Developmental regulation of nicotinic acetylcholine receptors within midbrain dopamine neurons

Abstract

We have combined anatomical and functional methodologies to provide a comprehensive analysis of the properties of nicotinic acetylcholine receptors (nAChRs) on developing dopamine (DA) neurons. Double-labeling in situ hybridization was used to examine the expression of nAChR subunit mRNAs within developing midbrain DA neurons. As brain maturation progressed there was a change in the pattern of subunit mRNA expression within DA neurons, such that α3 and α4 subunits declined and α6 mRNA increased. Although there were strong similarities in subunit mRNA expression in substantia nigra (SNc) and ventral tegmental area (VTA), there was higher expression of α4 mRNA in SNc than VTA at gestational day (G)15, and of α5, α6 and β3 mRNAs during postnatal development. Using a superfusion neurotransmitter release paradigm to functionally characterize nicotine-stimulated release of [ 3 H]DA from striatal slices, the properties of the nAChRs on DA terminals were also found to change with age. Functional nAChRs were detected on striatal terminals at G18. There was a decrease in maximal release in the first postnatal week, followed by an increase in nicotine efficacy and potency during the second and third postnatal weeks. In the transition from adolescence (postnatal days (P) 30 and 40) to adulthood, there was a complex pattern of functional maturation of nAChRs in ventral, but not dorsal, striatum. In males, but not females, there were significant changes in both nicotine potency and efficacy during this developmental period. These findings suggest that nAChRs may play critical functional roles throughout DA neuronal maturation. Keywords adolescent; fetal; nicotine; sex; striatum; maternal smoking Maternal smoking during pregnancy has been correlated with a number of adverse outcomes in the offspring (Lichtensteiger et al., 1988,Lichtensteiger andSchlumpf, 1993), including cognitive deficits that are often manifested in early childhood as attention deficit hyperactivity disorder (ADHD) (Millberger et al., 1996). Though the underlying neurobiological mechanism * Correspondence to: Dr. Layla Azam Department of Biology, University of Utah 257 South 1400 East Salt Lake City, UT 84112 Tel.: (801) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ,Pliszka et al., 1996,Castellanos, 1997. In animal studies, maternal nicotine exposure produces sexdependent alterations in the development of DA neurochemical markers (Fung, 1988,Fung, 1989,Ribary and Lichtensteiger, 1989,Lichtensteiger and Schlumpf, 1993,Muneoka et al., 1997, and induces hyperactivity in the offspring, which is believed...

Nicotine Alters Limbic Function in Adolescent Rat by a 5-HT1A Receptor Mechanism

“…This finding of early adolescence as a critical period of vulnerability to the effects of nicotine is consistent with other recent animal studies that have shown unique effects of nicotine at this age (Azam et al, 2007;Adriani et al, 2003;Belluzzi et al, 2004;Park et al, 2007;Kota et al, 2007). Furthermore, the actively maturing PFC-NAc-BLA triadic circuit appears to be highly sensitive to the effects of early adolescent nicotine exposure.…”

“…Both a 7 and a 4 b 2 * nAChRs are located on DA and 5-HT cell bodies in the ventral tegmental area and dorsal raphe, respectively, and their stimulation can enhance the release of monoamines in terminal fields such as PFC, NAc, and BLA (Azam et al, 2007;Mihailescu et al, 1998;Galindo-Charles et al, 2008;Wonnacott et al, 2005). It is not clear from this study whether the effect of nicotine on adolescent limbic function that we have observed results from a transient appearance of these nAChRs or from an increase in drug sensitivity.…”

“…In particular, the prefrontal cortex (PFC)-basolateral amygdala (BLA)-nucleus accumbens (NAc) triadic circuit, responsible for reward and motivated behavior, is dynamically developing during this period, as are its monoamine afferents (Ernst et al, 2006;Ernst and Fudge, 2009). Mesolimbic DA systems, which are integral to cocaine selfadministration and locomotor sensitization (Thomas et al, 2008), undergo major reorganization during adolescence (Tarazi et al, 1999;Cao et al, 2007b;Benoit-Marand and O'Donnell, 2008;Brenhouse et al, 2008;Andersen et al, 2000) and exhibit unique sensitivity to nicotine (Azam et al, 2007). Less is known about the adolescent maturation of 5-HT systems, which have a significant role in cocaine selfadministration (Rocha et al, 1997;Rodd et al, 2005;Fletcher et al, 2002) and locomotor sensitization (Tassin, 2008).…”

α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

“…However, work to date has not previously been able to address the striking functional dominance of a6*-nAChRs in the control of DA release in NAc that we reveal here. For example, nAChR subunit expression data in the DA cell body regions (VTA and SNc) that give rise to ascending DA projections to NAc and CPu appears similar between cell groups (for non-a7 subunits) (Azam et al, 2002;Azam et al, 2007;Champtiaux et al, 2003;Klink et al, 2001;Wooltorton et al, 2003) and studies of nicotine-evoked [ 3 H]-DA release report a a-CtxMII-sensitive fraction of release that is similar in synaptosomes derived from NAc or CPu (rodents: 40-55% (Champtiaux et al, 2003;Grady et al, 2002); monkeys: 70-80% (McCallum et al, 2005)). However, differences between nicotine-evoked [ 3 H]-DA release studies and the physiological nAChR function identified in this study in an endogenous setting should be expected.…”

“…Unlike other subunits, expression of the a6 subunit is relatively restricted to catecholaminergic (and some visual system) neurons (Le Novere et al, 1996;Quik et al, 2001Quik et al, , 2002. Moreover, after somatic expression of a6 mRNA in VTA/SN DA neurons (Azam et al, 2002(Azam et al, , 2007, plasmamembrane a6*-nAChRs on DA axon terminals (Quik et al, 2002;Zoli et al, 2002) may account for up to 40% of b2*-nAChRs (in rat) . Given their restricted localization to striatal DA axons, a6*-nAChRs are attracting attention as promising targets for selective pharmacotherapies in dopaminergic disorders including nicotine addiction and Parkinson's disease (Quik and McIntosh, 2006).…”