Cannabinoids attenuate norepinephrine‐induced melatonin biosynthesis in the rat pineal gland by reducing arylalkylamine N‐acetyltransferase activity without involvement of cannabinoid receptors

Jun 30, 2006Journal of neurochemistry

Cannabinoids reduce stress hormone-triggered melatonin production in the rat pineal gland by lowering enzyme activity without using cannabinoid receptors

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Abstract

Cannabinoids significantly reduced norepinephrine-induced melatonin biosynthesis in cultured rat pineals.

Treatment with THC, cannabidiol, or cannabinol decreased the activity of the enzyme AANAT, which is crucial for melatonin production.
The observed reductions in melatonin biosynthesis were not replicated by the cannabinoid receptor agonist WIN55,212-2.
Cannabinoid receptor antagonists did not reverse the effects of cannabinoids on melatonin synthesis.
Cannabinoids did not affect the increase in cAMP/Ca(2+) levels induced by norepinephrine.
Cannabinoids directly inhibited AANAT activity in pineal gland lysates without impacting the enzyme HIOMT, which is involved in the final step of melatonin production.

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Cannabinoids modulate neuronal and neuroendocrine circuits by binding to cannabinoid receptors acting upon cAMP/Ca(2+)-mediated intracellular signaling cascades. The rat pineal represents an established model to investigate intracellular signaling processes because a well defined input, the neurotransmitter norepinephrine, is transformed via cAMP/Ca(2+)-dependent mechanisms into an easily detectable output signal, the biosynthesis of melatonin. Here we investigated the impact of cannabinoids on norepinephrine-regulated melatonin biosynthesis in the rat pineal. We demonstrated that treatment of cultured rat pineals with 9-carboxy-11-nor-delta-9-tetrahydrocannabinol (THC), cannabidiol or cannabinol significantly reduced norepinephrine-induced arylalkylamine N-acetyltransferase (AANAT) activity and melatonin biosynthesis. These effects were not mimicked by the cannabinoid receptor agonist WIN55,212-2 and were not blocked by cannabinoid 1 and 2 receptor antagonists. The cannabinoids used did not affect norepinephrine-induced increases in cAMP/Ca(2+) levels. Notably, cannabinoids were found to directly inhibit AANAT activity in lysates of the pineal gland. This effect was specific in so far as cannabinoids did not influence the activity of hydroxyindole-O-methyltransferase (HIOMT), the last enzyme in melatonin biosynthesis. Taken together, our data strongly suggest that cannabinoids inhibit AANAT activity and attenuate melatonin biosynthesis through intracellular actions without involvement of classical cannabinoid receptor-dependent signaling cascades.

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Cannabinoids attenuate norepinephrine‐induced melatonin biosynthesis in the rat pineal gland by reducing arylalkylamine N‐acetyltransferase activity without involvement of cannabinoid receptors

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