Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the human and guinea-pig hippocampus

Abstract

We examined the question of whether cannabinoid receptors modulating noradrenaline release are detectable in the brain of humans and experimental animals. For this purpose, hippocampal slices from humans, guinea-pigs, rats and mice and cerebellar, cerebrocortical and hypothalamic slices from guinea-pigs were incubated with [3H]noradrenaline and then superfused. Tritium overflow was evoked either electrically (0.3 or 1 Hz) or by introduction of Ca2+ ions (1.3 mM) [corrected] into Ca(2+)-free, K(+)-rich medium (25 mM) [corrected] containing tetrodotoxin 1 microM. Furthermore, the cAMP accumulation stimulated by forskolin 10 microM was determined in guinea-pig hippocampal membranes. We used the following drugs: the cannabinoid receptor agonists (-)-cis-3-[2-hydroxy-4-(1,1- dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclo-hexanol (CP-55,940) and R(+)-[2,3-dihydro-5-methyl-3- [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]- (1-naphthalenyl)methanone (WIN 55,212-2), the inactive S(-)-enantiomer of the latter (WIN 55,212-3) and the CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR 141716). The electrically evoked tritium overflow from guinea-pig hippocampal slices was reduced by WIN 55,212-2 (pIC30% 6.5) but not affected by WIN 55,212-3 up to 10 microM. The concentration-response curve of WIN 55,212-2 was shifted to the right by SR 141716 (0.032-microM) (apparent pA2 8.2), which by itself did not affect the evoked overflow. WIN 55,212-2 1 microM also inhibited the Ca(2+)-evoked tritium overflow in guinea-pig hippocampal slices and the electrically evoked overflow in guinea-pig cerebellar, cerebrocortical and hypothalamic slices as well as in human hippocampal slices but not in rat and mouse hippocampal slices. SR 141716 (0.32 microM) markedly attenuated the WIN 55,212-2-induced inhibition in guinea-pig and human brain slices. SR 141716 0.32 microM by itself increased the electrically evoked tritium overflow in guinea-pig hippocampal slices but failed to do so in slices from the other brain regions of the guinea-pig and in human hippocampal slices but failed to do so in slices from the other brain regions of the guinea-pig and in human hippocampal slices. The cAMP accumulation stimulated by forskolin was reduced by CP-55,940 and WIN 55,212-2. The concentration-response curve of CP 55,940 was shifted to the right by SR 141716 (0.1 microM; apparent pA2 8.3), which by itself did not affect cAMP accumulation. In conclusion, cannabinoid receptors of the CB1 subtype occur in the human hippocampus, where they may contribute to the psychotropic effects of cannabis, and in the guinea-pig hippocampus, cerebellum, cerebral cortex and hypothalamus. The CB1 receptor in the guinea-pig hippocampus is located presynaptically, is activated by endogenous cannabinoids and may be negatively coupled to adenylyl cyclase.

Involvement of the Endocannabinoid System in the Ability of Long-Term Tricyclic Antidepressant Treatment to Suppress Stress-Induced Activation of the Hypothalamic–Pituitary–Adrenal Axis

“…The primary pharmacological property of desipramine is its ability to inhibit norepinephrine reuptake and thus potentiate the synaptic action of norepinephrine (Frazer, 1997;Wong et al, 2000). Both in vivo and ex vivo work in rodent and human tissue has demonstrated that CB 1 receptors in the hippocampus and hypothalamus negatively regulate noradrenergic neurotransmission (Tzavara et al, 2001;Schlicker et al, 1997). Thus, the upregulation of CB 1 receptors in the hippocampus and hypothalamus seen in this study could be an adaptive response launched by the central nervous system to decrease noradrenergic transmission by increasing the density of presynaptic CB 1 receptors, which in turn would reduce NE release and normalize the increased synaptic availability induced by desipramine treatment.…”

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

“…*P<0.05, compared with the corresponding control (not shown). From Kathmann et al (2001a), Kurz et al (2008), Nakazi et al (2000), Schlicker et al (1996Schlicker et al ( , 1997Schlicker et al ( , 2003, Schultheiss et al (2005) and unpublished data brain regions of the guinea pig (Kathmann et al 1999;Schlicker et al 1997). A facilitating effect of rimonabant was also found in the rat medial prefrontal cortex and nucleus accumbens (Tzavara et al 2003).…”

“…Antagonism of inhibition of cAMP formation has also been observed in peripheral tissues such as the rat vas deferens (Pertwee et al 1996c) or the trabecular meshwork and ciliary process of the human eye (Stamer et al 2001). Whereas some studies report that rimonabant does not affect intracellular cAMP levels in the absence of exogenous cannabinoids (Rinaldi-Carmona et al 1994;Schlicker et al 1997), others have found cAMP elevations upon in vitro or in vivo treatment with rimonabant (Mato et al 2002;Rubino et al 2000). Interestingly, rimonabant treatment was also found to activate protein kinase A (Rubino et al 2000;Tzavara et al 2000).…”

“…The release of noradrenaline is inhibited by cannabinoids in the human hippocampus and in the hippocampus and other brain regions of the guinea pig (Kathmann et al 1999;Schlicker et al 1997). The inhibitory effect was antagonized by rimonabant, suggesting that a CB 1 receptor is involved.…”

“…When given alone, rimonabant facilitated noradrenaline release, whereas SR 144528 had no effect. From Schlicker et al (1997) and Szabo and Schlicker (2005) . Tritium overflow corresponds to the release of noradrenaline, acetylcholine, dopamine, and serotonin.…”