A heroin-, but not a cocaine-expecting, self-administration state preferentially alters endogenous brain peptides

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Abstract

The purpose of the current study was to assess neuropeptidergic alterations during a phase of the drug addiction cycle associated with drug craving as compared to a time period when the drug had been recently self-administered. Male Wistar rats were allowed to self-administer cocaine, heroin or saline for 6 h for 5 consecutive days. Immediately following the last self-administration session (`acute drug on board' state), and just before the next scheduled session (`drug expecting' state), the animals were decapitated and the levels of dynorphin A and B, [Met5]- and [Leu5]-enkephalin and substance P were measured in different brain areas. During the `acute drug on board' state, peptide levels in animals that self-administered heroin or cocaine were not significantly changed. In contrast, during the `drug expecting' state, heroin-treated animals had increased levels of dynorphin A, dynorphin B and [Met5]-enkephalin in the caudal striatum as compared to the cocaine- and saline-treated animals, and the level of [Leu5]-enkephalin was increased as compared to the cocaine-treated group. In the septum, an increase of [Met5]-enkephalin and substance P was observed in the animals expecting heroin as compared to the saline- and/or cocaine-treated animals. In the caudal striatum, substance P levels were elevated in the heroin- and cocaine-expecting animals. In conclusion, heroin, as compared to cocaine, appears to have a more pronounced effect on dynorphin, enkephalin and substance P levels in the caudal striatum and septum, especially during periods when self-administration of the drug is expected.

Introduction

Previous studies have demonstrated that the endogenous opioid neuropeptide systems may be involved in the neural processes of drug addiction, not only related to the intake of opiates, but also of stimulant drugs. Chronic infusion or repeated morphine injections elevate the concentration of prodynorphin peptides in the striatum, with the most pronounced effects observed in the dorsal (sensorimotor) areas, while the concentration of proenkephalin peptides levels is not changed (Bergström and Terenius, 1979; Trujillo et al., 1995). Following intracerebroventricular (i.c.v.) administration of morphine the dynorphin A-immunoreactivity in the hypothalamus, hippocampus and striatum is unchanged after the administration of both opioid receptor agonists and antagonists, but there is down-regulation of the prodynorphin gene expression (Romualdi et al., 1991, Romualdi et al., 1995). A single injection of cocaine has been shown to have little (Hurd and Herkenham, 1992) or no effect (Daunais and McGinty, 1994) on prodynorphin gene expression. Short-term (4 days) intermittent cocaine administration, in contrast, increases dynorphin and to a lesser extent enkephalin mRNA expression in the striatum (Steiner and Gerfen, 1993): then 1–24 h following the last injection of cocaine dynorphin-immunoreactivity is increased, but enkephalin- and substance P-immunoreactivity is unchanged (Sivam, 1989; Smiley et al., 1990). The self-administration of cocaine also increases striatal prodynorphin mRNA levels (Hurd et al., 1992; Daunais et al., 1993). Chronic `binge' cocaine administration increases both μ-opioid receptor densities in a number of brain regions, such as the striatum, nucleus accumbens and amygdala (Unterwald et al., 1993), and prodynorphin mRNA expression in caudate–putamen (Daunais and McGinty, 1995). More recently, it was shown that acute `binge' cocaine administration increases both prodynorphin and proenkephalin mRNA in the caudate–putamen, whereas μ-opioid receptor mRNA decreased in the substantia nigra (Spangler et al., 1997).

Although the effects of acute and chronic drug administration have been investigated, only a few studies have addressed the potential involvement of the endogenous opioids at a moment when the `craving' for an addictive drug is expected to be enhanced. A study comparing the effects of heroin and cocaine self-administration on β-endorphin brain levels showed that animals awaiting their daily self-administration of cocaine or heroin have a marked decrease of β-endorphin-immunoreactivity in the anterior part of the limbic system, whereas immediately after a drug session this was normal in animals self-administering cocaine or heroin (Sweep et al., 1989). In the present study, the drug self-administration model was used to examine the effects of drugs of abuse on the levels of dynorphins, enkephalins and substance P in different regions of the rat brain. Heroin, an opiate inducing both psychological and physical dependence, and eliciting a withdrawal syndrome when its administration is discontinued, and cocaine, a stimulant inducing psychological but not physical dependence, were selected (Kalant, 1978). Naive animals were allowed to self-administer intravenously (i.v.) cocaine or heroin for five consecutive daily sessions lasting 6 h. Peptide levels were measured immediately following the last drug self-administration session (`acute drug on board' state) and just before the next scheduled self-administration session, i.e., 18 h following the last session (`drug expecting' state), when the `craving' for the addictive drugs was expected to be enhanced.

Section snippets

Animals and housing conditions

Male Wistar rats (Cpb: Wu) weighing 250–300 g at the start of the experiments were used. Before surgery, the animals were group-housed, had water and food ad libitum and were maintained under a 12-h light/dark cycle (lights on 7:00 AM). Following the operation, the animals were housed individually. Three days before the start of the self-administration tests (i.e., 5–7 days following the operation) all animals were brought to the experimental rooms and were deprived of food in order to obtain a

Self-administration

The number of self-infusions for the animals with saline, heroin or cocaine is shown in Fig. 1. Two-way analysis of variance revealed a significant interaction between treatment and time (five sessions) [F(4,184)=11.6, P<0.001] without a significant difference between animals studied during the `acute drug on board' or the `drug expecting' state [F(1,46)=1.5, n.s.]. In addition, a significant main treatment effect (cocaine vs. saline) [F(1,28)=38.2, P<0.001] and treatment and time interaction [F

Discussion

Peptide levels were studied immediately following the last self-administration of heroin or cocaine (referred to as the `acute drug on board' state) and just prior to the next scheduled self-administration session, when the `craving' for drugs is expected to be enhanced (referred to as the `drug expecting' state). Since the neurobiology underlying drug `craving' is still unknown and the term is not clearly defined (Markou et al., 1993; Robinson and Berridge, 1993; Altman et al., 1996), we

Acknowledgements

The authors would like to thank Dr. M.A.F.M. Gerrits for assistance during the self-administration procedure and Mrs. A. Selander for excellent technical assistance with peptide analyses. This work was supported by the Swedish Medical Research Council and the National Institute on Drug Abuse (Rockville, MD). S.L.T.C. was supported by the Catharina van Tussenbroek Stichting, Volksbond Rotterdam, and the Systembolaget Research Fund.

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