In the present study we investigated whether serotonin release in the hippocampus is subject to regulation via cannabinoid receptors. Both rat and mouse hippocampal slices were preincubated with ...super(3)Hserotonin ( super(3)H5- HT) and superfused with medium containing serotonin reuptake inhibitor citalopram hydrobromide (300 nM). The cannabinoid receptor agonist R(+)- 2,3-dihydro-5-methyl-3-(morpholinyl)methylpyrrolo1,2,3-de-1,4 - benzoxazinyl-(1-naphthalenyl) methanone mesylate (WIN55,212-2, 1 mu M) did not affect either the resting or the electrically evoked super(3)H5-HT release. In the presence of the ionotropic glutamate receptor antagonists d(- )-2-amino-5-phosphonopentanoic acid (AP-5, 50 mu M) and 6-cyano-7- nitroquinoxaline-2,3-dione-disodium (CNQX, 10 mu M) the evoked super(3)H5-HT release was decreased significantly. Similar findings were obtained when CNQX (10 mu M) was applied alone with WIN55,212-2. This effect was abolished by the selective cannabinoid receptor subtype 1 (CB sub(1)) antagonists N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methy l-1H- pyrazole-3-carboxamide (SR141716, 1 mu M) and 1-(2,4-dichlorophenyl)-5-(4- iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt (AM251, 1 mu M). Similarly to that observed in rats, WIN55,212-2 (1 mu M) decreased the evoked super(3)H5-HT efflux in wild-type mice (View the MathML source). The inhibitory effect of WIN55,212-2 (1 mu M) was completely absent in hippocampal slices derived from mice genetically deficient in CB sub(1) cannabinoid receptors (View the MathML source). Relatively selective degeneration of fine serotonergic axons by the neurotoxin parachloramphetamine (PCA) reduced significantly the tritium uptake and the evoked super(3)H5-HT release. In addition, PCA, eliminated the effect of WIN55,212-2 (1 mu M) on the stimulation-evoked super(3)H5-HT efflux. In contrast to the PCA-treated animals, WIN55,212-2 (1 mu M) reduced the super(3)H5-HT efflux in the saline-treated group. Our data suggest that a subpopulation of non-synaptic serotonergic afferents express CB sub(1) receptors and activation of these CB sub(1) receptors leads to a decrease in 5- HT release.
