movement 110,111,112,113 .…”

Deviating from the norm: cocaine-induced synaptic plasticity in the nucleus accumbens via σ1 receptors and endocannabinoid signaling

“…Indeed, after brain slices were incubated in cocaine for an hour, LTD could no longer be induced with low-frequency stimulation. Cocaine exposure, via activation of σ 1 receptors, occluded other forms of eCB-dependent synaptic plasticity [2]. At the level of the neural circuit, these findings suggest that prior cocaine exposure may alter the way salience is encoded by PV-INs.…”

“…In midbrain dopamine neurons, activation of σ 1 receptors by cocaine mobilizes the secretion of the endocannabinoid 2-AG in extracellular vesicles through a process that likely involves the exchange of GDP for GTP [3]. In contrast, Manz et al [2] showed that in PV-INs, activation of σ 1 receptors mobilized anandamide, but not 2-AG. The mechanism of anandamide secretion was not completely resolved but involved the release of calcium from intracellular calcium stores.…”

“…However, a growing body of research shows that some effects of cocaine occur through activation of intracellular sigma-1 (σ 1 ) receptors [1]. In this issue of Neuropsychopharmacology, Manz and colleagues [2] performed a thorough series of pharmacological experiments in mouse brain slices to reveal a non-canonical mechanism of cocaine-induced synaptic plasticity in parvalbumin-expressing fast-spiking interneurons (PV-INs) in the nucleus accumbens.…”