Nociceptin inhibits acquisition of amphetamine-induced place preference and sensitization to stereotypy in rats

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Abstract

Nociceptin (also called orphanin FQ), a 17-amino-acid peptide, is the natural ligand of the nociceptin opioid peptide (NOP) receptor. This peptide shows similarities, in its structure, to opioid peptides, mainly to dynorphin A. However, unlike opioid peptides, it does not produce a conditioned place preference or aversion but inhibits rewarding effect of drugs of abuse. The present study was designed to examine the ability of nociceptin to block the acquisition of amphetamine-induced place preference, and the development of amphetamine-induced sensitization to stereotypy in rats. Our experiments indicated that repeated administration of nociceptin at increasing doses during conditioning significantly attenuated the reinforcing effect of amphetamine in conditioned place preference paradigm. Nociceptin did not change the acute effect of amphetamine-induced stereotypy but prevented the development of sensitization to stereotypy measured on the challenge day. Our results suggest the involvement of nociceptin in long-lasting neuronal adaptation after repeated amphetamine treatment.

Introduction

Repeated administration of psychostimulants (e.g. cocaine, amphetamine) results in a progressive augmentation of their stimulatory effects, a phenomenon referred to as sensitization (Kalivas and Stewart, 1991). This phenomenon, which can persist for weeks or months following the cessation of drug treatment, has been implicated in drug-craving and reinstatement of compulsive drug-seeking behavior (Robinson and Berridge, 1993). Rewarding effect of drug is thought to be associated with a feeling of “euphoria” that may also lead to compulsive drug-seeking and taking in humans. Conditioned place preference paradigm is an animal model for evaluation of the reward produced by drugs of abuse Tzschentke, 1998, Schechter and Calcagnetti, 1993, Schechter and Calcagnetti, 1998, Carr et al., 1989. Both these animal models underlay many aspects of drug addiction and craving in humans.

The rewarding and psychomotor-stimulating effects of cocaine and amphetamine seem to be associated with the increase in dopaminergic and glutamatergic transmission in mesolimbic corticostriatal pathways Wolf, 1998, Pierce and Kalivas, 1997. These neurotransmitters are also involved in the development of increased sensitivity to psychostimulants after repeated exposure to the drug (e.g. behavioral sensitization) Karler et al., 1994, Karler et al., 1995.

Our previous studies have demonstrated a suppressive effect of centrally administered nociceptin, the natural ligand of the G-protein-coupled NOP receptor on the expression of cocaine-induced conditioned place preference in rats (Kotlinska et al., 2002). Nociceptin, despite the structural similarity with dynorphin A Meunier et al., 1995, Reinscheid et al., 1995, does not bind to the opioid receptors, and its pharmacological effects are not sensitive to naloxone treatment (Jenck et al., 2000). However, in contrast to opioids, nociceptin elicits hyperalgesia rather than analgesia when administered at a supraspinal site and, furthermore, it affects feeding, learning, and memory, anxiety, and vegetative functions (for review, see Mogil and Pasternak, 2001). One aspect in which the classical opioid and NOP receptors resemble each other is that they occur presynaptically on a variety of neurons where they cause inhibition of release of a respective neurotransmitter (Schlicker and Morari, 2000).

The NOP receptors (Mollereau et al., 1994) and nociceptin-like immunoreactivity are widely distributed in the brain Anton et al., 1996, Peluso et al., 1998, particularly in areas involved in motivational and emotional behaviors. Unlike opioid peptides, nociceptin does not produce a conditioned place preference or aversion (Devine et al., 1996a) but inhibits rewarding effect of drugs of abuse Ciccocioppo et al., 2000a, Ciccocioppo et al., 2000b. The aim of present study was to investigate the influence of nociceptin on the acquisition of amphetamine-induced place preference and the acquisition of amphetamine-induced sensitization to stereotypy in rats.

Section snippets

Subjects and surgery

Male Wistar rats (220–250 g, Gorzkowska, Warszawa, Poland) were chosen as the strain sensitive to rewarding effects of drugs (Bardo et al., 1995). The animals were housed six per cage with standard food (Bacutil-Motycz, Poland) and water ad libitum. The animals were kept under a 12:12-h light–dark cycle and were adapted to the laboratory conditions for at least 1 week. The rats were handled once a day for 5 days before the beginning of the experiment. At least 5 days before the experiments, the

Effect of nociceptin on the acquisition of conditioned place preference induced by amphetamine

On the pre-conditioning test day, the rats spent significantly more time in the black compartment (>480 s) than in the white compartment (<60 s). The side preference was not statistically different between groups. The natural preferences of rats were not changed by saline injection during conditioning sessions.

The data were expressed as a score, i.e. testing minus pre-testing time (in seconds) spent in a drug-associated (white) compartment. One-way ANOVA revealed significant differences between

Discussion

The main finding of the present study is that the increasing doses of nociceptin given i.c.v. prior to systemic amphetamine administration during conditioned phase of place preference paradigm block the acquisition of amphetamine-induced place preference. Furthermore, chronic injection of nociceptin at the increasing doses, prior to the amphetamine injection, blocks amphetamine sensitization to stereotypy. Single injection of nociceptin (i.e. 5 nmol) does not change the acute

Acknowledgments

This work was supported by the grant from the Medical Academy (DS 23/02) and a grant from the Polish Committee for Scientific Research (KBN 3P04B02024).

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