A focus on nAChRs

While I have the ability to focus for short periods (and jump from thing to thing well!), sustained attention and general cognitive inflexibility are things that I really struggle with, leading to further problems in sustaining goal-directed activity.  I’m trying to work on them non-pharmacologically but that is easier said than done…

I believe there are avenues worthy of further exploration:

  • In a recent trial, encenicline (an α7 nAChR partial agonist) was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia [1].
  • Preliminary findings with CDP-choline (citicoline) [Examine] in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with it as a pro-cognitive strategy [2]. Healthy adolescent males receiving 28 days of citicoline showed improved attention and psychomotor speed and reduced impulsivity [3].
  • Galantamine, a potent allosteric potentiating ligand of nAChRs, has produced neurocognitive benefits in only one study with schizophrenia patients. Buchanan et al. found that galantamine improved working memory and verbal learning over placebo in 86 schizophrenia patients while no other study has found good evidence of its procognitive benefits [4]. That said, “cholinergic agents, in particular galantamine and nicotine, appear to have the most promising cognitive enhancing effects in schizophrenia patients” [5].
  • DMXB-A:

    “3-(2,4-dimethoxy-benzylidene)-anabaseine (DMXB-A) is an a-7 nicotinic receptor partial agonist that demonstrated positive benefits on neurocognitive functions—particularly attention—in a proof of-concept study that used a randomized, double-blind, cross-over design to study 12 schizophrenia patients. However, in the phase II study, Freedman et al. found no benefits of DMXB-A over placebo on neurocognition in 31 patients with schizophrenia. They attributed the failure of the phase II trial to the possibility that strong practice effects across the study arms may have obscured any DMXB-A benefits on neurocognition.” [4]

Some recent articles:

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats.

Alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced α7-nAChR agents has not been extensively characterised in animal models of schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N’-(5-methyl-3-isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI), respectively, and galantamine, an acetylcholinesterase inhibitor (AChE) that also allosterically modulates nAChRs, against ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric α7-nAChR agonist octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole (A-582941) was used as a positive control. Additionally, the antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test. PNU-120596, CCMI, galantamine and A-582941 reversed ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against ketamine-induced impairment in the novel object recognition task (NORT). PNU-120596, CCMI, and A-582941 ameliorated ketamine-induced social interaction deficits, whereas galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of α7-nAChRs demonstrates preclinical efficacy not only against schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of α7-nAChR PAMs as a potential treatment strategy in schizophrenia is supported.

Disruptions of executive function, including attentional deficits, are a hallmark of a number of diseases. Acetylcholine in the prefrontal cortex (PFC) regulates attentive behaviour; however the role of α7 nicotinic acetylcholine receptor (α7nAChRs) in attention is contentious. In order to probe attention we trained both wild type and α7nAChR knockout mice on a touchscreen based 5-choice serial reaction time task (5-CSRT). Following training procedures we then tested sustained attention using a probe trial experiment. To further dissect the role of specific nicotinic receptors in attention we then tested the effects of both α7nAChR and β2nAChR agonists on the performance of both wild type and knockout mice on the 5-CSRT task. At low doses, α7nAChR agonists improved attentional performance of wild-type mice, while high doses had deleterious effects on attention. α7 nAChR knockout mice displayed deficits in sustain attention that were not ameliorated by α7nAChR agonists. However, these deficits were completely reversed by the administration of a β2nAChR agonist. Furthermore, administration of a β2nAChR agonist in α7 nAChR knockout mice elicited the same biochemical response in the prefrontal cortex as the administration of α7nAChR agonists in wild type mice. Our experiments reveal an intricate relationship between distinct nicotinic receptors to regulate attentional performance and provide the basis for targeting β2nAChRs pharmacologically to decrease attentional deficits due to α7nAChR dysfunction.

Other cholinergics

  • Rivastigmine and donepezil have similarly failed to demonstrate benefits as neurocognitive enhancers in schizophrenia in several placebo-controlled trials. In a 12-week open-label trial, Chung et al. found that 28 schizophrenia patients who received up to 10 mg/day of donepezil as an adjunct to atypical antipsychotics demonstrated improvements in attention, memory, psychomotor speed, and mental set-shifting. [4].

See more here

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