Abstract
The endocannabinoid (eCB) system possesses neuromodulatory functions by influencing the release of various neurotransmitters, including γ-aminobutyric acid (GABA) and glutamate. A functional interaction between eCBs and the serotonergic system has already been suggested. Previously, we showed that cannabinoid type-1 (CB1) receptor mRNA and protein are localized in serotonergic neurons of the raphe nuclei, implying that the eCB system can modulate serotonergic functions. In order to substantiate the physiological role of the CB1 receptor in serotonergic neurons of the raphe nuclei, we generated serotonergic 5-hydroxytryptamine (5-HT) neuron-specific CB1 receptor-deficient mice, using the Cre/loxP system with a tamoxifen-inducible Cre recombinase under the control of the regulatory sequences of the tryptophan hydroxylase 2 gene (TPH2-CreERT2), thus, restricting the recombination to 5-HT neurons of the central nervous system (CNS). Applying several different behavioral paradigms, we revealed that mice lacking the CB1 receptor in serotonergic neurons are more anxious and less sociable than control littermates. Thus, we were able to show that functional CB1 receptor signaling in central serotonergic neurons modulates distinct behaviors in mice.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is present in many central and peripheral tissues, where it functions as a neurotransmitter or hormone
cannabinoid type-1 (CB1) Receptor Gene Inactivation in Serotonergic Neurons of the Raphe Nuclei In order to induce a deletion of the CB1 receptor gene in central serotonergic neurons, CB1fl/fl mice were crossed with the TPH2CreERT2tg/+ transgenic mice
We demonstrated that specific deletion of CB1 receptor in central serotonergic neurons leads to distinct behavioral alterations, which emerged only under stressful situations, while no behavioral differences were observed in basal locomotion and anxiety paradigms under low levels of stress
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is present in many central and peripheral tissues, where it functions as a neurotransmitter or hormone. Projections from the raphe nuclei innervate nearly every region of the central nervous system (CNS), including cortex, hippocampus, amygdala, striatum, hypothalamus, and spinal cord. This broad anatomical distribution is in line with the diverse behavioral functions which are modulated by serotonergic signaling. A wide distribution can be seen by the cannabinoid type-1 (CB1) receptor, a central component of the endocannabinoid (eCB) system controlling synaptic activity (Kano et al, 2009). The presence of functional CB1 receptor has been verified in several important
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