Pergamou PII: SOO2S3908(9@00043-3 Neuropharmacology, Vol. 35, No. 8, pp. 1101-1107, 1996 Copyright 0 1996 Elsevier Science Ltd. All rights resewed Printed in Great Britain 00%3908/96 $15.00 + 0.00 Action of Harman (l-methyl-P-carboline) on the Brain: Body Temperature and In zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE Viva Efflux of 5-HT from Hippocampus of the Rat A. ADELL1’2, T. A. BIGGS’ and R. D. MYERS’* ‘Departments CIf Pharmacology and Psychiatric Medicine, School of Medicine, East Carolina University, Greenville, NC 27858, U.S.A.; and 2Departtnent of Neurochemistry, Centro de Investigation y Desarrollo, C.S.I.C., Barcelona, Spain (Accepted 4 April 1996) Summary-Harman (1-methyl-/?-carboline) has been shown previously to act on the hippocampus of the rat in terms of its evocation of anxiogenic responses and induction of alcohol preference. In the present experiments, the localized perfusion of 200 PM harman in the dorsal hippocampus of freely moving rats increased the levels of serotonin (5HT) but not S-hydroxyindoleacetic acid (5HIAA) in cerebral dialysates. The systemic administration of 5.0-20 mg/kg harman also enhanced 5-HT in the perfusates but reduced the levels of 5-HIAA in a dose-depend.ent manner, probably as a result of the inhibition of the enzyme monoamine oxidase type A (MAO-A). Harman given systemically in doses of 2.5-20 mg/kg induced an intense hypothermia, with a maximum fall produced by the 5.0 mg/kg dose. This fall in body temperature (Tb) induced by 5.0 mg/kg harman was not antagonized by 5.0 mg/kg of (*)-pindolol. Further, pretreatment of the rats with para- chlorophenylalanine @CPA) also failed to alter the harman-induced hypothermia. The systemic administration of 10 mg/kg of the MAO-A inhibitor, clorgyline, also lowered Tb significantly. Overall, the present experiments show that harman apparently influences 5-HT systems in the brain by its action in inhibiting MAO-A. This property is likely responsible also for the harman-induced increase of 5-HT in the hippocampus of the rats. Copyright 0 1996 Elsevier Science Ltd. Keywords-Harman (1-methyl-fl-carboline), body temperature, serotonin, (Q-pindolol, p-chlorophenylala- nine, hippocampus, microdialysis. Harman (1-methyl-j?-carboline) occurs in vivo in the brain of the rat (Shoemaker et al., 1980; Bosin et al., 1989; Rommelspacher et al., 1994) and can influence a variety of central neuro’transmitter systems. For instance, harman binds with high affinity to benzodiazepine receptors and tryptamine sites in the brain of the rat (Airaksinen et al., 198,7; Miiller et al., 1981; Rommel- spacher et al., 1980) and evokes an anxiety-like state similar to that of other j?-carbolines (Briining and Rommelspacher, 1984) which is attenuated by a benzodiazepine (Rommelspacher et al., 1982a,b). In addition to anxiogenesis, harman induces myoclonus and stereotypy behavior corresponding to the prototypical serotonin (5hydroxytryptamine, 5-HT) syndrome (Pran- zatelli and Snodgrass, 1987). Further, harman is a potent inhibitor of monoamine oxidase type A (MAO-A) (Rommelspacher et al., 1994), by virtue of its binding to the active site of the enzyme (May et al., 1991). Previously, it has been shown that a p-carboline infused acutely into the hippocampus can induce an intense anxiety-like state as well as a strong preference for alcohol in the rat (Huttunen and Myers, 1986, 1987). When harman is infused into the dorsal hippocampus continuously for 14 days in low alcohol drinking (LAD) rats, the volitional ingestion of alcohol also increases significantly (Adell and Myers, 1994). Harman perfused unilaterally in the hippocampus of the LAD rat also elevates the levels of S-HT and norepinephrine (NE) both ipsilaterally and contralaterally, as well as in other areas remote from the site of its perfusion (Adell and Myers, 1995). The increase in these monoamines after the sustained infusion of harman coincides with its property of inhibiting MAO-A. However, the neurochemical changes induced by harman are dissociated from alcohol drinking, since a lower concentration of 5.5 nmol/h of the /?-carboline augments drinking without altering amine efflux (Adell and Myers, 1995). *To whom correspondence should be addressed. The present study was undertaken to characterize 1101