α7 Receptor-selective agonists and modes of α7 receptor activation

Papke, Roger L.; Meyer, Edwin M.; Nutter, Tom; Uteshev, Victor V.

doi:10.1016/s0014-2999(00)00009-1

Cited by 108 publications

(114 citation statements)

References 55 publications

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“…That result is consistent with previous estimates that ␣7* nAChRs have an IC 50 for nicotine-induced desensitization of up to 7 µM (Fenster et al 1997;Frazier et al 1998;McQuiston and Madison 1999;Alkondon et al 2000;Quick and Lester 2002). This result may be surprising to some because high concentrations of agonist desensitize ␣7* nAChRs more rapidly than other nAChR types (Alkondon and Albuquerque 1991;Bertrand et al 1992;Dani et al 2000;Papke et al 2000). Despite the rapid kinetics, the lower affinity of ␣7* nAChRs for nicotine underlies the lack of desensitization.…”

Section: Figuresupporting

confidence: 92%

“…9B). Although ␣7* nAChRs desensitize rapidly when exposed to high concentrations of nicotine or ACh (Alkondon and Albuquerque 1991;Bertrand et al 1992;Dani et al 2000;Papke et al 2000;Wooltorton et al 2003), they have a relatively low affinity for desensitization by nicotine. The results of Figure 9 are consistent with measurement of ␣7* nAChRs from rodent hippocampus or expressed in oocytes, where estimates of IC 50 for nicotine-induced desensitization of ␣7* nAChRs range from about 0.5 to 7 µM (Fenster et al 1997;Frazier et al 1998;McQuiston and Madison 1999;Alkondon et al 2000;Quick and Lester 2002).…”

Section: Learning and Memory 63mentioning

confidence: 99%

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Nicotinic Cholinergic Synaptic Mechanisms in the Ventral Tegmental Area Contribute to Nicotine Addiction

Pidoplichko¹,

Noguchi²,

Areola³

et al. 2004

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Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs). A component of nicotine's addictive power is attributable to actions on the mesolimbic dopaminergic system, which serves a fundamental role in the acquisition of behaviors that are inappropriately reinforced by addictive drugs. Here we show that nicotine, in the same concentration and time ranges as obtained from tobacco, has three main actions that regulate the activity of midbrain dopamine (DA) neurons. Nicotine first activates and then desensitizes nAChRs on the DA neurons. This process directly excites the DA neurons for a short period of time before the nAChRs desensitize. Nicotine also enhances glutamatergic excitation and decreases GABAergic inhibition onto DA neurons. These events increase the probability for synaptic plasticity, such as long-term potentiation. The short-lived direct excitation of the DA neurons coupled with the enhanced glutamatergic afferent activity provides the presynaptic and postsynaptic coincidence necessary to initiate synaptic potentiation. In total, these synaptic events lead to a relatively long-lasting heightened activity of midbrain DA neurons. Consistent with other summarized studies, this work indicates that the synaptic changes normally associated with learning and memory can be influenced and commandeered during the nicotine addiction process.

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Section: Figuresupporting

confidence: 92%

Section: Learning and Memory 63mentioning

confidence: 99%

Nicotinic Cholinergic Synaptic Mechanisms in the Ventral Tegmental Area Contribute to Nicotine Addiction

Pidoplichko¹,

Noguchi²,

Areola³

et al. 2004

Learn. Mem.

170

156

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“…Thus, alternative nicotinic agonists that are less potentially toxic would be helpful in the treatment of schizophrenia. The first agent which has proved successful in early testing for enhancement of cognition is DMXBA, a partial agonist at the α7 nicotinic cholinergic receptor [84,85] and a weak competitive antagonist at the α4ß2 nicotinic cholinergic receptor and 5HT 3 receptors [86,87,119]. Additionally, P50 auditory gating was also improved [119].…”

Section: Discussionmentioning

confidence: 99%

“…This is one of a series of compounds derived from anabaseine, an alkaloid found in marine worms [82,83]. DMXBA is a partial agonist at the α7 nicotinic cholinergic receptor [84,85] and a weak competitive antagonist at the α4ß2 nicotinic cholinergic receptors and 5HT 3 receptors [86,87]. The first step in testing of this compound was to administer DMXBA in DBA/2 mice.…”

Section: Dmxba As a Prototype Drugmentioning

confidence: 99%

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

125

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Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

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“…Macroscopic dose-response and single-channel kinetic analyses of homomeric Cys-loop receptors suggest that two to five agonist molecules are required for maximal activation (Amin and Weiss, 1996;Palma et al, 1996;Papke et al, 2000;Mott et al, 2001;Gentet and Clements, 2002;Beato et al, 2002Beato et al, , 2004Solt et al, 2007). However, because dose-response and single-channel measurements cannot directly reveal the number and locations of functional binding sites, this remains a crucial gap in our mechanistic understanding of homomeric Cys-loop receptors.…”

Section: Introductionmentioning

confidence: 99%