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4. PSYCHOPHARMACOLOGY OF DEPENDENCE FOR DIFFERENT DRUG CLASSES

has played a major role in the recent advances in cannabinoid pharma-
cology.
The endogenous ligands undergo depolarization-induced synthesis and
release from neurons and are removed from the extracellular space by a
carrier-mediated uptake process that is present in the membranes of neurons
and astrocytes (Di Marzo et al., 1998; Maccarrone et al., 1998; Di Marzo, 1999;
Piomelli et al., 1999; Hillard & Jarrahian, 2000). This is taken as evidence that
these endogenous cannabinoids behave as transmitters in the brain.
Although cannabis is widely used, the mechanisms of its euphoriant and
dependence-producing effects are largely unknown. There is a compelling
body of evidence that delta-9-THC increases dopamine activity in the
mesolimbic pathway projecting from the VTA to the nucleus accumbens, a
key region in the development of dependence (see Chapter 3). In vivo studies
have shown that delta-9-THC increases extracellular concentrations of
dopamine in the nucleus accumbens (Chen et al., 1990). More recently, it
has been shown by brain microdialysis that delta-9-THC increases
extracellular dopamine concentration preferentially in the shell of the nucleus
accumbens, similar to the action of many psychoactive substances (Tanda,
Pontieri & Di Chiara, 1997). Systemic administration of delta 9-THC or
synthetic cannabinoids also increases spontaneous firing of dopamine
neurons within the VTA (French, 1997; Gessa et al., 1998).
The brain distribution of CB1 binding sites correlates with the effects of
cannabinoids on memory, perception, motor control and anticonvulsant
effects (Ameri, 1999). CB1 receptor agonists impair cognition and memory
and alter motor function control. Thus, the cerebral cortex, hippocampus,
lateral caudate-putamen, substantia nigra, pars reticulata, globus pallidus,
entopeduncular nucleus and the molecular layer of the cerebellum are all
populated with particularly high concentrations of CB1 receptors (Pertwee,
1997). Intermediate levels of binding are found in the nucleus accumbens.
CB1 receptors are also found on pain pathways in the brain and spinal cord
and at the peripheral terminals of primary sensory neurons (Pertwee, 2001)
thus explaining the analgesic properties of cannabinoid receptor agonists.
CB1 receptors are expressed on neurons of the heart, vas deferens, urinary
bladder and small intestine (Pertwee, 1997).
The CB1 receptors located at nerve terminals (Pertwee, 1997; Ong & Mackie,

1999; Pertwee, 2001)suppress the neuronal release of transmitters that include
acetylcholine, noradrenaline, dopamine, 5-hydroxy-tryptamine, GABA,
glutamate and aspartate (Pertwee, 2001). CB2 receptors found in immune
cells, with particularly high levels in B-cells and natural killer cells (Galiegue
et al., 1995), are immunomodulatory (Molina-Holgado, Lledo & Guaza, 1997).

Tolerance and withdrawal

Tolerance rapidly develops to most effects of cannabis, cannabinoids, and
related drugs acting at the CB1 cannabinoid receptor. The development of

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