Mice Lacking the α4 Nicotinic Receptor Subunit Fail to Modulate Dopaminergic Neuronal Arbors and Possess Impaired Dopamine Transporter Function

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) at presynaptic sites can modulate dopaminergic synaptic transmission by regulating dopamine (DA) release and uptake. Dopaminergic transmission in nigrostriatal and mesolimbic pathways is vital for the coordination of movement and is associated with learning and behavioral reinforcement. We reported recently that the D2 DA receptor plays a central role in regulating the arbor size of substantia nigra dopaminergic neurons. Given the known effects of nAChRs on dopaminergic neurotransmission, we assessed the ability of the ␣ 4 nAChR subunit to regulate arbor size of dopaminergic neurons by comparing responses of wild-type and ␣ 4 nAChR subunit knockout [␣ 4 (Ϫ/Ϫ)] mice to long-term exposure to cocaine, amphetamine, nicotine, and haloperidol, and after substantia nigra neurotoxic lesioning. We found that dopaminergic neurons in adult drug-naive ␣ 4 (Ϫ/Ϫ) mice had significantly larger terminal arbors, and despite normal shortterm behavioral responses to drugs acting on pre-and postsynaptic D2 DA receptors, they were unable to modulate their terminal arbor in response to pharmacological manipulation or after lesioning. In addition, although synaptosome DA uptake studies showed that the interaction of the D2 DA receptor and the dopamine transporter (DAT) was preserved in ␣ 4 (Ϫ/Ϫ) mice, DAT function was found to be impaired. These findings suggest that the ␣ 4 subunit of the nAChR is an independent regulator of terminal arbor size of nigrostriatal dopaminergic neurons and that reduced functionality of presynaptic DAT may contribute to this effect by impairing DA uptake.

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…However, basal striatal DA levels were significantly greater in α4 KO mice than in WT mice [109]. An additional abnormality in dopaminergic function has been reported: α4 KO mice have reduced DA transporter function when compared to WT mice [126]. Although the similarities between β2 and α4 KO mice in response to nicotine suggest that α4β2* nAChRs are involved in the effects of nicotine on pain perception, locomotor activity, body temperature, and nicotine-induced changes in DA release, many of the phenotypes examined in β2 KO mice have yet to be tested in α4 subunit KO mice.…”

Nicotine Improves Cognitive Deficits of Dopamine Transporter Knockout Mice without Long-Term Tolerance

“…This hypothesis is suggested by the colocalization of DAT, D2, and D3 autoreceptors and some nAChRs as a4b2 receptors on midbrain neurons (Diaz et al, 2000; for reviews, see Wonnacott, 1997;Le Novere et al, 2002) and studies reporting a role of D2 DAergic receptors and a4* nAChR subunits in modulating the neuronal arbor (Parish et al, 2005).…”

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

“…147 Morphological changes in nigrostriatal dopaminergic neurons in drug-naive adult a4(À/À)-mice have been described; KO mice had significantly larger terminal arbors than WT. 148 In addition, KO mice had impaired DA transporter levels and impairment in locomotor activity in response to DA agonist and antagonist. 148 The mouse strain dependent A529 polymorphism in the a4-subunit modulates nicotine intake among different strains.…”

“…148 In addition, KO mice had impaired DA transporter levels and impairment in locomotor activity in response to DA agonist and antagonist. 148 The mouse strain dependent A529 polymorphism in the a4-subunit modulates nicotine intake among different strains. This functional polymorphism (alanine to threonine residue exchange at position 529, located in the second intracellular loop), which was shown to influence nicotine-induced 86 Rb þ efflux, plays a pivotal role in nicotine but not ethanol, consumption and preference.…”