Nicotinic Acetylcholine Receptors and Nicotinic Cholinergic Mechanisms of the Central Nervous System

Abstract

Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are constructed from numerous subunit combinations that compose channel-receptor complexes with varied functional and pharmacological characteristics. Structural and functional diversity and the broad presynaptic, postsynaptic, and nonsynaptic locations of nAChRs underlie their mainly modulatory roles throughout the mammalian brain. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, postsynaptic nAChRs contribute a small minority of fast excitatory transmission, and nonsynaptic nAChRs modulate many neurotransmitter systems by influencing neuronal excitability. Nicotinic receptors have roles in development and synaptic plasticity, and nicotinic mechanisms participate in learning, memory, and attention. Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to dysfunctions such as epilepsy, schizophrenia, Parkinson's disease, autism, dementia with Lewy bodies, Alzheimer's disease, and addiction.

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

“…These findings suggest that more than one nAChR subtype is expressed in dopaminergic neurons, but this conclusion must be treated with caution because the in situ hybridization strategies that were used in the studies discussed above lack the anatomical resolution required to determine whether specific cell types express a given mRNA. This is a major problem given that these dopamine-rich brain regions also include high concentrations of GABAergic neurons [30].…”

“…Studying functional properties of the naturally occurring (native) neuronal nAChRs has been important in identifying the subunit compositions and sites of expression of nAChRs. The observation that subunit composition has profound effects on the potencies and efficacies of routinely available nicotinic drugs suggests that new agents might be developed that are highly subtype selective and thereby could be used to treat disease with limited, or reduced, toxic side effects.Electrophysiological evidence indicates that nAChRs are expressed on dendrites, cell bodies, axons as well as in perisynaptic and presynaptic sites [30]. Those receptors that are expressed on or near nerve terminals modulate calcium-dependent release of neurotransmitters [35,36,37,38] including dopamine [39,40,41,42], norepinephrine [43,44], glutamate [45,46], GABA [47], and acetylcholine [48,49].…”

“…These findings suggest that more than one nAChR subtype is expressed in dopaminergic neurons, but this conclusion must be treated with caution because the in situ hybridization strategies that were used in the studies discussed above lack the anatomical resolution required to determine whether specific cell types express a given mRNA. This is a major problem given that these dopamine-rich brain regions also include high concentrations of GABAergic neurons [30].The lack of anatomical resolution associated with standard in situ hybridization studies prompted two experiments that were designed to assess mRNA expression in dopaminergic cells. One of these used a double-label in situ hybridization approach where the mRNAs for tyrosine hydroxylase, the rate limiting enzyme involved in dopamine synthesis, and nAChR mRNAs were measured in rat brain SN and VTA [66].…”

“…Unexpectedly, in both cases, a compensatory biochemical increase in release is seen in that component modulated by receptors that do not contain the deleted gene product see Figure 5). These biochemical compensations occur without detectable alterations in the number of receptors.As indicated previously, nAChRs are expressed on cell bodies, dendrites, and axons, as well as close to and at the nerve terminal [30]. A series of studies have attemptal to evaluate which of these expression sites is most important in regulating dopamine release and conflicting results have been obtained.…”

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD)

“…Different DA neurons can be categorized based upon the expression of the specific subtype composition [27]. CNS nAChRs and their modulation of neurotransmitter release have been reviewed recently [47,48]. Thus, the presence of specific mRNAs encoding a particular subunit, the relative ratio of transcribed subunits, specific expression of nAChR subtypes by different DA neurons, and pharmacological history are all important to neuronal function and potentially play a role in the response to nicotine and to drugs which block the effect of nicotine.…”