Endocannabinoid Brain System Involvement in dopamine mechanisms of Behavioural Sensitization to psychostimulants

The paper deals with the involvement of endocannabionid brain system in dopamine mechanisms of behavioural sensitization to psychostimulants. The development and manifestation of behavioural sensitization to methamphetamine are described. Results obtained in our previous studies, showing an interaction between the endocannabinoid system and methamphetamine brain mechanisms, in the rat intravenous drug self-administration model and with qPCR CB1 mRNA expression, are discussed. Behavioural sensitization, endocannabinoid system, dopamine, methamphetamine, review Psychostimulants elicit during repeated administration behavioural sensitization, a phenomenon characterised by a gradually increasing response to the drug. It has been described that the crucial importance for reward-related effects of abused drugs is associated with dopamine; furthermore, that structures involved in development of sensitization to psychostimulants are parts of the midbrain; and finally, that dopamine D1 and D2 receptors play critical roles in the development of altered behavioural response. In addition, there is accumulated evidence suggesting that various aspects of drug dependence are regulated also by endocannabinoid system. The endocannabinoid system consists of two cannabinoid receptors (CB1, CB2), endogenous cannabinoids, and the molecules involved in the inactivation of endocannabinoids. A reciprocal crosstalk is reported between the cannabinoid CB1 and dopamine receptors, which are highly co-localized on brain neurons. This supports other findings suggesting the involvement of endocannabinoid system in dopamine mechanisms underlying behavioural sensitization to psychostimulants. This article shortly reviews the roles of dopamine and endocannabinoid system in processes of behavioural sensitization. Repeated administration of various drugs of abuse may result in an increase in behavioural response to these substances. This phenomenon is well known and described as behavioural sensitization (Robinson and Berridge 1993; Ohmori et al. 2000). Sometimes it is also called “reverse tolerance” in contrast to tolerance (a decreasing response after repeated drug administration). Behavioural sensitization is usually manifested after both repeated doses and application of a “challenge dose” administered after a certain period of withdrawal. Behavioural sensitization is believed to be caused by persistent adaptations in striatal neurotransmission associated with repeated exposure to drugs of abuse, and is thought to play an important role in certain aspects of drug addiction (Vanderschuren et al. 2001). For the development of behavioural sensitization in experimental models, intervals of drug administration are very important. Whereas tolerance occurs after continuous administration or after application of doses given in short intervals, development of sensitization is conditioned by administration of the substance in longer intervals, usually a minimum of 24 hours (Kalivas and Stewart 1991). Although behavioural sensitization in rodents has long been considered a model for the development of psychosis, recent reviews have underlined its potential importance as a model for the intensification of drug ACTA VET. BRNO 2009, 78: 491-496; doi:10.2754/avb200978030491 Address for correspondence: MVDr. Dagmar Vršková, Ph.D. Department of Pharmacology Faculty of Medicine, Masaryk University Komenského náměstí 2 662 43 Brno, Czech Republic Phone: +420 549495081 Fax: +420 549492364 E-mail: [email protected] http://www.vfu.cz/acta-vet/actavet.htm craving that characterizes addiction and promotes relapse (Robinson and Berridge 1993; Di Chiara 1995; Emmett-Oglesby 1995). Under experimental circumstances the sensitization can be elicited to behavioural effects of majority of drugs of abuse in laboratory rodents. Thus behavioural sensitization has been described for instance in relation to amphetamine (Costa et al. 2001), cocaine (Elliot 2002), MDMA (Kalivas et al. 1998), opioids (De Vries et al. 1999), cannabinoids (Cadoni et al. 2001) or nicotine (Shoaib et al. 1994). It is also well-known that an increased response to tested drug may be elicited by previous repeated administration of a drug different from the “challenge dose” of the drug tested. This phenomenon is termed cross-sensitization and it has been observed for example with tetrahydrocannabinol to morphine (Cadoni et al. 2001), heroin (Lamarque et al. 2001) or with morphine to methamphetamine (Landa et al. 2004). Thus not only behavioural sensitization (as mentioned above) but also cross-sensitization is considered to reinstate drug-seeking behaviour (De Vries et al. 2002). manifestation of behavioural sensitization The most frequent features of sensitization observed are stimulatory effects of drugs. In laboratory rodents an increase in locomotor/exploratory activities is considered as the most common symptom of behavioural sensitization. Besides this, sensitization can occur to some other types of behaviour, such as stereotypic sniffing, head movements or rearing (Laviola et al. 1999), nose rubbing (Landa et al. 2005; Landa et al. 2008) and defensive-escape activities (Votava et al. 2002). However, there also are reports on sensitization to inhibitory drug actions such as catalepsy (Lanis and Schmidt 2001) or an anti-aggressive effect during social conflict in mice after repeated administration of methamphetamine (Landa et al. 2006b). Although most research has focused on the characterization of sensitization to the behavioural effects of psychomotor stimulants in laboratory rodents, recent studies carried out on healthy human subjects, as well as drug users, suggest that behavioural sensitization also occurs in human beings (Strakowski et al. 1996; Bartlett et al. 1997). Strakowski et al. (1996) for example described behavioural sensitization after repeated administration of amphetamine in human volunteers that was manifested by increased activity and energy, elevated mood and speech rate (rate and amount). There is increasing evidence indicating that behavioural sensitization can be parcelled into two temporally defined domains, called development (or initiation) and expression (Kalivas et al. 1993). The term “development” of behavioural sensitization refers to the progressive molecular and cellular alterations that culminate in a change in the processing of environmental and pharmacological stimuli by the CNS. These alterations are transient and may not be detected after a few weeks of withdrawal (Kalivas et al. 1993). The term “expression” of behavioural sensitization is defined as enduring neural changes that arise from the process of development an that directly mediate the sensitized behavioural response (Pierce and Kalivas 1997). Various data indicate that these processes are distinct not only temporally but also anatomically. Development of behavioural sensitization to psychostimulant drugs occurs in the ventral tegmental area and substantia nigra, which are the loci of dopamine cells in the ventral midbrain that give rise to the mesocorticolimbic and nigrostriatal pathways. In contrast, the neuronal events associated with the expression are distributed among several interconnected limbic nuclei that are centred on the nucleus accumbens (Pierce and Kalivas 1997). Neuronal basis of behavioural sensitization and cross-sensitization to drugs relevant anatomical structures and neurotransmitters As can be seen from previous text, many studies indicate that behavioural sensitization has a neural basis and that the neuronal circuit important for behavioural sensitization consists 492