Induction of Fos proteins in regions of the nucleus accumbens and ventrolateral striatum correlates with catalepsy and stereotypic behaviours induced by morphine

Abstract

A history of intermittent exposures to drugs of abuse can cause long-term changes in acute behavioural responses to a subsequent drug exposure. In drug-naive rats, morphine can elicit intermittent cataleptic postures followed by sustained increases in locomotor activity. Chronic intermittent morphine treatment can reduce catalepsy and increase locomotor behaviour and stereotypy induced by morphine, even after prolonged periods of abstinence. The nucleus accumbens and limbic basal ganglia circuitry are implicated in the expression of various morphine-induced motor behaviours and catalepsy. We examined the effect of intermittent morphine exposure on the distribution of Fos proteins in the basal ganglia following a subsequent morphine challenge administered after a period of drug abstinence. We found that such exposures increased c-Fos induced by a morphine challenge in accumbens core regions that were immunoreactive for the μ-opioid receptor, and this correlated with the frequency of stereotypic behaviours displayed by the rats. We also found that a history of morphine exposures increased c-Fos in the ventrolateral striatum in response to a morphine challenge following 14 d but not 24 h of drug abstinence. In contrast, such a history induced acute Fras in the nucleus accumbens in response to a morphine challenge following 24 h but not 14 d of morphine abstinence. These data provide further confirmation that psychomotor sensitisation induced by repetitive morphine exposure involves long-term neuroadaptations in basal ganglia circuitry particularly at the level of the nucleus accumbens.

Introduction

Intermittent exposures to drugs of abuse typically cause long-term changes in the acute behavioural responses elicited by later re-exposure to the drug following a period of abstinence. The mechanisms underlying these changes have been studied extensively as not only do they contribute to drug tolerance and sensitisation, but they are also generally thought to contribute to the development and maintenance of drug addiction.

Opiates (e.g., morphine) can affect motor behaviours and locomotor activity when administered to drug-naive subjects (Bechara and van der Kooy, 1992, Leite-Morris et al., 2002, Vasko and Domino, 1978). The pattern of responding varies according to species, agonist properties and drug–dose; but most typically, an early phase of inhibition is followed by a longer period of facilitation. For example, in drug-naive rats higher doses of morphine initially inhibit locomotor activity or elicit intermittent cataleptic postures (Brown et al., 1983, De Ryck et al., 1980, Olmstead and Franklin, 1994, Wilcox et al., 1983), but this is followed by sustained increases in locomotor activity (Bechara and van der Kooy, 1992, Leite-Morris et al., 2002, Vasko and Domino, 1978). This pattern of behaviour changes when rats have previously received intermittent morphine administrations. The incidence of catalepsy is reduced (Cadoni and Di Chiara, 1999, Hand and Franklin, 1985), and opioid-induced stereotypy is facilitated (Cadoni and Di Chiara, 1999, Powell and Holtzman, 2001, Ranaldi et al., 2000, Vanderschuren et al., 2001, Vanderschuren et al., 1997, Vasko and Domino, 1978, Vezina and Stewart, 1989). Once established, these alterations in opioid-induced behaviours can be maintained for periods of many weeks or months in the absence of the drug (Powell and Holtzman, 2001).

Regulation of gene expression following opiate induction of psychomotor changes has been detected by measuring changes in the expression of Fos family transcription factors in the basal ganglia circuitry (D'Este et al., 2002, Erdtmann-Vourliotis et al., 1999, Moratalla et al., 1996, Vanderschuren et al., 2002). Two basic types of response have been reported by a majority of studies: down regulation of c-Fos, and up-regulation of ΔFosB, a stable product of FosB that accumulates in the nucleus accumbens during chronic drug administration and continues to be expressed following weeks of abstinence. On the basis of this and other evidence, Nestler and colleagues have identified induction of ΔFosB as a potential cellular mechanism that underlying the development of addictive behaviour (Nestler et al., 1999, Nestler et al., 2001).

Many studies have reported that c-Fos mRNA and protein are induced in the nucleus accumbens when drug-naïve rats are injected with morphine (Barrot et al., 1999, Bontempi and Sharp, 1997, Curran et al., 1996, D'Este et al., 2002, Garcia et al., 1995, Liu et al., 1994, Nye and Nestler, 1996, Sharp et al., 1995). Chronic morphine-pelleted rats show a progressive increase in the expression of ΔFosB in the accumbens (Nye and Nestler, 1996). Changes in c-Fos mRNA and protein have also been identified following acute morphine in drug-sensitised rats in cortex, thalamus, and dorsal striatum (Curran et al., 1996, Erdtmann-Vourliotis et al., 1999, Frankel et al., 1999). However, few studies have reported changes in the accumbens, and while D'Este et al. (2002) found that c-Fos protein was decreased in the accumbens shell in heroin-sensitised rats, Curran et al. (1996) found c-Fos mRNA was increased in the caudal accumbens in morphine-sensitised rats. On the basis of these conflicting findings, the present study has examined the effect of intermittent morphine exposure on the distribution of Fos proteins in the striatal complex when rats were later challenged with morphine after a period of drug abstinence. We found evidence of a positive correlation between morphine-induced stereotyped behaviour and numbers of c-Fos-positive neurons in specific regions of the striatum and nucleus accumbens. We also identified a population of neurons in the nucleus accumbens, which express Fos family proteins but do not express c-Fos, when morphine is administered after a short 24 h period of abstinence following previous intermittent morphine exposures.