Effects of pre-exposure and co-administration of the cannabinoid receptor agonist CP 55,940 on behavioral sensitization to cocaine

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Abstract

Rats given cocaine (15 mg/kg, i.p.) every second day over a 2-week period displayed a progressively greater locomotor response to the drug over days indicating behavioral sensitization. When the cannabinoid receptor agonist CP 55,940 ((−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]–trans-4-(3-hydroxypropyl)cyclohexanol) (10, 25 or 50 μg/kg) was administered under a similar regime, no such sensitization was observed. Rather, the two highest doses of CP 55,940 (25 and 50 μg/kg) caused locomotor suppression that lasted throughout administration. When rats pre-exposed 10 times to CP 55,940 were challenged with cocaine (15 mg/kg), no exaggerated locomotor response to cocaine was evident relative to non pre-exposed rats. When these rats were subsequently re-tested with CP 55,940, the cannabinoid continued to produce a dose-dependent suppression of locomotor activity. Finally, when CP 55,940 (50 μg/kg) was co-administered with cocaine, it significantly reduced the locomotor hyperactivity produced by the drug but did not block the development of behavioral sensitization. These results show that CP 55,940 does not sensitize locomotor activity with repeated administration in the same way as cocaine, and that pre-exposure or concurrent exposure to CP 55,940 does not enhance sensitivity to the subsequent behavioral effects of cocaine.

Introduction

Recent years have seen increased debate surrounding the possible health dangers resulting from cannabis use. One particular focus has been the possibility that cannabis may provide a `gateway' leading users to harder drugs such as heroin and cocaine. There is evidence that cocaine, heroin, tobacco and alcohol use is more prevalent among cannabis users than non-users (Hall et al., 1991; Miller et al., 1990; Swift et al., 1997) lending credence to the hypothesis that cannabis use may lead to enhanced vulnerability to the addictive effects of other drugs. However, the conclusions drawn from these human studies are based on correlation, rather than causation, suggesting the need for laboratory studies to allow a closer focus on possible gateway mechanisms.

Sensitization of mesolimbic dopamine efflux during repeated intermittent exposure to drugs of abuse has been recently hypothesized to be a key neural adaptation underlying the development of pathological drug craving (Robinson and Berridge, 1993). The most widely used behavioral index of such sensitization is the progressively greater locomotor activity response elicited in rats and mice to repeated administration of drugs. Such sensitization of locomotor activity has been documented to a wide range of drugs including nicotine, amphetamine, morphine, heroin, cocaine and phencyclidine (Robinson and Berridge, 1993; Stewart and Badiani, 1993). However, to our knowledge, no study has yet looked at whether similar sensitization may be obtained with cannabinoids. Thus it was an initial aim of the present study to test this hypothesis using the synthetic cannabinoid receptor agonist CP 55,940, a drug which is very similar to the main psychoactive constituent of cannabis (Δ9-tetrahydrocannabinol) in its behavioral and discriminative stimulus effects (Wiley et al., 1995) although it is approximately 30 times more potent (Gold et al., 1992; Little et al., 1988).

A further interesting phenomenon is cross-sensitization, whereby pre-exposure to one drug increases the sensitivity to the activating or rewarding effects of another (Cunningham et al., 1997; Lett, 1989; Stewart and Badiani, 1993). Using locomotor activity as a dependent variable, cross-sensitization is found between many drugs of abuse, for example, cocaine and amphetamine (Bonate et al., 1997), amphetamine and morphine (Cunningham et al., 1997; Vezina et al., 1989) or amphetamine and phencyclidine (Greenberg and Segal, 1985). Cross-sensitization constitutes one of the ways in which the gateway hypothesis might be tested with respect to cannabinoids. If pre-exposure to a cannabinoid rendered an animal hypersensitive to the activating effects of cocaine, then this would provide presumptive evidence in favor of the `gateway' claim. This hypothesis was tested in the present study by pre-exposing rats to CP 55,940 and testing their subsequent locomotor response to cocaine.

Cross-sensitization between cannabinoids and cocaine might be predicted given that the two drugs share certain key neurochemical effects. Firstly, both are found to enhance dopamine efflux in the nucleus accumbens (Gardner and Lowinson, 1991; Tanda et al., 1997), and this is a key neurochemical mechanism underlying sensitization and cross-sensitization processes (Robinson and Berridge, 1993). Secondly, a recent investigation has shown that the endogenous cannabinoid system may be intrinsically linked to cocaine reward circuitry. Thus the cannabinoid receptor antagonist SR 141716 was shown to block the acquisition of conditioned place preference to cocaine in rats (Chaperon et al., 1998).

Rather than produce cross-sensitization, some drugs may actually hinder the development of sensitization to another drug. For instance the following drugs all block the development of behavioral sensitization to cocaine; the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (Kalivas and Alesdatter, 1993; Wolf and Jeziorski, 1993), the dopamine receptor antagonist haloperidol (Mattingly et al., 1996b) and, the inhibitor of neuronal nitric oxide synthase, 7-nitroindazole (Haracz et al., 1997; Itzhak, 1997). The possibility that cannabinoids may prevent the development of behavioral sensitization to cocaine was also tested in the present study by examining whether co-administration of CP 55,940 with cocaine might inhibit behavioral sensitization.

Section snippets

Animals

All experiments involved male Lewis rats (ARC, Perth, Australia), aged between 75 and 90 days at the time of testing. The rats were group housed (eight animals per box) and were maintained on a 12-h reversed light–dark cycle (light off at 0830 h) with food and water available ad libitum. All testing occurred during the dark cycle. All rats were handled for 2 min per day on each of the 4 days prior to the start of experiments. All experiments were approved by the University of Sydney Animal Care

Habituation phase

The locomotor activity data for Experiment 1 are shown in Fig. 1. No significant differences between experimental groups (cocaine vs. saline) were found in activity over habituation days 1 and 2 (Fs<1.60).

Sensitization phase

Rats given cocaine demonstrated a clear increment in locomotor activity over days relative to saline-treated rats. A significant group by day interaction was seen when comparing activity on the first to seventh day of drug treatment across the two groups (F(1,14)=36.17, P<0.001).

Weekly probes

The

Discussion

The first important finding of the present study is that the cannabinoid receptor agonist CP 55,940 does not produce a sensitization of locomotor activity when administered under a regime that produces clear sensitization of the locomotor response to cocaine. The clear sensitization of activity to cocaine seen in the present study confirms previous findings (Camp et al., 1994; Kosten et al., 1994; Ortiz et al., 1995) and appears to be relatively long lasting since it remained at asymptotic

Conclusion

The present study provides presumptive evidence against the notion that cannabinoids act as a `gateway' towards cocaine. We do not claim that this demonstration is definitive and hope that other studies will be forthcoming on this issue. It may be important to test sensitization and cross-sensitization with other cannabinoid receptor agonists such as Δ9-tetrahydrocannabinol and anandamide, since different cannabinoids are sometimes found to have different behavioral and neural effects (McGregor

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