Ultra-low exposure to alpha-7 nicotinic acetylcholine receptor partial agonists elicits an improvement in cognition that corresponds with an increase in alpha-7 receptor expression in rodents: implications for low dose clinical efficacy

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Nicotine exposure caused an increase in a-Btx binding in mouse prefrontal cortex that was attributed to reduced proteasome-dependent degradation due to the accumulation of ubiquitinated a7 nAChR subunits (Rezvani et al, 2007). In addition, these studies complement past efforts demonstrating that ultra-low exposure to a7 nAChR partial agonists result in sustained efficacy in models of working memory because of upregulation of cell surface a7 nAChRs (Werkheiser et al, 2011) or because of reduced turnover from inhibition of proteasomal activity (Rezvani et al, 2007).…”

“…In vivo, this compound exhibited activity in a variety of preclinical models including novel object recognition (NOR) in mouse, reversal of short-term memory deficits in fimbria-fornix-lesioned rats, and improvement in working memory in the spatial delayed response task in rhesus monkey (Sydserff et al, 2009;Castner et al, 2011;Werkheiser et al, 2011). Quinuiclidine and ring expansion analogs have been extended by modification of functional linkers such as heteroaryls, amides, and carbamates.…”

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

“…Due to concerns around long-lasting carry-over effects for NAchA7 receptors activation mechanism after a single dose (Werkheiser et al, 2011), the experimental design did not include randomization, and hence all mice received saline in the first experimental session.…”

“…In the first experimental session, saline vehicle was administered, in the second session -15 mg/kg Lu AF58801 dissolved in 40% 2-hydroxypropylbeta-cyclodextrin (HPbCD) (i.p.). As there could be a high risk of long-lasting carry-over effects for NAchA7 receptors activation mechanism after a single dose (Werkheiser et al, 2011), we did not use cross-over design with randomization, and hence all mice received saline in the first experimental session. In a control condition we used saline vehicle, since HPbCD does not cross the blood-brain barrier (Camargo et al, 2001).…”

3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors

“…As far as MDMA is concerned, it has higher affinity for heteromeric than for α7 nAChR (Garcia-Ratés et al, 2007), thus a more marked effect on the heteromeric receptors was expected and confirmed by the experimental results. It has been reported that exposure to α7 nAChR partial agonists increases the expression of these receptors in rodents (Werkheiser et al, 2011) and that MDMA acts as a α7 partial agonist in PC12 cells (Garcia-Rates et al, 2010). This would account for its effect on the density of α7 nAChR in the parietal cortex and the synergy with NIC seen in the cortex and hippocampus.…”