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Methylphenidate facilitates learning-induced amygdala plasticity

Abstract

Although methylphenidate (Ritalin) has been used therapeutically for nearly 60 years, the mechanisms by which it acutely modifies behavioral performance are poorly understood. Here we combined intra–lateral amygdala in vivo pharmacology and ex vivo electrophysiology to show that acute administration of methylphenidate, as well as a selective dopamine transporter inhibitor, facilitated learning-induced strengthening of cortico-amygdala synapses through a postsynaptic increase in AMPA receptor–mediated currents, relative to those in saline-treated rats. Furthermore, local administration of methylphenidate in the lateral amygdala enhanced cue-reward learning through dopamine D1 receptor–dependent mechanisms and suppressed task-irrelevant behavior through D2 receptor–dependent mechanisms. These findings reveal critical and distinct roles for dopamine receptor subtypes in mediating methylphenidate-induced enhancements of neural transmission and learning performance.

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Figure 1: MPH enhances task performance by altering different aspects of behavior through distinct D1 and D2 receptor–dependent mechanisms.
Figure 2: Intra-LA NXT before training enhances memory retention but not acute task performance.
Figure 3: Inhibition of the dopamine transporter gates cortico-amygdala synaptic potentiation.
Figure 4: Dopamine modulates learning-induced increases in mEPSC amplitude but not frequency.
Figure 5: D1R antagonism in the lateral amygdala attenuates learning-induced synaptic changes.
Figure 6: Dopamine signaling in the amygdala is necessary for mediating enhancements of learning performance induced by systemic administration of MPH.

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Acknowledgements

We thank H.L. Fields, G.D. Stuber, J.A. Rosenkranz and E.E. Steinberg for helpful comments; and A.C. Hollowell, S.L. Cho, S.J. Chang, L. Wang and F.W. Hopf for technical assistance. This research was supported by the State of California for Medical Research on Alcohol and Substance Abuse through the University of California at San Francisco (A.B. and P.H.J.), NIDA DA15096-01 (A.B.) and a Massachusetts Institute of Technology Peter J. Eloranta Summer Undergraduate Research Fellowship (L.D.T.).

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K.M.T. supervised experiments and performed all whole-cell recordings. K.M.T., A.B. and P.H.J. contributed to study design, results analysis, interpretation and manuscript writing. K.M.T., L.D.T., J.J.C. and E.F.H. surgically implanted guide cannulae, performed intra-LA drug infusions, conducted behavioral experiments, sectioned acute slice preparations and performed data entry and analyses. A.B. and P.H.J. provided mentorship and resources.

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Correspondence to Patricia H Janak or Antonello Bonci.

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The authors declare no competing financial interests.

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Tye, K., Tye, L., Cone, J. et al. Methylphenidate facilitates learning-induced amygdala plasticity. Nat Neurosci 13, 475–481 (2010). https://doi.org/10.1038/nn.2506

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