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

Abstract

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, provide a new method for manipulating DA transmission in Parkinson’s disease, nicotine dependence, or attention deficit hyperactivity disorder.

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…On the behavioral level, KI animals were hyperactive both in the home cage and when introduced to a novel environment, consistent with increased DA release. 132 Taken together, these observation point to specific involvement of the a6* receptor in regulation of DA release.…”

“…30,132,226 Genetic support for the involvement of the CHRNA6-CHRNB3 cluster in ND has been reported in one GWAS and a large (B300) candidategene association study on the same sample, 76,78 and by several other candidate-gene studies analyzing ND and other smoking-related phenotypes. 90,108,109 Data from KO mice are supplementary: chrna6 KO nicotine-naive mice do not display self-administration of nicotine (in contrast to WT), but when the chrna6 gene is re-expressed in the a6À/À VTA, the reinforcement property of nicotine is restored.…”

“…131 Knock in (KI) and knock out (KO) mutations in nAChR genes provide a useful research tool to evaluate the particular contribution of specific receptor subunits to ND susceptibility, including modulation of dopaminergic transmission by the cholinergic system. 131,132 Recently, several review papers have addressed physiological and behavioral phenotypes relevant to ND of nAChR gene manipulation in mice. 77,131,133 In this short section and the companion table (Table 4), we will briefly highlight some of the findings most relevant to the current discussion but not describe them in detail.…”

“…145 This important study confirms that CHRNA6 and CHRNA4 (as well as CHRNB2) expression in the VTA is both necessary and sufficient for self-administration of nicotine. 145 Drenan et al 132 used genetically manipulated a6-nicotine-hypersensitive mice (substitution of Leu with Ser on the 9 0 residue in the M2 domain) to show the role of this subunit in modulating DA transmission. The hypersensitive a6-mice showed increased DA neuron firing in the VTA compared with WT.…”

A review of experimental techniques used for the heterologous expression of nicotinic acetylcholine receptors

“…Knockin mouse models that contain a gain-of-function mutation in the 9' position of the M2 domain include those for nAChR subunits α4 [130,131], α6 [132], α7 [133] and α9 [134]. Transgenic approaches have also been used to study mutations associated with congenital myasthenic syndromes (in the α1, δ and ε subunit) [135,136] and mutations associated with nocturnal frontal lobe epilepsy (in the α4 subunit) [137][138][139].…”