Dynamic Interactions Between Drugs of Abuse and the Endocannabinoid System: Molecular Mechanisms and Functional Outcome
Pp. 132-163 (32)
Miriam Melis, Anna L. Muntoni and Marco Pistis
Regulation of motivated behavior toward both natural stimuli and drugs of
abuse is among functions where the endocannabinoid system is deeply engaged. In fact,
endocannabinoids and their receptors (CB1) are abundant in the limbic system and,
particularly, they serve as retrograde signaling molecules at synapses onto midbrain
dopamine (DA) neurons in the ventral tegmental area (VTA). These neurons are
involved in neural processing contributing to drug addiction and DA plays a crucial role
as learning signal, by changing the synaptic strength of neural circuits involved in
action selection to optimize goal-directed behavior.
Endocannabinoids regulate different forms of synaptic plasticity in the VTA, exert a
critical modulation of DA release and, ultimately, of the circuits within the limbic
systems driving motivated behaviors. Hence, it is not surprising that drugs of abuse,
namely alcohol, nicotine, opioids and psychostimulants exert wide arrays of effects on
the endocannabinoid system, by affecting endocannabinoid release and catabolism as
well as modulation of the functions and number of cannabinoid CB1 receptors. On the
other hand, by genetic or pharmacological manipulation of the endocannabinoid system
we can modulate neurochemical and neurophysiological effects of the drugs as well as
their behavioral actions in experimental animals predictive of their addicting properties
in humans. Accordingly, blockade of CB1 receptors was a promising therapeutic
strategy against drug addiction, although rimonabant (the only clinically tested CB1
antagonist) was withdrawn due to serious side effects such as depression and suicide.
These adverse effects though underscore the general role that the endocannabinoid
system plays in the regulation of reward and motivation. Nevertheless, other drugs are
emerging, i.e. the indirect cannabinoid agonists, which enhance endocannabinoids by
blocking their catabolism or membrane transport, that are efficacious in animal model
of relapse to drug addiction and that might prove beneficial in humans.
Endocannabinoids, anandamide, 2-arachidonoylglycerol, dopamine
neurons, synaptic plasticity, cannabinoid receptors, nicotine addiction,
rimonabant, drug addiction, opiate addiction, morphine, alcohol, cocaine,
psychostimulants, long-term synaptic plasticity, short-term synaptic plasticity,
fatty acid amide hydrolase (FAAH), reward, relapse, oleoylethanolamide.
Department of Biomedical Sciences, University of Cagliari, Monserrato (CA), Italy.