Behavioural Brain Research 163 (2005) 227–236 Research report Evidence for the involvement of central serotonergic mechanisms in cholinergic tremor induced by tacrine in Balb/c mice Hina Mehta a , Reena Haobam a , Rajamma Usha b , Kochupurackal P. Mohanakumar a,∗ a Division of Clinical & Experimental Neurosciences, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Calcutta 700032, India b Manovikas Biomedical Research & Diagnostic Centre, 482 Madudah, Plot I-24, Sector J, Calcutta 700107, India Received 19 November 2004; received in revised form 12 May 2005; accepted 12 May 2005 Available online 28 June 2005 Abstract Tacrine is a potent and reversible inhibitor of acetylcholinesterase (AChE) in the brain. It produces tremor in animals, which is believed to be due to an increase in the brain acetylcholine level following AChE inhibition. The present study was undertaken to investigate the involvement, if any, of biogenic amines in the genesis of this motor dysfunction. Administration of tacrine (10–20 mg/kg, i.p.) produced dose- and time-dependent tremor in Balb/c mice. While in vivo inhibition of striatal AChE activity was observed only for the highest dose of tacrine, a dose-dependent increase in striatal choline acetyltransferase activity was obtained. Serotonin (5-HT) levels, as assayed following a sensitive HPLC-electrochemical procedure, were significantly increased in nucleus caudatus putamen, nucleus accumbens, substantia nigra, nucleus raphe dorsalis, olivary nucleus and the cerebellum. However, dopamine or norepinephrine levels remained unaltered in these areas of the brain. In animals treated with p-chlorophenylalanine, a specific tryptophan hydroxylase inhibitor and 5-HT depletor, tacrine failed to elevate the levels of 5-HT in the brain regions, and significantly attenuated tremor response to the drug. Tacrine-induced tremor was also significantly (83%) attenuated by 5-HT 2A/2C receptor antagonist mianserin (5 mg/kg, i.p.), but methysergide (5 mg/kg, i.v.) could block tacrine-induced tremor only by 20%. Atropine (5 mg/kg, i.p.) antagonized tacrine-induced tremor by about 53%, but a combination of atropine and mianserin completely blocked the tremor response. These results indicate that the cholinergic tremor produced by tacrine in Balb/c mice is mediated via central serotonergic mechanisms, and stimulation of 5-HT 2A/2C receptors plays a pivotal role in this motor dysfunction. © 2005 Elsevier B.V. All rights reserved. Keywords: Tremor; Catecholamines; Acetylcholine synthesis; Serotonin; 5-HT 2A/2C receptor; Cholinergic receptor; 5-HT synthesis inhibition 1. Introduction Tacrine (1,2,3,4-tetrahydro-9-aminoacridine) is a pow- erful inhibitor of brain acetylcholinesterase (AChE) when administered systemically. It is mostly accepted that the mechanism of action of tacrine is based on its inhibitory effect on AChE activity, which increases the level of acetyl- choline (ACh) in the brain [7,18,32]. Therefore, it has been tried as a therapeutic agent for memory improvement in Alzheimer’s disease (AD) patients [11,43]. However, tacrine produces severe undesirable peripheral and central choliner- gic effects, primarily associated with extrapyramidal motor ∗ Corresponding author. Tel.: +91 33 2413 3223 (O); fax: +91 33 2473 5197/2 3967. E-mail address: mohankumar@iicb.res.in (K.P. Mohanakumar). system [11,43], which limit its use in majority of AD patients. These effects include various parkinsonian symp- toms, such as bradykinesia, cogwheel rigidity and tremor [21,33]. Tacrine is also known to induce a type of parkinso- nian oral tremor or whole body tremor in laboratory animals [7,20,21,25,31]. AChE inhibitors, such as physostigmine, tacrine, soman, sarin, dichlorovos, quinolphos, tabun and diisopropylfluo- rophosphate, induce tremor in rodents [6,14,21,26,30,31, 40,42,47]. The biochemical basis of this behavioral abnor- mality has been linked to increased ACh levels in the brain following AChE inhibition [7,42]. Acute or chronic administration of anti-cholinesterase agents also produces changes in the levels of biogenic amines and their receptors [7,26,30,34]. Serotonergic mediation of tremor responses to some of these AChE inhibitors has been suggested, since 0166-4328/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2005.05.002