Concomitant development of oral dyskinesia and memory deficits in reserpine-treated male and female mice

Abstract

It has been suggested that reserpine-induced oral dyskinesia in rats may provide a new animal model of tardive dyskinesia. Both cognitive deficits and gender have been associated with the development of tardive dyskinesia. The aim of the present study was to investigate the effects of reserpine administration on the development of orofacial dyskinesia and on plus-maze discriminative avoidance task (DAT—an animal model of associative learning) in male and female mice. Male and female mice received 1.0 mg/kg reserpine or saline subcutaneously on day 1. On days 3, 6 and 8, the frequency of vacuous chewing movements (VCM) was quantified. On day 6, the DAT conditioning was performed, in a modified elevated plus-maze. In one of the enclosed arms, the animals received aversive stimulation (light and noise). On day 8, a test session was performed and the time spent by the animals in each of the enclosed arms was recorded. Our results showed that reserpine-treated male and female mice presented significantly higher VCM when compared with respective control groups in all observation days. On day 6, reserpine-treated female mice presented significantly higher VCM when compared with male mice injected with this drug. The DAT test performed on day 8 showed that the time spent in the aversive arm by saline-treated mice was significantly lower than the time spent in the non-aversive arm. This difference was not observed for reserpine-treated mice. Our results demonstrate the development of reserpine-induced oral dyskinesia in both male and female mice. While this oral dyskinesia is accompanied by a cognitive deficit in both genders, female mice tended to have more severe oral dyskinesia. It is suggested that reserpine-induced oral dyskinesia may provide a quick, simple and efficient mouse model of tardive dyskinesia.

Introduction

Tardive dyskinesia is a multifaceted neurological disorder, which develops following treatment with neuroleptics. The syndrome is characterized by abnormal, involuntary, irregular, repetitive movements, usually involving mouth, face and tongue and sometimes limb and trunk musculature. It usually persists for months after the neuroleptic has been discontinued and may be irreversible [4], [14].

Recently, Neisewander et al. [17] have suggested that reserpine-induced oral dyskinesia may provide an animal model of tardive dyskinesia. Indeed, rats treated acutely or repeatedly with this monoamine-depleting agent will develop orofacial dyskinesia characterized by twitching of the facial musculature, vacuous chewing movements and tongue protrusion [15], [16], [17], [21], [22], [31], [33]. In this regard, although reserpine is not classified as a neuroleptic, it has been used as an antipsychotic agent and has been associated with the development of tardive dyskinesia [32]. This reserpine-induced oral dyskinesia in rats has also other features that are consistent with tardive dyskinesia, including persistence following termination of administration and dose dependent blockade by a D₂-selection antagonist [15], [16]. Furthermore, whereas at high doses of reserpine the response appears 3 days after a single injection of the drug [31], at low doses the response is not evident until approximately 6–8 weeks [17], consistent with the protracted development of tardive dyskinesia in humans [8]. As with tardive dyskinesia [41], reserpine-induced oral dyskinesia is exacerbated by dopamine agonists like amphetamine and is mediated by the nigrostriatal dopaminergic system [18]. Importantly, while age is one of the most frequently implicated risk factor for tardive dyskinesia, increasing both the persistence and severity of the condition [25], [41], the authors have recently verified that when compared with control adult rats, the significant increase in oral dyskinesia induced by reserpine treatment was more persistent in the old rats than in the adult animals [2].

More recently, we have extended this animal model to mice. Indeed, using vacuous chewing movements frequency (since this parameter was the most reliable measure of the dyskinesia in this species) we verified that as with rats, reserpine-induced oral dyskinesia in mice was persistent, was attenuated by both conventional and atypical neuroleptic drugs and was much more severe in old animals (submitted data).

Besides aging, cognitive impairments and gender have been shown to be related to tardive dyskinesia. Concerning cognitive impairments, studies comparing schizophrenic patients with and without tardive dyskinesia who were matched for multiple variables (such as age, gender distribution and diagnostic composition) have shown cognitive impairments as the most consistently reported measure (see [37] for review). As regards gender, it is often asserted that women have a higher prevalence of and a more severe tardive dyskinesia than do men (see [42] for a review).

The aim of the present study was to investigate cognitive performance of male and female mice presenting reserpine-induced orofacial movements. Cognitive performance was evaluated by the plus-maze discriminative avoidance task [26]. This new animal model of learning/memory also provides simultaneous information about the anxiety and motor function levels of the animals [27].