The nucleus accumbens (NAc), a major component of the mesolimbic system, is involved in the mediation of reinforcing and addictive properties of many dependence-producing drugs. Glutamatergic synapses within the NAc can express plasticity, including a form of endocannabinoid (eCB)-long-term depression (LTD). Recent evidences demonstrate cross-talk between eCB signaling pathways and those of other receptor systems, including serotonin (5-HT); the extensive co-localization of CB1 and 5-HT receptors within the NAc suggests the potential for interplay between them. Here, we found that 20 min low-frequency (4 Hz) stimulation (LFS-4Hz) of glutamatergic afferences in rat brain slices induces a novel form of eCB-LTD in the NAc core, which requires 5-HT2 and CB1 receptors activation and L-type voltage-gated Ca2+ channel opening. Moreover, we found that exogenous 5-HT application (5 μM, 20 min) induces an analogous LTD (5HT-LTD) at the same synapses, requiring the activation of the same receptors and the opening of the same Ca2+ channels; LFS-4Hz-LTD and 5-HT-LTD were mutually occlusive. Present results suggest that LFS-4Hz induces the release of 5-HT, which acts at 5-HT2 postsynaptic receptors increasing Ca2+ influx through L-type voltage-gated channels and 2-arachidonoyl-glycerol production and release; the eCB travels retrogradely and binds to presynaptic CB1 receptors, causing a long-lasting decrease of glutamate release resulting in LTD. These observations might be helpful to understand the neurophysiological mechanisms underlying drug addiction, major depression and other psychiatric disorders characterized by dysfunction of 5-HT neurotransmission in the NAc.

PMID:

 

24335217

 

[PubMed – as supplied by publisher]