Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit
Introduction
Motor movement, a fundamental component of behavior, is the principle extrinsic action of the brain (Rekling et al., 2000). Numerous neurotransmitters and their receptors are involved in facilitating and modulating motor movements. The role of the serotonergic neurotransmitter system in modulating neuronal excitability and in turn modulating motor behavior has been extensively studied (for reviews, see Jacobs et al., 2002, Jacobs and Fornal, 1997). Evidence for the role of central serotonin (5-HT) in motor behavior was first demonstrated in rodents where administration of drugs that increase synaptic 5-HT, including 5-HT releasers, precursors, and direct-acting agonists, produced a motor syndrome similar to that seen in a large number of vertebrates including humans Jacobs, 1976, Sternbach, 1991. This motor syndrome consists of hyperactivity, tremor, rigidity, hindlimb abduction, lateral head weaving, straub tail, forepaw treading, hyperreactivity, and shaking behaviors (head shakes, head twitches, and body shakes). These behavioral features have been studied as models for activation of the endogenous 5-HT system and selective ligands have been used to relate subsets of these behaviors with activation of different 5-HT receptors in the central nervous system (CNS) Bedard and Pycock, 1977, Grahame-Smith, 1971, Jacobs, 1976. For example, in the rodent, systemic administrations of 5-HT2A/2C receptor agonists such as (1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)hydrochloride (DOI) elicits head and body movements (head shakes, head twitches, and body shakes), which have been established as behavioral correlates of 5-HT2A receptors activation Dursun and Handley, 1996, Pranzatelli, 1990, Schreiber et al., 1995, Wettstein et al., 1999. In the rat, head and body shakes have been shown to be mediated by 5-HT2A receptors in the brain Ciccocioppo et al., 1995, Hawkins et al., 2002, Nagayama and Lu, 1996. In the rabbit, systemic administration of DOI also dose-dependently elicits head movements (vertical down–up head bobs) and body shakes (Dave et al., 2002). Similar to the rodent, the head bobs in the rabbit are mediated by 5-HT2A receptors. However, unlike the rodent, the body shakes in the rabbit are mediated by 5-HT2C receptors, indicating species differences in the receptors mediating 5-HT-elicited motor movements.
The present study was designed to determine whether, in the rabbit, the 5-HT2A and 5-HT2C receptors mediating the separate DOI-elicited behaviors are located in the brain or the periphery. First, systemic injections of the peripherally acting 5-HT2A/2C receptor antagonist xylamidine were employed to study its effects on head bobs and body shakes produced by systemic injections of DOI. Second, DOI was infused into the lateral ventricle to determine whether head bobs and body shakes could be elicited by direct central administrations of DOI and whether central administrations of ketanserin and xylamidine would block these behavioral effects.
Section snippets
Animals
Adult male New Zealand rabbits (Covance, Denver, PA) weighing 1.6–1.8 kg were housed individually upon arrival. They were housed under a 12/12-h light/dark cycle with access to 125 g of chow per day and free access to water in an AAALAC-approved animal facility maintained at 22 °C. Rabbits were adapted to their home-cages for 5 days and were handled for at least 2 days before the initiation of experiments. All animal experiments were carried out in accordance with the National Institute of
Systemic DOI administration: effects of systemic xylamidine on DOI-elicited behaviors
DOI (0.3 μmol/kg) administration elicited 40.9±3.2 head bobs in the vehicle-pretreated group (Fig. 1, upper panel). Pretreatment with the peripheral 5-HT2A/2C receptor antagonist xylamidine had no significant effect on head bobs elicited by DOI (0.3 μmol/kg) [F(2,13)=0.9]. For example, in rabbits pretreated with xylamidine (0.2 μmol/kg), DOI elicited 43.0±2.3 head bobs. Even a 10 times higher dose of xylamidine (2.0 μmol/kg) had no significant effect on DOI-elicited head bobs (36.2±1.3)
Discussion
The major finding of this study is that 5-HT2A and 5-HT2C receptors mediating separate motor movements have divergent underlying neuronal circuitry localized to different brain regions. 5-HT2A receptors mediating head movements are located centrally in areas accessible to lateral ventricle infusions. In contrast, 5-HT2C receptors mediating the body movements appear to be located in the brain and the periphery. In contrast to the 5-HT2A receptors mediating the head bobs, 5-HT2C receptor
Acknowledgments
This research was supported by USPHS Grant No. MH16841 from the National Institute for Mental Health. The authors also thank Dr. Anthony G. Romano and Dr. Kenny J. Simansky for their thoughtful suggestions and advice during the course of these experiments.
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