Figure 1 - Highly simplified scheme of converging acute actions of drugs of abuse on the VTA-NAc.


From the following article

Is there a common molecular pathway for addiction?

Eric J Nestler

Nature Neuroscience 8, 1445 - 1449 (2005) Published online: 26 October 2005

doi:10.1038/nn1578

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Drugs of abuse, despite diverse initial actions, produce some common effects on the VTA and NAc1, 2, 3, 4, 5, 6, 7, 8. Stimulants directly increase dopaminergic transmission in the NAc. Opiates do the same indirectly: they inhibit GABAergic interneurons in the VTA, which disinhibits VTA dopamine neurons. Opiates also directly act on opioid receptors on NAc neurons, and opioid receptors, like D2 dopamine (DA) receptors, signal via Gi; hence, the two mechanisms converge within some NAc neurons. The actions of the other drugs remain more conjectural. Nicotine seems to activate VTA dopamine neurons directly via stimulation of nicotinic cholinergic receptors on those neurons and indirectly via stimulation of its receptors on glutamatergic nerve terminals that innervate the dopamine cells. Alcohol, by promoting GABAA receptor function, may inhibit GABAergic terminals in VTA and hence disinhibit VTA dopamine neurons. It may similarly inhibit glutamatergic terminals that innervate NAc neurons. Many additional mechanisms (not shown) are proposed for alcohol. Cannabinoid mechanisms seem complex, and they involve activation of CB1 receptors (which, like D2 and opioid receptors, are Gi linked) on glutamatergic and GABAergic nerve terminals in the NAc, and on NAc neurons themselves. Phencyclidine (PCP) may act by inhibiting postsynaptic NMDA glutamate receptors in the NAc. Finally, there is some evidence that nicotine and alcohol may activate endogenous opioid pathways and that these and other drugs of abuse (such as opiates) may activate endogenous cannabinoid pathways (not shown). PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum.

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