Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology

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Science  06 Feb 2015:
Vol. 347, Issue 6222, pp. 659-664
DOI: 10.1126/science.1260776

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Reversing cocaine-evoked behavior in mice

Therapeutic optogenetic protocols are highly effective at reversing symptoms in animal models of neuropsychiatric disease. However, translating these protocols into the clinic is challenging because we have not yet made the technical leap required to perform effective optogenetic stimulation in primates. Creed et al. tested whether it would be possible to circumvent these challenges by avoiding the problem altogether. They adjusted an existing therapeutic approach—deep brain stimulation—to mimic an effective optogenetic stimulation protocol to treat a mouse model of cocaine addiction.

Science, this issue p. 659


Circuit remodeling driven by pathological forms of synaptic plasticity underlies several psychiatric diseases, including addiction. Deep brain stimulation (DBS) has been applied to treat a number of neurological and psychiatric conditions, although its effects are transient and mediated by largely unknown mechanisms. Recently, optogenetic protocols that restore normal transmission at identified synapses in mice have provided proof of the idea that cocaine-adaptive behavior can be reversed in vivo. The most efficient protocol relies on the activation of metabotropic glutamate receptors, mGluRs, which depotentiates excitatory synaptic inputs onto dopamine D1 receptor medium-sized spiny neurons and normalizes drug-adaptive behavior. We discovered that acute low-frequency DBS, refined by selective blockade of dopamine D1 receptors, mimics optogenetic mGluR-dependent normalization of synaptic transmission. Consequently, there was a long-lasting abolishment of behavioral sensitization.

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