ADDICTION Stress and Drugs and Midbrain Synapses

Different drugs of abuse act on different molecular targets and mediate distinct effects on physiology and behavior. All of the classes of addictive substances, however, have a common effect of increasing dopamine release from a group of neurons whose cell bodies are in a region of the midbrain called the ventral tegmental area. This suggests that activation of these neurons may be involved in the mechanisms underlying addiction. Cocaine produces long-term potentiation (LTP)-like increases in excitatory synaptic transmission to midbrain dopaminergic neurons. Saal et al. examined the effects of different classes of addictive drugs with distinct molecular mechanisms, as well as the effects of stress, which can facilitate addiction and elicit relapse, to see if they produced similar changes. The authors measured the ratio of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated synaptic currents to N-methyl-D-aspartate (NMDA)-receptor mediated currents as a marker of LTP, using whole-cell recording from dopaminergic neurons in slices of mouse midbrain 24 hours after in vivo drug exposure. Cocaine, amphetamine, morphine, nicotine, and ethanol all increased the AMPA receptor to NMDA receptor excitatory post-synaptic potential (EPSP) ratio, whereas fluoxetine and carbemazepine, psychoactive drugs that are not addictive, did not. Acute stress, caused by a swim in cold water, elicited an even greater increase in the AMPA receptor to NMDA receptor EPSP ratio than did the drugs of abuse. The effects of stress on potentiation of glutamatergic transmission, but not those of cocaine, were blocked by a glucocorticoid antagonist, indicating that cocaine's effects were not mediated through a stress response. See the Perspective by Kauer.

D. Saal, Y. Dong, A. Bonci, R. C. Malenka, Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37, 577-582 (2003). [Online Journal]

J. A. Kauer, Addictive drugs and stress trigger a common change at VTA synapses, Neuron 37, 449-450 (2003). [Online Journal]