Reinstatement of nicotine-conditioned place preference by drug priming: Effects of calcium channel antagonists

Abstract

Reinstatement of drug-seeking behaviour in animals is relevant to drug relapse in humans. In the present study, we used the conditioned place preference paradigm to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, the reinstatement of place conditioning was investigated. For this purpose, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs renewed a marked preference for the compartment previously paired with nicotine. In the second step, we examined the influence of the calcium channel antagonists, nimodipine (10 and 20 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine-conditioned place preference induced by priming doses of nicotine and morphine. It was shown that the calcium channel blockers dose dependently attenuated the reinstatement of nicotine place preference induced by both drugs. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in nicotine- and morphine-induced reinstatement. Finally, the conditioned place preference paradigm appears to be a useful tool for studies of the relapse of drug-seeking behaviour in laboratory animals.

Introduction

Relapse to drug use after a long period of abstinence is a common problem of drug users (Fiore, 2000). Several factors seem to be associated with relapse, including exposure to drug-associated cues, stress, negative affect and withdrawal symptoms (Brigham et al., 1990, Kassel et al., 2003). Many detoxified drug abusers report that they relapse due to craving induced by the environment that was previously associated with drug taking. Others report that relapse is followed by exposure to the previously abused drug (Shelton et al., 2004). High rates of relapse are also characteristic for people trying to quit tobacco smoking. It is estimated that 85–100% of smokers that ever experience a smoking lapse will eventually relapse to regular smoking (Kenford et al., 1994). It has been already documented that nicotine, an alkaloid present in tobacco, is responsible for pharmacological actions of smoking and for its addictive effects, including drug-seeking and relapse.

In animal models, the relapse to drug taking can be investigated in drug self-administration studies and with the place preference paradigm using the reinstatement procedure. In the first model, laboratory animals are initially trained to self-administer drugs by pressing a lever for drug infusion in operant conditioning chambers. Then, the drug-reinforced behaviour is extinguished by substituting the drug solution with saline or by disconnection of the infusion pump. After extinction of the drug-reinforced behaviour, an acute exposure to drug (non-contingent injection, priming dose) or non-drug stimuli (previously associated with the self-administered drug) reinstates drug-seeking behaviour (Stretch et al., 1971). This effect has been described for a number of drugs of abuse, such as alcohol (Le et al., 1998), cocaine (de Wit and Stewart, 1981), heroin (De Vries et al., 1998, de Wit and Stewart, 1983) and nicotine (Shaham et al., 1997). The second procedure, conditioned place preference, is a simple non-invasive method, compatible with classical Pavlovian conditioning (Itzhak and Martin, 2002). In this paradigm, animals are initially trained to associate one distinctive environment with drug injection and a different environment with vehicle injection. Following training, animals spend more time in the drug-paired environment, when given a choice between the two environments on a drug-free test day. This acquired preference can be extinguished by daily injections of saline (alternatively, the days without any injections) with free access to both drug-paired and saline-paired environments. It was found that after extinction, injection of a drug of abuse (priming dose) reinstated the extinguished place preference, increasing the attractiveness of the environment previously paired with this drug (Mueller and Stewart, 2000, Parker and McDonald, 2000). This animal model has been used to measure the appetitive value of different stimuli as well as to evaluate relapse to abuse of drugs, such as cocaine (Mueller and Stewart, 2000), opiates (Parker and McDonald, 2000), alcohol and amphetamine (see review of Tzschentke, 1998). Several animal studies have also demonstrated that drugs other than those previously received can reinstate drug-seeking behaviour. This phenomenon, termed cross-reinstatement, has been already described using drugs from different classes. For instance, amphetamine may reinstate responding in heroin-trained animals, whereas morphine infusion into the ventral tegmental area or heroin into the nucleus accumbens reinstates cocaine-seeking behaviour (Stewart, 1984, Pierce and Kalivas, 1997).

A large body of evidence indicates the participation of dopaminergic transmission in the reinforcing properties of drugs of abuse, including drug-seeking behaviour (Di Chiara and Imperato, 1988). The mesocorticolimbic dopaminergic system, which projects from the ventral tegmental area to the ventral striatum, especially to the nucleus accumbens, and the increase in extracellular dopamine concentration in these pathways, is thought to be a major neurobiological substrate of the addictive properties of drugs (Corrigall et al., 1992, Spanagel and Weiss, 1999). For example, amphetamine and cocaine, indirect dopamine agonists, block dopamine transporters, increasing dopamine release in this way (Seiden et al., 1993). The opioid receptor agonists enhance dopamine release in terminal regions by inhibiting GABAergic neurons in the ventral tegmental area, which provide tonic inhibition of dopamine neurons (Leone et al., 1991). Nicotine is thought to increase dopamine transmission in the nucleus accumbens by stimulating the nicotinic cholinergic receptors located on the dopaminergic neurons in this area (Corrigall et al., 1992, Dani et al., 2001, Shim et al., 2001). Although the dopaminergic system has been considered as a major neural substrate for the motivational and reinforcing properties of nicotine, there is evidence that other neurotransmitter systems, including the opioidergic system, might be also involved in its behavioural effects (Isola et al., 2002).

Although the conditioned place preference paradigm has been extensively used to examine the reinstatement of cocaine, amphetamine, morphine or alcohol, relatively few studies have examined reinstatement of nicotine place conditioning. The present experiments were undertaken to establish a model of nicotine reinstatement in rats. We used the nicotine-conditioned place preference procedure evaluated in our previous studies (Biala, 2003). In a set of our experiments, nicotine place preference, once acquired, was extinguished by repeated test trials in a few successive days. Afterwards, in an attempt to reinstate nicotine-conditioned place preference, the animals were given a priming dose of nicotine. Based on the finding that similar neural substrates are involved in the rewarding effects of nicotine and morphine (Biala and Weglinska, 2004, Di Chiara, 2000), we also evaluated cross-reinstatement between nicotine and morphine. For this purpose, we examined the ability of a priming dose of morphine to reinstate extinguished nicotine place preference. Furthermore, in accordance with previous studies suggesting the participation of calcium ions and calcium channels in several aspects of drug reward and addiction (Biala and Langwinski, 1996), we investigated the influence of calcium channel antagonists on the reinstatement of nicotine-conditioned place preference provoked by a priming dose of nicotine or morphine. In this experiment, two representative L-type voltage dependent calcium channel antagonists, flunarizine and nimodipine, which are characterized by their high lipophility and central effects, were used. All these experiments were undertaken to study the neurobiological mechanisms underlying relapse to nicotine taking.