Research reportChanges in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine
Introduction
It is generally accepted that the endocannabinoid signalling system plays modulatory roles in the control of motor behavior, nociception, memory and learning, regulation of emesis, appetite or temperature, and brain development [20], [24], [51], [64]. Recent evidence has also attributed to this system a novel role in brain reward processes [2], [12], [17], [32], [38], [41], [43], [66]. This argument has been used to explain why the chronic consumption of plant-derived cannabinoids produces behavioral and molecular changes that might be seen as similar to the states of dependence/withdrawal from other drugs of abuse ( [13], [19], [34], [49]; for a recent review, see Ref. [28]), despite the difficulties to observe patterns of self-administration of psychoactive cannabinoids in experimental animals [40], [42], [58]. It has also been argued that compounds that increase or decrease endocannabinoid transmission may: (i) increase the vulnerability to other drugs of abuse [27], [39], [62], or (ii) attenuate drug seeking behavior or other signs of dependence/withdrawal to morphine ( [9], [38], [61]; for a recent review, see Ref. [41]), cocaine [1], [22] or alcohol [2], [11], [25], [37].
In the attempt to further explore the involvement of endocannabinoid transmission in the brain reward circuitry, several studies have addressed the possibility that chronic exposure to some of the most powerful habit-forming drugs causes changes in CB1 receptors in several brain regions, directly or indirectly related to drug reinforcement. However, such studies have produced results that were either controversial, as in the case of opiates, with authors showing increases [53] or no changes [50], [56] in cannabinoid receptors, or limited, as in the case of alcohol, where the data available have been obtained only in whole brain [3], [4]. Furthermore, no published study has investigated so far the effect of chronic treatment with cocaine or nicotine on endocannabinoid transmission. Recently, we have explored this issue by performing a comparative analysis of the changes caused by the chronic exposure to morphine, cocaine or alcohol in CB1 receptor density and mRNA expression in several rat brain regions [30], and we found that the changes were very different for each drug. Data on changes in cannabinoid receptor endogenous ligands after a chronic exposure to some of these drugs are instead scarce. In a recent preliminary report, Vigano et al. [63] have demonstrated a decrease in endocannabinoid contents in several brain regions of morphine-exposed rats. However, equivalent studies in vivo with the other habit-forming drugs have not been performed yet, whereas a rise of endocannabinoids after a chronic alcohol exposure was observed in vitro using cell cultures [5], [6]. Therefore, in the present study, we wanted to explore whether there is any similarity in the changes induced by chronic exposure to cocaine or ethanol in the contents of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in several rat brain regions. We also examined the effect of a chronic exposure to nicotine on endocannabinoid transmission, including the analysis of both endogenous ligands and CB1 receptors, since this drug was not examined in our earlier study [30]. In the three cases, we used paradigms of chronic exposure according to well-established procedures [29], [46], [59], which, together with opiates, are among the more highly consumed drugs by humans and also those more frequently combined with marihuana.
Section snippets
Animals, treatments and sampling
Male Wistar rats were housed in a room with controlled photoperiod (08:00–20:00 h light) and temperature (23±1 °C). They had free access to standard food and water and were used at adult age (3 months old; 250–300 g weight) for three different experiments, all conducted according to European rules (directive 86/609/EEC). In the experiment I, rats were injected i.p., twice daily (08:00 h and 20:00 h), with a dose of 15 mg/kg weight of cocaine (kindly provided by the ‘Servicio de Restricción de
Results
In this study, we measured endocannabinoid levels in several rat brain regions with a well established isotope-dilution GC–MS procedure [15], [26]. Although it is possible in principle that the derivatization procedure may affect artefactually the levels of endocannabinoids, it is worthwhile noting that the amounts found in the present study were not too dissimilar from those found in some previous studies from our group using a technique similar to that used here [8], as well as from the
Discussion
The hypothesis that the endocannabinoid system plays a modulatory role in reward circuitry [2], [12], [32], [38], [41], [43], [66] would be compatible with the possible observation of similar effects on endocannabinoid transmission (at least in those regions directly or indirectly related to reinforcement processes) after a prolonged exposure to different habit-forming drugs, and despite the differences in the molecular processes activated by each of these drugs. This has been previously
Acknowledgements
This work has been supported by grants from CICYT (PM99-0056), ‘Plan Nacional sobre Drogas’ and Agencia Antidroga de la CAM (Madrid, Spain), and MURST (grants 3933 and Fondi Strutturali). The authors are indebted to the ‘Servicio de Restricción de Estupefacientes, Agencia Española del Medicamento, Ministerio de Sanidad’ (Madrid, Spain) for kindly providing cocaine. Sara González is a predoctoral fellow supported by the ‘Plan Nacional sobre Drogas’.
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These authors contributed equally to this work.