The β3 Nicotinic Receptor Subunit: A Component of α-Conotoxin MII-Binding Nicotinic Acetylcholine Receptors that Modulate Dopamine Release and Related Behaviors

Abstract

Nigrostriatal dopaminergic neurons express many nicotinic acetylcholine receptor (nAChR) subunits capable of forming multiple nAChR subtypes. These subtypes are expressed differentially along the neuron and presumably mediate diverse responses. beta3 subunit mRNA has restricted expression but is abundant in the substantia nigra and ventral tegmental areas. To investigate the potential role(s) of nicotinic receptors containing the beta3 subunit in dopaminergic tracts, we generated mice with a null mutation in the beta3 gene. We were thereby able to identify a population of beta3-dependent alpha-conotoxin MII-binding nAChRs that modulate striatal dopamine release. Changes were also observed in locomotor activity and prepulse inhibition of acoustic startle, behaviors that are controlled, in part, by nigrostriatal and mesolimbic dopaminergic activity, respectively, suggesting that beta3-containing nAChRs modulate these behaviors.

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

“…These properties of naturally occurring α4β2 receptors could explain the discrepancy between binding and function seen in the α5 subunit null mutant mouse where high affinity (α4β2*) binding appears unchanged but the high affinity function is decreased. (Figure 3) or in a detectable change in brain mRNA concentrations for any of the other subunits (α2-α7, β2, β4) that are normally expressed in mouse brain [100]. Thus, β3 gene deletion elicited an increase in a response that appears to be modulated by α4(α5)β2 nAChRs, but it did not change the number of receptors that are measured by a binding assay that requires expression of α4 and β2 subunits.…”

“…Deleting the β3 gene resulted in an unexpected increase in the αCtxMII-resistant component of ACh-stimulated dopamine release. This increase was not accompanied by a discernable change in cytisine-sensitive [ 3 H]-epibatidine binding (Figure 3) or in a detectable change in brain mRNA concentrations for any of the other subunits (α2-α7, β2, β4) that are normally expressed in mouse brain [100]. Thus, β3 gene deletion elicited an increase in a response that appears to be modulated by α4(α5)β2 nAChRs, but it did not change the number of receptors that are measured by a binding assay that requires expression of α4 and β2 subunits.…”

“…Since that time, others have established that nicotine, and other nicotinic agonists, will elicit Ca ++ -dependent release of dopamine from striatal tissue slices (see, for examples [98,99]) and synaptosomes [39]. We have used a variant of the synaptosomal dopamine release assay that was originally developed in the Wonnacott laboratory [39] in a series of studies that characterized the pharmacological properties of dopamine release from striatum [40,89,90,100,101,102], as well as in other brain regions such as the nucleus accumbens, olfactory tubercles and frontal cortex [103]. Dose-response curves for agonist-stimulated dopamine release were obtained with many agonists, and, without exception, the results suggested that dopamine release is modulated by a single receptor subtype.…”

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

“…Results from a comprehensive molecular genetics study in which an individual subunit gene (i.e., α4, α5, α7, β2, β3, and β4) was deleted suggested that at least 6 different subtypes mediate nicotine-evoked DA release from mouse striatal synaptosomes, including 2 classes of nAChRs: α-CtxMII-sensitive nAChRs (i.e., α6β2β3*, α4α6β2β3* and possibly a small amount of α6β2* or α4α6β2* subtypes) and α-CtxMIIresistant nAChRs (i.e., α4β2* and α4α5β2* subtypes), whereas deletion of β4 and α7 subunits had no effect [39]. Also, α6-and β3-containing nAChRs have been implicated in nicotineevoked DA release [24,40,41]. Additionally, substantia nigra neurons express high levels of both α6 and β3 mRNA [26,[40][41][42][43] consistent with their involvement in mediating nicotineevoked DA release.…”

“…Also, α6-and β3-containing nAChRs have been implicated in nicotineevoked DA release [24,40,41]. Additionally, substantia nigra neurons express high levels of both α6 and β3 mRNA [26,[40][41][42][43] consistent with their involvement in mediating nicotineevoked DA release.…”