In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity α6^* Nicotinic Acetylcholine Receptors

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. α6^L9′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.