Neuron
Volume 60, Issue 1, 9 October 2008, Pages 123-136
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Article
In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity α6 Nicotinic Acetylcholine Receptors

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Summary

α6-containing (α6) nicotinic ACh receptors (nAChRs) are selectively expressed in dopamine (DA) neurons and participate in cholinergic transmission. We generated and studied mice with gain-of-function α6 nAChRs, which isolate and amplify cholinergic control of DA transmission. In contrast to gene knockouts or pharmacological blockers, which show necessity, we show that activating α6 nAChRs and DA neurons is sufficient to cause locomotor hyperactivity. α6L9′S mice are hyperactive in their home cage and fail to habituate to a novel environment. Selective activation of α6 nAChRs with low doses of nicotine, by stimulating DA but not GABA neurons, exaggerates these phenotypes and produces a hyperdopaminergic state in vivo. Experiments with additional nicotinic drugs show that altering agonist efficacy at α6 provides fine tuning of DA release and locomotor responses. α6-specific agonists or antagonists may, by targeting endogenous cholinergic mechanisms in midbrain or striatum, provide a method for manipulating DA transmission in neural disorders.

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Present address: Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA