Alterations in the level of OFQ/N-IR in rat brain regions by cocaine

Abstract

We have previously shown that administration of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, into the lateral ventricles or VTA blocked cocaine sensitization. In the present study, we determined the effect of acute and chronic cocaine treatment on the level of endogenous OFQ/N in rat brain regions. Male Sprague Dawley rats were tested for motor activity in response to saline or cocaine (20 mg/kg) injection once daily for three consecutive days. To determine the effect of single or repeated cocaine administration on the level of OFQ/N, rats were sacrificed 1 h following saline or cocaine injection either on day 1 or 3, respectively. Additional groups of rats were treated similarly with saline or cocaine on days 1–3 and sacrificed or tested for locomotor sensitization on day 8. Consistent with previous studies, repeated cocaine administration induced locomotor sensitization to a challenge dose of cocaine (7.5 mg/kg) given on day 8. Measurements of tissue content of OFQ/N-IR using radioimmunoassay indicated that the rat hypothalamus and striatum, respectively, contained the highest and lowest levels of the peptide among the brain regions tested. Acute cocaine decreased the level of OFQ-IR in the rat midbrain and to a lesser extent in the striatum. On the other hand, the level of OFQ/N was higher in rats treated with cocaine on days 1–3 and sacrificed on day 8. These findings suggest that endogenous OFQ/N may be involved in the actions of cocaine and possibly in cocaine-induced motor stimulation and locomotor sensitization.

Introduction

Drug addiction is a chronic relapsing brain disorder that involves neuroadaptive alterations in numerous neuronal circuits leading to compulsive drug seeking and drug taking behaviors despite catastrophic consequences associated with continued drug use/abuse. Research in laboratory animals has also revealed neuroadaptions following administration of cocaine and other drugs of abuse in different brain circuits. Behavioral changes which accompany these neuroadaptive changes mimic some aspects of addictive behaviors in humans.

In rodents, repeated intermittent cocaine administration has been shown to induce a progressive and enduring increase in motor activity, a phenomenon referred to as locomotor sensitization (Kalivas and Weber, 1988, Post and Rose, 1976, Robinson and Becker, 1986, Stripling and Ellinwood, 1977). This phenomenon is thought to play an important role in the development and maintenance of drug dependency through an increase in drug “wanting” upon repeated administration such that the urge to take the drug becomes irresistible, i.e., drug craving. Thus, behavioral sensitization is considered as an animal model of some aspects of addiction, particularly craving (Robinson and Berridge, 1993, Robinson and Berridge, 2000).

The phenomenon of behavioral sensitization is believed to be due to numerous changes that occur along the mesolimbic dopaminergic neurons following repeated drug administration (Anderson and Pierce, 2005, Everitt and Wolf, 2002, Vanderschuren and Kalivas, 2000, White and Kalivas, 1998, Woolverton and Johnson, 1992). In particular, changes in the dynamics of dopaminergic neurotransmission, and dopamine receptor number and signaling have been reported (Kalivas and Duffy, 1990, Pierce and Kalivas, 1995, Pierce et al., 1995, Zahniser et al., 1988, Anderson and Pierce, 2005). Furthermore, alterations in the function of the guanine regulatory binding proteins have been implicated in the phenomenon of sensitization (Cunningham and Kelley, 1993, Hummel and Unterwald, 2003, Nestler et al., 1990). Hyperactivity of the glutamatergic system is another hallmark of behavioral sensitization (for reviews, see Carlezon and Nestler, 2002, Everitt and Wolf, 2002, Vanderschuren and Kalivas, 2000). Recent evidence has also implicated protein kinase A (for review, see Anderson and Pierce, 2005) as well as extracellular signal-regulated kinase (for review, see Girault et al., 2007) in the phenomenon of locomotor sensitization.

The endogenous opioid system has long been known to modulate the function of the mesolimbic dopaminergic neurons. Thus, while mu and delta receptor agonists increase, kappa receptor agonists decrease the function of the mesolimbic dopaminergic neurons (Di Chiara and Imperato, 1988, Herz, 1997). The endogenous opioid system may also be involved in the phenomenon of locomotor sensitization. For example, drugs that block the mu and delta opioid receptors (Hummel et al., 2004, Hummel et al., 2006, Kim et al., 1997, Schroeder et al., 2007) or activate the kappa opioid receptor (for review, see Shippenberg and Rea, 1997) have been shown to attenuate the development of psychostimulant-induced locomotor sensitization. Repeated intermittent cocaine treatment has also been shown to modify the level of endogenous opioid peptides (Hurd and Herkenham, 1992, Hurd et al., 1992, Hurd et al., 1999, Hurd, 1996, Sivam, 1989) and receptors (Hammer, 1989, Izenwasser et al., 1996, Unterwald et al., 1994).

In 1994, several laboratories cloned a receptor that showed approximately 65% homology to the classical (mu, delta and kappa) opioid receptors (Bunzow et al., 1994, Chen et al., 1994, Fukuda et al., 1994, Hammer, 1989, Mollereau et al., 1994). This receptor was termed as the opioid receptor-like (ORL-1) receptor. A year later, two independent laboratories isolated orphanin FQ/nociceptin (OFQ/N) as the endogenous ligand of the ORL-1 receptor (Meunier et al., 1995, Reinscheid et al., 1995). OFQ/N, a 17 amino acid peptide, is structurally similar to the endogenous opioid peptides, in particular to dynorphin A (1–17) (Julius, 1995, Meunier et al., 1995). However, OFQ/N does not display appreciable affinity for the classical opioid receptors and the endogenous opioid peptides do not bind to the ORL-1 receptor. Thus, the endogenous OFQ/N/ORL-1 receptor system has its unique pharmacology.

The OFQ/N/ORL-1 receptor system regulates the function of the mesolimbic dopaminergic neurons and attenuates the rewarding and addictive effects of abused drugs. Thus, intracerebroventricular OFQ/N administration has been reported to attenuate elevations in accumbal dopamine induced by morphine (Di Giannuario et al., 1999) or cocaine (Lutfy et al., 2001). Furthermore, OFQ/N has been shown to block the development of behavioral sensitization (Lutfy et al., 2002), raising the possibility that the endogenous OFQ/N/ORL-1 receptor system may be involved in the phenomenon of locomotor sensitization. Thus, the present study was designed to determine whether repeated cocaine treatment that induces locomotor sensitization would alter the level of endogenous OFQ/N in various brain regions in rats. We also determined the effect of acute cocaine on the level of OFQ/N-immunoreactivity (OFQ/N-IR) in rat brain regions.