Effects of SKF-38393, a dopamine D1 receptor agonist on expression of amphetamine-induced behavioral sensitization and expression of immediate early gene arc in prefrontal cortex of rats

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Abstract

Repeated administrations of psychostimulants into rodents produce behavioral sensitization. We examined whether a dopamine D1 agonist can reverse behavioral sensitization once established by repeated amphetamine (AMP) administrations and determined the mRNA expression levels of the D1 and D2 receptors, metabotropic glutamate receptor 1 (mGluR1), and activity-regulated cytoskeleton-associated protein (arc) in rats. Rats were pretreated with six intermittent AMP injections. Following a 14-day withdrawal period, the rats were divided into six groups and treated with either SKF-38393 (SKF; dopamine D1 agonist), SCH-23390 (SCH; selective D1 antagonist), YM-09151-2 (YM; selective D2 antagonist), SKF + SCH, SKF + YM or physiological saline once daily for 5 days. Three days or 4 weeks after the reversal treatments, all the rats were rechallenged with AMP. D1 and D2 antagonist treatments produced no significant decreases in locomotor activity or stereotyped behavior rate, respectively. In the SKF treatment group, stereotyped behavior rate decreased markedly after the three-day and four-week withdrawal periods. SKF + SCH treatment inhibited the effect of SKF treatment. The rats in the other groups that received AMP with or without SKF were decapitated 1 h after treatment, and the mRNA levels of the D1 and D2 receptors, mGluR1, and arc were measured by TaqMan real-time reverse transcriptase-polymerase chain reaction (RT-PCR). AMP administration significantly increased arc level. SKF also increased arc level significantly after the first single injection and after repeated injections of AMP during the pretreatment. There was no significant difference in arc expression level between the saline and SKF treatment groups after the AMP challenge, suggesting that arc expression level is not involved in the reversal effects of SKF in AMP sensitization.

Introduction

In Japan, amphetamine (AMP) and methamphetamine (MAP) are two of the most popular drugs that are abused. Drug addiction is a major social problem. Eighty-five percent of the people who have abused these drugs for over 5 years, have psychological problems (Wada, 1990). In the USA, Rawson suggested that significant MAP problems may persist or even expand (Rawson et al, 2002). MAP users are at much higher risk of infection with HIV than opiate users. Partly because MAP enhances libido, users of the drug typically also have many more sexual partners (Gibson et al., 2002).

Repeated intermittent administrations of psychostimulants, such as AMP, MAP and cocaine, produce behavioral sensitization characterized by either a progressive enhancement in the behavioral activity induced by these drugs or an enduring behavioral hypersensitivity to these drugs after treatment in animals (Utena, 1966, Robinson and Becker, 1986, Tadokoro and Kuribara, 1986). Behavioral sensitization persists for months and is thought to represent a permanent change in the neurobiology of an organism (Kalivas and Stewart, 1991). This phenomenon can be used in developing an animal model for drug-induced psychosis and drug craving in humans (Robinson and Becker, 1986, Robinson and Berridge, 1993, Lieberman et al., 1997, Laruelle, 2000 ).

Behavioral sensitization is closely associated with dopaminergic and glutamatergic systems in the brain (Steketee, 2003, Vanderschuren and Kalivas, 2000) (for review: Steketee, 2003, Vanderschuren and Kalivas, 2000). The mesocorticolimbic dopamine system, which arises from the ventral tegmental area and innervates the nucleus accumbens among other regions, has been implicated in processes associated with drug addiction, including behavioral sensitization. Another important region is the frontal cortex, including the medial prefrontal cortex (mPFC). mPFC, defined as the cortical region that has reciprocal innervation with the mediodorsal nucleus of the thalamus, is also a terminal region of the mesocorticolimbic dopamine system. mPFC contains pyramidal glutamatergic neurons that serve as the primary output of this region. These pyramidal neurons are modulated by numerous neurotransmitter systems, including gamma aminobutyric acidergic interneurons and dopaminergic, noradrenergic, serotonergic, glutamatergic, cholinergic and peptidergic afferents. Indeed, ibotenic acid lesions in mPFC inhibit the induction of behavioral sensitization to cocaine (Li et al., 1999a, Li et al., 1999b). Damage to the dorsal prefrontal cortex caused by ibotenic acid prevents behavioral sensitization to cocaine (Pierce et al., 2000). These findings provide a rationale for examining the role of PFC in behavioral sensitization, because the changes in the interactions between the aforementioned neurotransmitter systems in this region may lead to alterations in behavioral responses. In PFC, Lu et al. (1999) have reported that metabotropic glutamate receptor 1 (mGluR1) mRNA level increased 3 days after withdrawal from five daily injections of amphetamine (5 mg/kg/day) (Lu and Wolf, 1999). Moreover, repeated exposures to cocaine (20 mg/kg) for 10 days, followed by a 14-h withdrawal period, induced marked effects on D1 and D2 dopamine receptor mRNA expression levels in PFCz (Schmidt-Mutter et al., 1999).

Li et al. (2000) reported that cocaine-induced behavioral sensitization (locomotor activity) can be reversed by a dopamine receptor agonist (Li et al., 2000) without the need for continuous medication. Additionally, there have been a number of reports on the reversal effects of D1 agonists on other psychostimulant-related behaviors and mental activities in animals and humans. D1 receptor agonists effectively suppress self-administration and seeking behaviors for cocaine. Self-administration and seeking behaviors are suppressed in rats (Barrett et al., 2004, Alleweireldt et al., 2003, Haile and Kosten, 2001, Caine et al., 1999), monkeys (Mutschler and Bergman, 2002) and humans (Haney et al., 1999) by the administration of D1 receptor agonists after subchronic treatment of cocaine abuse. Haney et al. (1999) reported that ABT-431, a selective D1 dopamine receptor agonist, produces significant dose-dependent decreases in the subjective effects of cocaine, including ratings of “high” and “stimulated”, and suppresses cocaine craving. However, pergolide, a D1/D2 dopamine receptor agonist, increased the ratings of “I want cocaine” (Haney et al., 1998). These results suggest that D1 agonists have potential utility for the treatment of cocaine abuse. To our knowledge, however, no report on the effect of D1 receptor agonists on AMP-induced behavioral sensitization has been published yet.

The long-lasting behavioral effects of psychostimulants are presumably caused by neuroplastic changes at the circuit, cellular, and molecular levels, mainly in the dopaminergic and glutamatergic systems (Nestler, 2005) (for review: Nestler, 2005). It is therefore reasonable to analyze the expression patterns of neuroplasticity-related genes to gain insight into the molecular mechanism of behavioral sensitization. The activity-regulated cytoskeleton-associated protein (arc) is suitable for this analysis, first because arc has been implicated in neuronal plasticities, such as LTP (Guzowski et al., 2000) and neuritic elongation (Ujike et al., 2002), and second because arc is up-regulated in the prefrontal cortex by the administration of psychostimulant drugs, including amphetamine (Klebaur et al., 2002), methamphetamine (Kodama et al., 1998) and cocaine (Freeman et al., 2002). The strong association of arc with neuronal plasticity is also supported by the fact that newly synthesized arc mRNA is not only transported into dendrites but also accumulates specifically at synaptic sites that have experienced strong activity (Steward et al., 1998).

On the basis of these findings, we evaluated the effects of a D1 agonist on AMP-induced behavioral sensitization (locomotor and stereotyped activities) and the mRNA expression levels of the D1 and D2 receptors, mGluR1 and arc in the prefrontal cortex of rats.

Section snippets

Animals

Male Sprague–Dawley rats, initially weighing 280 to 300 g (Charles River Laboratories, Japan), were housed individually with free access to food and water under a 12-h light/12-h dark cycle (lights on at 6:00 a.m.) and handled for 1 week before treatment was started.

Drugs

d-Amphetamine sulfate (AMP), SKF-38393 (SKF; Sigma) and SCH-23390 (SCH; Sigma) were dissolved in 0.9% physiological saline. YM-09151-2 (YM) was dissolved in 0.1 N HCl and neutralized with NaOH. All doses were calculated for the salt

Establishment of behavioral sensitization by six intermittent AMP injections

As shown in Fig. 1, repeated administrations of AMP-induced sensitization to locomotor activity [F(drug × administration) = 25.393, p < 0.001] and stereotyped activity [F(drug × administration) = 7.717, p < 0.01]. The activity counts and the rates of stereotypy at the sixth administration of AMP were significantly higher than those at the first administration. On the other hand, the repeated administrations of saline elicited no significant change in locomotor [F(drug × administration) = 0.224, NS] or

Discussion

This study demonstrated (i) that AMP-induced stereotypy is reversed by a D1 agonist, and (ii) that the reversal effect of this D1 agonist on stereotypy lasts for 4 weeks.

Acknowledgements

We thank Akira Kifune, M.D., Ph.D., Fumiaki Aoki, M.D., Ph.D. and Motoko Uchiyama for their technical assistance. YM-09151-2 was provided by Astellas Pharma Inc.

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