Effects of lithium chloride on induction and expression of methylphenidate sensitization

Abstract

Repeated administration of psychomotor stimulants produces an enduring and progressively enhanced behavioral response known as behavioral sensitization, which has been implicated as a model for psychiatric disorders such as mania, schizophrenia, and drug addiction. The objective of the study was to determine whether lithium chloride (LiCl), an anti-manic agent, is effective in blocking the development and/or the expression of behavioral sensitization to methylphenidate. Male Sprague–Dawley rats (n=64) weighing 170–190 g were randomly divided into seven treatment groups. A computerized animal activity monitor system continuously recorded locomotor activity for 16 days. Effects of LiCl on induction of methylphenidate sensitization were studied by giving LiCl before or during six daily methylphenidate administrations. Effects of LiCl on the expression of methylphenidate sensitization were studied by injecting LiCl after sensitization to methylphenidate was induced. It was shown that LiCl treatment modulated the acute methylphenidate effects by transiently attenuating the locomotor response to methylphenidate during the six daily methylphenidate administrations but neither single nor multiple treatments with LiCl blocked the development or the expression of behavioral sensitization.

Introduction

Repeated intermittent administration of psychostimulants, such as cocaine, amphetamine, and methamphetamine, results in behavioral sensitization Segal and Mandell, 1974, Post and Rose, 1976, Post et al., 1984, Kalivas, 1995, Pierce and Kalivas, 1997, Sax and Strakowski, 1998, which is characterized by an increase in locomotor and/or stereotypic behaviors Robinson and Becker, 1986, Segal and Kuczenski, 1987. Behavioral sensitization also occurs with repeated intermittent administration of methylphenidate (commonly known as Ritalin) Shuster et al., 1982, Gaytan et al., 1996, Gaytan et al., 1997a, Gaytan et al., 1997b, Crawford et al., 1998, Sripada et al., 1998, a psychomotor stimulant widely used in the treatment of attention deficit/hyperactivity disorder in children and adults Goldman et al., 1998, Safer et al., 1996. Psychostimulants produce effects, such as behavioral sensitization, that are similar in some respects to the symptoms of mania and bipolar disorder in humans Smith and Davis, 1977, Cappeliez and Moore, 1990, Gessa et al., 1995. It has been shown that repeated administration of psychostimulants can induce manic states and enhance the chance of relapses in psychotic patients who are in remission Janowsky et al., 1973, Snyder, 1973, Gessa et al., 1995. Moreover, it has been suggested that repetitive use of psychostimulants changes the catecholamine system that causes behavioral sensitization and psychosis induced by psychostimulants. Changes in the level of catecholamine output by the neurons, which are associated with manic or mixed episodes, can alter illness course or treatment response by mechanisms related to behavioral sensitization Gessa et al., 1995, Robinson and Becker, 1986. Hence, behavioral sensitization is also used as a model to study bipolar disorders. Studying drugs that modulate behavioral sensitization may provide further insight on the mechanisms underlying these disorders.

Lithium chloride (LiCl) is the preferred treatment for mania and bipolar disorder Schou, 1968, Gershon and Shopsin, 1973, Prien et al., 1984, Cappeliez and Moore, 1990. Repeated treatment with LiCl has been shown to reduce the hyperactivity induced by d-amphetamine and methamphetamine Borison et al., 1978, Namina et al., 1998. Attention deficit/hyperactivity disorder patients often have other psychiatric disorders such as mania and depression (Spencer et al., 1999) for which they may take LiCl in addition to methylphenidate for attention deficit/hyperactivity disorder. Little is known about interactions between LiCl and sensitization resulted from repetitive methylphenidate treatment. In the present study, sensitization was used as a model for bipolar disorder to determine the effects of LiCl on behavioral sensitization to methylphenidate in rats. The study had two parts: the first was concerned with LiCl's ability to prevent the development of sensitization; the second was to determine whether LiCl, given after sensitization to methylphenidate was developed, prevents the expression of methylphenidate-sensitization. To test these possibilities, six different LiCl regimens were given to the rats before, during and after methylphenidate treatment.