Role of central 5-HT₂ receptors in mediating head bobs and body shakes in the rabbit

Abstract

Systemic administration of the 5-HT_2A/2C agonist DOI [(1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)hydrochloride] in rabbits elicits head bobs and body shakes, which are mediated by 5-HT_2A and 5-HT_2C receptors, respectively. This study was designed to determine whether the receptors mediating these behaviors are primarily located in the brain or in the periphery. Systemic administration of the peripheral 5-HT_2A/2C antagonist xylamidine 30 min before systemic DOI challenge attenuated DOI-elicited body shakes by 50% without an effect on head bobs, suggesting a central origin for head bobs and a partial peripheral and a partial central origin for body shakes. Central administration of DOI into the lateral ventricle (ICV) elicited head bobs but not body shakes, demonstrating that the receptors mediating head bobs are centrally located. Pretreatment with ICV xylamidine blocked head bobs elicited by ICV DOI, indicating that the lack of inhibition, when systemically administered, is due to xylamidine's failure to reach central receptors. ICV pretreatment with the 5-HT_2A receptor antagonist ketanserin inhibited ICV DOI-elicited head bobs establishing that 5-HT_2A receptors activation elicits head bobs. In conclusion, 5-HT_2A receptors mediating head movements are located in the brain whereas 5-HT_2C receptors mediating the body movements appear to be located at different central sites as well as in the periphery.

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-HT_2A/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-HT_2A 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-HT_2A 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-HT_2A receptors. However, unlike the rodent, the body shakes in the rabbit are mediated by 5-HT_2C 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-HT_2A and 5-HT_2C receptors mediating the separate DOI-elicited behaviors are located in the brain or the periphery. First, systemic injections of the peripherally acting 5-HT_2A/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.