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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

central effects sometimes described to be of clinical relevance (O´Brien,
2001).
Cannabis derivatives produce clear subjective motivational responses in
humans, leading to drug-seeking behaviour and repeated drug use. Indeed,
cannabis derivatives are the most widely used illicit drugs in the world (Adams
& Martin, 1996).
Animal studies have demonstrated that cannabinoids fulfil most of the
common features attributed to substances with reinforcing properties
(reviewed in Maldonado & Rodriguez de Fonseca, 2002). Thus, subjective
effects have been demonstrated in animals by using a large range of doses of
cannabinoids in the drug discrimination paradigm. The rewarding
characteristics of these subjective effects have also been defined in animals
by using the conditioned place preference and the intracranial self-
stimulation paradigm. Animal studies have also revealed that cannabinoids
interact with brain reward circuits and share with other psychoactive
substances some biochemical features (e.g. changes in dopamine and opioid
activity) that have been directly related to their reinforcing properties (Koob,
1992). These biochemical findings clearly support the dependence-producing
ability of cannabinoids that has been reported in humans.

Mechanism of action
Cannabinoid receptors and their endogenous ligands together constitute
what is now referred to as the ‘endocannabinoid system’. Plant-derived
cannabinoids or their synthetic analogues are classical cannabinoid receptor
agonists (reviewed in Pertwee, 1999; Reggio & Traore, 2000; Khanolkar, Palmer
& Makriyannis, 2000).
Cannabinoid compounds induce their pharmacological effects by
activating two different receptors that have been identified and cloned: the
CB-1 cannabinoid receptor, which is highly expressed in the central nervous
system (Devane et al., 1988; Matsuda et al., 1990), and the CB-2 cannabinoid
receptor, which is localized in the peripheral tissues mainly at the level of
the immune system (Munro, Thomas & Abu-Shaar, 1993). THC and its
analogues show good correlation between their affinity for these receptors
and their effects, denoting that these receptors are the targets for these
compounds. After the identification of the first cannabinoid receptor, the
search for an endogenous ligand for this receptor was started. The discovery
of the first endogenous cannabinoid (endocannabinoid) ligand took place
in 1992 when the anandamide, arachidonoyl ethanolamide, was isolated
from pig brain (Devane et al., 1992). A second type of endocannabinoid
was discovered in 1995, also a derivative of arachidonic acid (Mechoulam
et al., 1995; Sugiura et al., 1995). Recently, a third endocannabinoid ligand
has been identified (Hanus et al., 2001). The identification of these
endocannabinoid compounds and the development of potent and selective
synthetic cannabinoid agonists, as well as selective cannabinoid antagonists

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