Endocannabinoid release from midbrain dopamine neurons: A potential substrate for cannabinoid receptor antagonist treatment of addiction Carl R. Lupica * , Arthur C. Riegel Neurophysiology Section, Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, U.S. Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA Received 16 December 2004; received in revised form 18 February 2005; accepted 9 March 2005 Abstract Substantial evidence suggests that all commonly abused drugs act upon the brain reward circuitry to ultimately increase extracellular concentrations of the neurotransmitter dopamine in the nucleus accumbens and other forebrain areas. Many drugs of abuse appear to increase dopamine levels by dramatically increase the firing and bursting rates of dopamine neurons located in the ventral mesencephalon. Recent clinical evidence in humans and behavioral evidence in animals indicate that cannabinoid receptor antagonists such as SR141716A (Rimonabant) can reduce the self-administration of, and craving for, several commonly addictive drugs. However, the mechanism of this potentially beneficial effect has not yet been identified. We propose, on the basis of recent studies in our laboratory and others, that these antagonists may act by blocking the effects of endogenously released cannabinoid molecules (endocannabinoids) that are released in an activity- and calcium-dependent manner from mesencephalic dopamine neurons. It is hypothesized that, through the antagonism of cannabinoid CB1 receptors located on inhibitory and excitatory axon terminals targeting the midbrain dopamine neurons, the effects of the endocannabinoids are occluded. The data from these studies therefore suggest that the endocannabinoid system and the CB1 receptors located in the ventral mesencephalon may play an important role in regulating drug reward processes, and that this substrate is recruited whenever dopamine neuron activity is increased. Published by Elsevier Ltd. Keywords: Drug abuse; Nucleus accumbens; Ventral tegmental area; SR141716A; Rimonabant; Marijuana; Glutamate; GABA The neurons located in the mammalian ventral midbrain that synthesize and release dopamine (DA) are implicated in a variety of neuropsychiatric and neurodegenerative diseases, as well as in the develop- ment and maintenance of compulsive drug use in humans. Virtually every abused drug increases extracel- lular DA levels in the axon terminal fields of the DA neurons whose cell bodies are located in the area of the mesencephalon known as the ventral tegmental area (VTA). The axons from these neurons course rostrally to innervate, primarily, the medial prefrontal cortex (PFC) and the ventral striatum, also known as the nucleus accumbens (NAc). This VTA DAergic pro- jection can therefore be further anatomically subdivided into both the mesocortical and mesolimbic pathways (Fig. 1A). The VTA DA neurons represent the primary source of DA in these forebrain areas, where this * Corresponding author. Tel.: C1 410 550 6565x132; fax: C1 410 550 1621. E-mail address: clupica@intra.nida.nih.gov (C.R. Lupica). 0028-3908/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.neuropharm.2005.03.016 Neuropharmacology 48 (2005) 1105e1116 www.elsevier.com/locate/neuropharm