Section I. The Cholinergic System

Smythies, J. R.

doi:10.1016/s0074-7742(05)64001-9

Cited by 30 publications

(38 citation statements)

References 707 publications

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“…Viewing the function of cholinergic circuits as the result of the summation of actions of ACh at all of its receptors, although initially daunting, may resolve some apparent conflicts in the literature and guide the way to new therapeutic approaches (for reviews see Calabresi et al, 2000;Gotti and Clementi, 2004;Laviolette and van der Kooy, 2004;MacDermott et al, 1999;Mansvelder et al, 2006;Sarter and Parikh, 2005;Smythies, 2005;Wonnacot et al, 2005).…”

Section: Nicotinic (Ionotropic)mentioning

confidence: 99%

“…The role of cholinergic signaling in aspects of memory and cognition are typically attributed to the broad spectrum of effects that ACh elicits in altering the excitability of prefrontal cortical and hippocampal circuits (for reviews see Albuquerque et al, 1996;Buzsaki, 2002;Levin et al, 2006;Mansvelder et al, 2006;Newhouse et al, 2004;Picciotto, 2003;Role and Berg, 1996;Sacco et al, 2004;Smythies, 2005;Wonnacott et al, 2005). Analysis of the pros and cons of the many theories on how ACh actually does what it does to regulate synaptic efficacy in these regions, as with striatum, is best served by considering the potential interaction of ACh with each of its five major sets of binding partners: ChAT, AChE, VAChT, muscarinic, and nAChRs (see discussion above).…”

Section: Physiology Of Ach Circuits In Pfc and Hippocampusmentioning

confidence: 99%

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Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

Berman

Talmage

Role

2007

International Review of Neurobiology

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Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification-particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena-the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.

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Section: Nicotinic (Ionotropic)mentioning

confidence: 99%

Section: Physiology Of Ach Circuits In Pfc and Hippocampusmentioning

confidence: 99%

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

Berman

Talmage

Role

2007

International Review of Neurobiology

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“…Biochemical, histological, and physiological investigations indicate that the most abundant forms of nAChRs in the central nervous system are ␣4␤2 and ␣7, whereas ␣3␤4, although detected in some brain regions (habenulopeduncular system, cerebellum, and locus ceruleus), predominates in the periphery (Smythies, 2005). The discovery that the ␣4␤2 nAChR plays a crucial role in learning mechanism (Picciotto et al, 1995), pain control (Marubio et al, 1999), and nicotine dependence (Picciotto et al, 1998;Lester et al, 2003) has stimulated efforts to develop potent neuronal nAChR subtypeselective compounds that readily penetrate the blood-brain barrier and exhibit reduced side effects.…”

mentioning

confidence: 99%

2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine Is a Novel Potent Competitive Antagonist of Human Neuronal α4β2 nAChRs

Abdrakhmanova

Damaj²,

Carroll³

et al. 2006

Mol Pharmacol

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A patch-clamp technique in a whole-cell configuration was used to examine the functional activity of recently developed 2-fluoro-3-(substituted phenyl)deschloroepibatidine analogs on two major subtypes of neuronal nicotinic acetylcholine receptors (nAChRs), ␣4␤2 and ␣3␤4, that predominate in the central and peripheral nervous systems, respectively. These epibatidine analogs have been shown previously to possess high binding affinity to ␣4␤2 but not to ␣7 nAChRs and to inhibit nicotine-induced analgesia in behavioral pain tests. The 2-fluoro-3-(4-nitro-phenyl)deschloroepibatidine (4-nitro-PFEB) exhibited the most pronounced antagonist activity among these analogs when tested electrophysiologically on ␣4␤2 nAChRs. It inhibited acetylcholine (ACh)-induced currents in a concentration-dependent manner with an IC 50 value of 0.1 M and produced complete inhibition at ϳ1 M concentration.4-Nitro-PFEB at 0.1 M concentration produced a 4-fold rightward shift in the ACh concentration-response curve without altering maximum ACh-induced response. This inhibitory effect of 4-nitro-PFEB was voltage-and use-independent and was partially reversible at its 1 M concentration. The rise and decay kinetics of ACh-induced currents was not altered in the presence of 4-nitro-PFEB. In contrast to ␣4␤2 nAChRs, this compound did not affect ␣3␤4 nAChR-mediated currents at Յ1 M (IC 50 ϳ63.9 M). Overall, these functional data agree with previous binding and behavioral findings and suggest collectively that 4-nitro-PFEB is the most effective and selective antagonist of ␣4␤2 versus ␣3␤4 and ␣7 nAChRs among the tested analogs, acting on ␣4␤2 nAChR through a competitive mechanism with a potency 17-fold higher than that of dihydro-␤-erythroidine.

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“…ACh is widely distributed within the central nervous system (CNS) and is involved in a number of important processes, including roles in sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation, and reward (Lucas-Meunier et al, 2003;Perry et al, 1999b;Smythies, 2005).…”

Section: Acetylcholinementioning

confidence: 99%

“…The neurotransmitter ACh is synthesized from acetyl-coenzyme A and choline by choline acetyltransferase (ChAT), an enzyme primarily expressed by cholinergic neurons (Smythies, 2005). ChAT is a specific marker for identifying cholinergic neurons (Oda, 1999).…”

Section: Acetylcholinementioning

confidence: 99%