Vol. 300, Issue 2, 621-628, February 2002

Acute and Chronic Effects of Methamphetamine on Tele-Methylhistamine Levels in Mouse Brain: Selective Involvement of the D₂ and not D₃ Receptor

S. Morisset, C. Pilon, J. Tardivel-Lacombe, D. Weinstein, W. Rostene, C. Betancur, P. Sokoloff, J.-C. Schwartz and J.-M. Arrang

Unité de Neurobiologie et Pharmacologie Moléculaire (U109) de l'Institut National de la Santé et de la Recherche Médicale, Centre Paul Broca, Paris, France (S.M., C.P., J.T.-L., D.W., P.S., J.-C.S., J.-M.A.); and Imagerie Cellulaire des Neurorécepteurs et Physiopathologie Neuroendocrinienne, Hôpital Saint-Antoine, Paris, France (W.R., C.B.)

We have explored the role of endogenous dopamine in the control of histaminergic neuron activity in mouse brain regions evaluated by changes in tele-methylhistamine (t-MeHA) levels. In vitro, methamphetamine released [³H]noradrenaline but failed to release [³H]histamine from synaptosomes. In vivo, methamphetamine enhanced t-MeHA levels by about 2-fold with ED₅₀ values of ~1 mg/kg in caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus. This response selectively involved the D₂ and not the D₃ receptor as indicated by its blockade by haloperidol and by its persistence after administration of nafadotride, a D₃ receptor preferential ligand, or in (/) D₃ receptor-deficient mice. The t-MeHA response to methamphetamine was delayed compared with the locomotor-activating effect of this drug, suggesting that it is of compensatory nature. In agreement, ciproxifan, an inverse agonist known to enhance histamine neuron activity, decreased the hyperlocomotion induced by methamphetamine. Repeated methamphetamine administration resulted in the expected sensitization to the hyperlocomotor effect of the drug but did not modify either the ED₅₀ or the E_max regarding t-MeHA levels. However, it resulted in an enhanced basal t-MeHA level (+30-40%), which was sustained for at least 11 days after withdrawal in hypothalamus, striatum, and cerebral cortex and suppressed by haloperidol. Hence, both the acute and chronic administration of methamphetamine enhance histamine neuron activity, presumably in a compensatory manner. Repeated methamphetamine administration also resulted in a modified balance in the opposite influences of dopamine and serotonin on histaminergic neurons as revealed by the enhanced response to haloperidol and abolished response to ketanserin, respectively.