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The Journal of Neuroscience, September 10, 2008, 28(37):9092-9100; doi:10.1523/JNEUROSCI.1001-08.2008

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Cellular/Molecular
Mechanism and Time Course of Cocaine-Induced Long-Term Potentiation in the Ventral Tegmental Area

Emanuela Argilli,^1,2 David R. Sibley,³ Robert C. Malenka,⁴ Pamela M. England,^5,6 and Antonello Bonci^1,2

¹Ernest Gallo Clinic and Research Center and ²Department of Neurology, University of California, San Francisco, Emeryville, California 94608, ³Molecular Neuropharmacology Section, National Institute on Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, ⁴Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California 94304, and Departments of ⁵Pharmaceutical Chemistry and ⁶Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94158

Correspondence should be addressed to Dr. Antonello Bonci, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: antonello.bonci{at}ucsf.edu

Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activity-dependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D₅ receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaine-induced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spike-timing-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocaine in vivo or in vitro.

Key words: cocaine; dopamine; glutamate receptor; long-term potentiation (LTP); patch clamp; ventral tegmental area

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Received March 6, 2008; revised July 29, 2008; accepted Aug. 1, 2008.

Correspondence should be addressed to Dr. Antonello Bonci, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: antonello.bonci{at}ucsf.edu

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