α6β2* and α4β2* nicotinic acetylcholine receptors as drug targets for Parkinson's disease

Abstract

Parkinson's disease is a debilitating movement disorder characterized by a generalized dysfunction of the nervous system, with a particularly prominent decline in the nigrostriatal dopaminergic pathway. Although there is currently no cure, drugs targeting the dopaminergic system provide major symptomatic relief. As well, agents directed to other neurotransmitter systems are of therapeutic benefit. Such drugs may act by directly improving functional deficits in these other systems, or they may restore aberrant motor activity that arises as a result of a dopaminergic imbalance. Recent research attention has focused on a role for drugs targeting the nicotinic cholinergic systems. The rationale for such work stems from basic research findings that there is an extensive overlap in the organization and function of the nicotinic cholinergic and dopaminergic systems in the basal ganglia. In addition, nicotinic acetylcholine receptor (nAChR) drugs could have clinical potential for Parkinson's disease. Evidence for this proposition stems from studies with experimental animal models showing that nicotine protects against neurotoxin-induced nigrostriatal damage and improves motor complications associated with l-DOPA, the "gold standard" for Parkinson's disease treatment. Nicotine interacts with multiple central nervous system receptors to generate therapeutic responses but also produces side effects. It is important therefore to identify the nAChR subtypes most beneficial for treating Parkinson's disease. Here we review nAChRs with particular emphasis on the subtypes that contribute to basal ganglia function. Accumulating evidence suggests that drugs targeting α6β2* and α4β2* nAChR may prove useful in the management of Parkinson's disease.

Fig. 1.

Schematic representation of the nigrostriatal dopaminergic systems in the rat brain and its links to the pedunculopontine (PPT) nucleus. a, sagittal section, stained with cresyl violet, illustrating the nigrostriatal pathway (green) that projects from cell bodies in the SN pars compacta of the midbrain to the caudate-putamen (CPu; dorsal striatum) of the rat forebrain. Note its “striated” appearance. The ventral striatum, below the CPu, corresponds to the nucleus accumbens (NAc). The SN receives cholinergic (red) and glutamatergic (blue) inputs from the PPT in the brain stem. The CPu receives glutamatergic (blue) inputs from the somatosensory and association cortices. Cc, corpus callosum; Cer, cerebellum; MFB, medial forebrain bundle. b, transverse sections at the level of the dashed lines in a. Bregma coordinates indicate distance anterior (+) and posterior (−) to this landmark on the skull. [Reprinted from Rice ME, Avshalumov MV, and Patel JC (2007) Hydrogen peroxide as a diffusible messenger: evidence from voltammetric studies of dopamine release in brain slices, in Electrochemical Methods for Neuroscience (Michael AC and Borland LM eds) pp 205–232, CRC Press. Copyright © 2007 CRC Press. Used with permission.].

Fig. 2.

Dense and overlapping distribution of ACh and dopamine in the rat striatum. Top, bright-field photomicrographs show tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) antibody staining of forebrain sections. Arrows, anterior commissure; CC, corpus callosum; CPu, caudate putamen; NAc, nucleus accumbens; S, septum. Bottom, higher magnification immunofluorescence images of striatum double labeled for TH (left) and ChAT (right), revealing sparse cholinergic interneurons and dense fiber tracts for both transmitters. Scale bars, 50 μm. [Reproduced from Zhou FM, Liang Y, and Dani JA (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat Neurosci 4:1224–1229. Copyright © 2001 Nature Publishing Group. Used with permission.].

Fig. 3.

Schematic of the nigrostriatal pathway in relation to the basic circuitry of the basal ganglia. Dopaminergic neurons of the SN pars compacta and corticostriatal glutamatergic neurons converge on the medium spiny neurons of the striatum. These are the principal output neurons of the “direct” (D) or “indirect” (I) pathways. The direct pathway (heavy shaded lines) projects directly to the entopeduncular nucleus (EPN; internal segment of the globus pallidus in primates) or the SN pars reticulata (SNr), and thence to the thalamus or brain stem, respectively. The indirect pathway (heavy dashed shaded lines) makes synaptic connections in the globus pallidus (GP; external segment of the globus pallidus in primates) and subthalamic nucleus (STN) en route to the EPN and SNr. Some additional connections are shown as dotted lines. See Bolam et al. (2000) for details.

Fig. 4.

Cellular localization of nAChR subtypes in striatum (a) and SN (b). a, in the striatum, the nigrostriatal and corticostriatal afferents converge on the shafts and heads, respectively, of the spines of medium spiny projection neurons. The nigrostriatal dopaminergic terminals (DA) bear a variety of α4β2* and α6β2* nAChR subtypes. α7 nAChRs are proposed to reside on the glutamatergic terminals (Glu). Other neuronal elements in the striatum, the GABAergic and cholinergic interneurons and serotonergic afferents from the raphe nucleus, are also indicated. GABAergic terminals express α4β2* nAChRs: these may arise from interneurons, as illustrated, or from axon collaterals, medium spiny neurons, or globus pallidus neurons (not shown). A fast-spiking subpopulation of GABAergic interneurons may express an unidentified subtype of nAChR, possibly α7 (gray receptor). Evidence for the presence of nAChRs on cholinergic interneurons and serotonergic afferents is inconclusive (gray receptor). The subunit composition of nAChR subtypes expressed in the striatum is illustrated in the right panel. Two agonist-binding sites are indicated at the interface between α and β2 subunits in heteromeric nAChRs, whereas α7 nAChRs have five putative binding sites. b, in the SN, the dopaminergic neurons (DA) that project to the striatum are modulated by glutamatergic, cholinergic, and GABAergic afferents, as well as GABAergic interneurons. The dopamine neurons bear α4β2* and α6β2* nAChR subtypes that may be distinct from those expressed on the striatal terminals. Proposed subunit combinations are illustrated on the right. α7 nAChRs are also present on a proportion of these cell bodies, in contrast to the striatal dopaminergic terminals. GABAergic interneurons express heteromeric nAChRs; α4β2* nAChRs may also be present on GABAergic afferents, for example from the substantia nigra pars reticulata. In contrast to the VTA, glutamatergic afferents may bear both α7 and non-α7 nAChRs, but cholinergic afferents are apparently devoid of nAChRs.

Fig. 5.

Pivotal role of DARPP-32 in postsynaptic signaling in medium spiny neurons, illustrating the potential for nicotinic modulation. DARPP-32 integrates inputs from multiple systems to regulate PP-1; only dopamine and glutamate receptors are shown for clarity. Postsynaptic dopamine D1 and D2 receptors are largely segregated to the “direct” (striatonigral) and “indirect” (striatopallidal) projection pathways, respectively. Other components shown are presumed to be common to all medium spiny neurons. DARPP-32 via PP-1 influences the activity of numerous target proteins, including receptors, ion channels and transcription factors. nAChRs that modulate dopamine release, notably α4β2* and α6β2* subtypes (shown here on nigrostriatal terminals but also present on dopaminergic cell bodies in the SN) can also affect postsynaptic excitability and synaptic plasticity through these mechanisms.

Fig. 6.

Schematic diagram depicting the effects of partial and near-complete dopaminergic lesioning on expression of nAChR subtypes in striatum. In intact striatum (left), α6β2* nAChRs are primarily expressed on nigrostriatal dopaminergic terminals (DA). α4β2* nAChRs are also located on dopaminergic terminals and comprise 30 to 50% of the striatal α4β2* population. The remaining 70 to 50% of α4β2* nAChRs, which are likely to be predominantly composed only of the α4 and β2 subunits, are present on other neuronal or non-neuronal elements (other). α7 nAChRs are inferred to be located on glutamatergic (Glu) afferents. In rats with a partial striatal lesion (middle), the α6α4β2β3 nAChR subtype disappears first, and thus the effects of nicotine or nicotinic drugs would be mediated by residual α6β2* subtypes and by α4β2* and possibly α7 nAChR subtypes. With a near-complete lesion (right), all presynaptic nAChRs are lost from nigrostriatal dopaminergic terminals. However, α4β2 nAChRs are preserved on other elements and, possibly together with α7 nAChRs, will contribute to local nAChR-mediated effects. Enhanced glutamatergic signaling is indicated. See Huang et al. (2011) for further details.