Cannabinoid CB1 receptor-mediated inhibition of NMDA- and kainate-stimulated noradrenaline and dopamine release in the brain

Abstract

Guinea-pig hippocampal slices preincubated with [3H]noradrenaline were superfused with medium containing desipramine and rauwolscine and rat striatal slices preincubated with [3H]dopamine were superfused with medium containing nomifensine; the effect of cannabinoid receptor ligands on tritium overflow stimulated by NMDA or kainate was examined. Furthermore, the affinity of the drugs for cannabinoid CB1 receptors was determined in rat brain cortex membranes using [3H]SR 141716. In guinea-pig hippocampal slices preincubated with [3H]noradrenaline, tritium overflow stimulated by NMDA 100 microM and 1000 microM and by kainate 1000 microM was inhibited by the cannabinoid receptor agonists CP-55,940 and/or WIN 55,212-2. The CB1 receptor antagonist SR 141716 increased the NMDA (1000 microM)-stimulated tritium overflow but did not affect tritium overflow stimulated by NMDA 100 microM or kainate 1000 microM. The inhibitory effect of WIN 55,212-2 on the NMDA (100 microM)- and kainate (1000 microM)-evoked tritium overflow was antagonized by SR 141716. In rat striatal slices preincubated with [3H]dopamine, WIN 55,212-2 inhibited the NMDA (1000 microM)-stimulated tritium overflow. SR 141716, which, by itself, did not affect tritium overflow, counteracted the inhibitory effect of WIN 55,212-2. [3H]SR 141716 binding to rat cortical membranes was inhibited by SR 141716, CP-55,940 and WIN 55,212-2 (pKi 8.53, 7.34 and 5.93, respectively) but not affected by desipramine, rauwolscine and nomifensine (pKi < 5). In conclusion, activation of CB1 receptors inhibits the NMDA- and kainate-stimulated noradrenaline release in guinea-pig hippocampus and the NMDA-stimulated dopamine release in rat striatum. The explanation for the facilitatory effect of SR 141716 might be that it acts as an inverse agonist at CB1 receptors or that these receptors are activated by endogenous cannabinoids.

Cannabis and Neurological Soft Signs in Schizophrenia: Absence of Relationship and Influence on Psychopathology

“…It is widely accepted that schizophrenia is associated with increased mesolimbic and decreased prefrontal dopaminergic activity [68], with the former mostly related to positive and the latter to negative symptoms [69][70]. Animal studies suggest that activation of cannabinoid CB1 receptors result in improved fronto-cortical function, and in either improved or worsened limbic dopaminergic function with cannabinoid receptor activation [71][72][73]. Hence, negative symptoms are more likely to be improved by cannabinoid use, whereas the effect on positive symptoms should be more controversial and unpredictable.…”

Carotid sinus nerve section abolishes NMDA evoked respiratory effects in anaesthetised rats

“…NMDA is considered to have the stimulatory effects on dopamine release from brains of the rat and guinea pig (Kathmann et al, 1999;Whitehead et al, 2001).…”

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).…”

“…Whereas in vitro studies in the rat striatum showed rimonabant-sensitive inhibitory effects of exogenous cannabinoids (Cadogan et al 1997;Kathmann et al 1999), in vivo studies in the same tissue reported stimulatory effects (Malone and Taylor 1999). The cannabinoid receptors in the latter model may be located on GABAergic interneurones synapsing with the dopaminergic perikarya.…”

“…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.…”