Effects of the H₃-receptor inverse agonist thioperamide on the psychomotor effects induced by acutely and repeatedly given cocaine in C57BL/6J mice

Abstract

Previous studies have shown that histamine H₃ blockers potentiate the psychomotor and rewarding effects of cocaine. The present study examined the influence of thioperamide, an inverse H₃ receptor agonist, on the development of psychomotor sensitization and stereotyped activity induced by acute or intermittent cocaine in C57BL/6J mice. In the first experiment, mice were injected i.p. with saline, 10 or 20 mg/kg thioperamide and saline or 8 mg/kg cocaine, 10 min apart, before being tested for their locomotor activity (providing data on the acute effects of thioperamide on cocaine-induced activity). Subsequently, mice were treated in the same manner every other day over six additional sessions. Sensitization was assessed by the responsiveness to a cocaine challenge (8 mg/kg, i.p.) given 2 and 14 days following the intermittent treatment. In experiments 2 and 3, we tested the effects of thioperamide (10 or 20 mg/kg, i.p.) on gnawing and sniffing induced or affected by relatively high doses of cocaine (24 or 32 mg/kg, s.c.), the drugs being given 10 min apart. In the first experiment, both doses of thioperamide amplified cocaine-induced psychomotor hyperactivity almost on all experimental sessions. However, the histamine inverse agonist did not affect the induction of a psychomotor sensitization. All cocaine-treated mice showed similar levels of sensitized activity 2 and 14 days after the intermittent treatments, whether they received thioperamide or not. The second and the third experiments showed that thioperamide did not affect gnawing and sniffing induced by cocaine. Taken together, these results indicate that H₃ receptors clearly contribute to the neurobiological mechanisms of the locomotor component of cocaine-induced psychomotor activation, but less likely to those underlying the development of cocaine behavioral sensitization or the expression of cocaine-induced oro-facial stereotypies.

Introduction

Histamine neurons originate exclusively from the tuberomamillary nucleus (TMN) of the hypothalamus and project to the entire brain. To date, three types of histamine receptors have been identified in the brain: the H₁, H₂ and H₃ receptors. H₁ and H₂ receptors are mainly located postsynaptically and their activation leads to excitatory effects. The H₃ receptors were initially described as presynaptic autoreceptors located on histaminergic neurons, where they play a negative feedback role on histamine synthesis and release (Haas and Panula, 2003, Leurs et al., 2005). However, they are also widely distributed on non-histaminergic neurons. For example, H₃ receptors on dopaminergic and glutamatergic neurons operate as heteroreceptors inhibiting the release of dopamine and glutamate in the striatum (Schlicker et al., 1993, Molina-Hernandez et al., 2000, Molina-Hernandez et al., 2001). Histamine H₃ receptors are believed to be involved in many biological functions, such as circadian rhythms and sleep (Monti et al., 1991), antinociception (Malmberg-Aiello et al., 1994), water and food consumption (Clapham and Kilpatrick, 1993, Attoub et al., 2001) and learning and memory (Brown et al., 2001, Haas and Panula, 2003). Although the available results are conflicting, there is also growing evidence suggesting a role for histamine H₃ receptors in the behavioral effects of abused drugs. Consistently, a very high density of H₃ receptors has been found in the striatum and the nucleus accumbens, which are known to play a major role in the brain mechanisms of drug psychomotor and addictive effects (Pollard et al., 1993).

Consistent with the high distribution of H₃ receptors in the striatum, there is evidence that the blockade of H₃ receptors can increase the neurochemical and behavioral effects of several psychomotor stimulants. For example, in vivo microdialysis studies show that the H₃ receptor inverse agonist thioperamide increases dopamine release in the rat ventral striatum in the presence of methamphetamine or cocaine (Munzar et al., 2004, Hyytiä et al., 2003). Additionally, thioperamide amplifies the subjective effects of methamphetamine and cocaine in rats trained to discriminate the subjective effects of these psychostimulants from those of saline using a drug-discrimination procedure (Mori et al., 2002, Munzar et al., 1998, Munzar et al., 2004). The reinforcing effects of methamphetamine and cocaine can also be increased by H₃ receptors inverse agonists/antagonists. For example, thioperamide and clobenpropit, another H₃ antagonist, readily promote the intravenous self-administration of a low dose of methamphetamine (0.03 mg/kg) that was not self-administrated alone in rats (Munzar et al., 2004). Comparable results are available with cocaine self-administration in rats (Hyytiä et al., 2003) or with cocaine inducing a conditioned place preference in mice (Brabant et al., 2005). In contrast to these rewarding effects, H₃ receptor inverse agonists seem to exert opposite effects on hyperactivity induced by cocaine and other psychostimulants. Whereas thioperamide has been reported to enhance cocaine-induced locomotion in rats (Hyytiä et al., 2003) and mice (Brabant et al., 2005), it decreases the stimulant effects of amphetamine in mice (Clapham and Kilpatrick, 1994). Moreover, other potent H₃ receptor inverse agonists, such as ciproxifan and ABT-239, have been found to attenuate methamphetamine-induced psychomotor hyperactivity (Morisset et al., 2002, Fox et al., 2005). The modulation of H₃ receptor activity was also shown to alter the oro-facial stereotypies induced by apomorphine (Farzin and Attarzadeh, 2000). Whereas thioperamide potentiated apomorphine-induced licking stereotypies, the H₃ receptor agonist imetit induced the opposite effect. However, it remains unknown whether H₃ receptors are involved in the stereotypies induced by other stimulants and in particular by cocaine. Although the studies reported above indicated that the H₃ receptor activity modulates a number of acute effects of psychostimulants, such as methamphetamine and cocaine, no studies have investigated the role of these receptors in the sensitization of the psychostimulant effects after repeated administration.

The aim of the present study was to investigate the involvement of H₃ receptors in the behavioral sensitization and the stereotypies induced by cocaine in C57BL/6J mice. In a first experiment, we tested the effects of thioperamide on the development of the sensitization to the locomotor effects of cocaine after repeated administrations. Results from the first session provided information on the interactive effects between thioperamide and cocaine given acutely. Several experimental data suggest distinguishing short-term sensitization observed less than 10 days post-treatment from long-term sensitization that is observed later. These studies demonstrate that distinct neuronal mechanisms are involved in the induction of short- and long-term sensitization (Vanderschuren and Kalivas, 2000 for a review). Therefore, cocaine challenges were performed 2 and 14 days after the development phase of sensitization. A second experiment was conducted to study the effect of thioperamide on cocaine-induced gnawing activity directed onto corrugated paper, a form of oro-facial stereotypy typically caused by a relatively high dose of psychomotor stimulant. A third experiment investigated the potential effect of thioperamide on (acute) cocaine-induced sniffing and grooming considered as stereotypies in environmental conditions that were inadequate for gnawing to be expressed (no appropriate target).