Memory impairment following combined exposure to Δ9-tetrahydrocannabinol and ethanol in rats

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Abstract

Cannabis derivatives and alcohol are widely co-abused, particularly among adolescents. Since both ethanol and cannabinoids are known to impair learning and memory, the present study investigated in rats the effects of combined exposure to ethanol and Δ9-tetrahydrocannabinol (THC) in a memory task, the object recognition test. The results of the present study provide evidence that ethanol, voluntarily ingested in alcohol-preferring rats, and THC, given by intraperitoneal injection, have a synergic action to impair object recognition, when a 15-min interval was adopted between the sample phase and the choice phase of the test. Neither voluntary ethanol ingestion nor 2 or 5 mg/kg of THC were able per se to modify object recognition in these experimental conditions, but when voluntary ethanol ingestion was combined with administration of these doses of THC object recognition was markedly impaired. THC impaired object recognition only at the dose of 10 mg/kg, when its administration was not combined with that of ethanol. The selective cannabinoid CB1 receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole carboxamide·HCl) at the dose of 1 mg/kg reversed the amnesic effect of THC, 10 mg/kg, suggesting that the effect is mediated by this receptor subtype. The synergism of ethanol and THC was not detected when an inter-trial interval of 1 min was adopted. The present findings are in keeping with the notion that Cannabis derivatives impair memory processes and provide evidence for a synergic action of THC and ethanol, thus emphasizing the risks consequent to their co-administration.

Introduction

A large body of evidence indicates that alcohol and Cannabis derivatives are widely co-abused, particularly among adolescents Patton et al., 1995, Poulin and Elliott, 1997. The combined exposure to these drugs has been shown to markedly reduce the driving skill and has been proposed to be responsible for a number of driving accidents among young drivers (Augsburger and Rivier, 1997).

It is well known that ethanol abuse is associated with cognitive impairment and loss of memory in humans Butters, 1985, Freund, 1973, as well as in experimental animal models Arendt et al., 1989, Hodges et al., 1991. Moreover, naturally occurring cannabinoids, such as Δ9-tetrahydrocannabinol (THC), endogenous cannabinoids, such as anandamide, or synthetic agonists at cannabinoid CB1 receptors have been demonstrated to impair learning and memory in humans (Croft et al., 2001), in nonhuman primates (Evans and Wenger, 1992) and in rodents Fehr et al., 1976, Stiglick and Kalant, 1983, Stiglick et al., 1984, Lichtman et al., 1995, Brodkin and Moerschbaecher, 1997, Jentsch et al., 1997, Stella et al., 1997, Mallet and Beninger, 1998, Nava et al., 2000.

These findings raise interest for the possible interactions between alcohol and cannabinoids on learning and memory processes when their consumption is combined. Thus, the present study was aimed at investigating in rats the effects of combined exposure to ethanol and THC in a memory task, the object recognition test.

The choice of this test was adopted because cannabinoids have been reported to affect the working memory in rats (Jentsch et al., 1997), and the object recognition test has been proposed to represent a “pure” working memory task, which does not involve the retention of a rule, but it is entirely based on the spontaneous exploratory behaviour of rats towards objects Ennaceur and Delacour, 1988, Ennaceur and Meliani, 1992, Scali et al., 1997, Ennaceur et al., 1997, Bartolini et al., 1996. In addition, unlike the radial maze that represents the most popular working memory test in the rat (Olton, 1987), the object recognition task does not involve the use of a positive reward (usually a small food pellet). The use of food as a reward may render difficult to interpret the results obtained in a memory test with THC, which is known to affect both reward Lepore et al., 1995, Cheer et al., 2000, Cossu et al., 2001, Braida et al., 2001 and feeding mechanisms Colombo et al., 1998, Williams et al., 1998, Giuliani et al., 2000, Koch, 2001.

Moreover, to more closely mimic the effect of the spontaneous use of these drugs, the present study was carried out using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, which voluntarily ingest pharmacologically active doses of ethanol in order to experience positive psychotropic effects of ethanol (Ciccocioppo et al., 1999a, Ciccocioppo et al., 1999b. Indeed, under the experimental conditions adopted in this study ethanol consumption by msP rats may mimic the recreational consumption of alcoholic beverages in humans.

Section snippets

Animals

Male genetically selected alcohol-preferring rats were employed in most of the experiments. They were bred in the Department of Pharmacological Sciences and Experimental Medicine of the University of Camerino (Marche, Italy) for 36–38 generations from Sardinian alcohol-preferring rats of the 13th generation, provided by the Department of Neurosciences of the University of Cagliari, Italy Agabio et al., 1996, Colombo, 1997, Lobina et al., 1997. These animals are referred to as Marchigian

One-minute inter-trial interval

Comparisons of the total time spent exploring the test objects indicated that there were no group differences for either the sample (T1) or the choice trial (T2) (P>0.05).

The overall analysis of variance of the d2 values revealed a statistically significant treatment effect [F(5, 43)=4.34; P<0.01].

In rats that did not receive access to ethanol, a statistically significant reduction of d2 values was observed in response to THC, 10 mg/kg, but not 5 mg/kg.

On the other hand, no significant effect

Discussion

The results of the present study provide evidence that ethanol, voluntarily ingested by alcohol-preferring rats, and THC have a synergistic action to impair memory in the object recognition task, when an interval of 15 min was adopted between the sample and the choice trial. In these experimental conditions, neither voluntary ethanol ingestion nor doses of 2 or 5 mg/kg of THC were able per se to modify object recognition; but when voluntary ethanol ingestion was combined with administration of

Acknowledgements

This work was supported by the University of Camerino (Fondo Ricerca Ateneo, 1999 and 2000) and from MURST (Cofin 99, Project “Cannabinoid-induced effects on cognitive functions: behavioural, biochemical and electrophysiological studies”, coordinated by Prof. G.L. Gessa). The authors wish to thank Sanofi-Synthélabo Recherche (Montpellier, France) for the generous gift of SR 141716A.

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