3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat α7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner

Meyer, Edwin M.; Tay, Ee Tein; Papke, Roger L.; Meyers, Craig; Huang, Gang; Fiebre, Christopher M. de

doi:10.1016/s0006-8993(97)00536-2

Cited by 154 publications

(95 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of a7nAChRs, like activation of NMDARs, increases the performance of experimental animals in the MWM (Duffy et al, 2008;Meyer et al, 1997;Riekkinen and Riekkinen, 1997;Timmermann et al, 2007;Wallace et al, 2011), a task that is extensively used to test hippocampusdependent spatial navigation and reference memory in rodents. On the other hand, reduced activity of either of these two receptors causes cognitive deficits in this paradigm (Boess et al, 2007;Curzon et al, 2006;Morris, 2006;Wallace et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

141

158

View full text Add to dashboard Cite

Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

show abstract

Section: Discussionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

141

158

View full text Add to dashboard Cite

show abstract

“…Passive avoidance deficits are normalized in rats [115] and ischemia-induced hippocampal cell death and impaired passive avoidance performance in gerbils are prevented by treatment with DMXBA [116]. DMXBA also improves performance on the Morris water maze [117].…”

Section: Dmxba As a Prototype Drugmentioning

confidence: 95%

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

Olincy

Stevens

2007

Biochemical Pharmacology

125

View full text Add to dashboard Cite

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

show abstract

“…Both ␣4␤2 and ␣7 nicotinic agonists are effective. Anabaseine-related analogs that are selective ␣7 agonists significantly improved working memory in younger and aged rats (Meyer et al, 1994;Arendash et al, 1995;Meyer et al, 1997). Systemic administration of another type of ␣7 agonist ARR 17779 significantly improved learning on the radial-arm maze and reversed the working memory impairment caused by fimbria-fornix sections (Levin et al, 1999a).…”

Section: Systemic Nicotine Effects On Memorymentioning

confidence: 99%

Nicotinic receptor subtypes and cognitive function

2002

View full text Add to dashboard Cite

ABSTRACT:Nicotinic receptor systems are involved in a wide variety of behavioral functions including cognitive function. Nicotinic medications may provide beneficial treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Nicotine has been shown to improve attentional performance in all of these disorders. Better efficacy with fewer side effects might be achieved with novel nicotinic ligands selective for particular nicotinic subtypes. To develop these novel selective nicotinic ligands it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function. Nicotineinduced cognitive improvement in rats is most consistently seen in working memory tasks. We have found that both acute and chronic nicotine administration significantly improves working memory performance of rats in the radial-arm maze. The pharmacologic and anatomic mechanisms for this effect have been examined in our laboratory in a series of local drug infusion studies. Both ␣4␤2 and ␣7 nicotinic receptors in the ventral hippocampus and basolateral amygdala are involved in working memory function. Working memory impairments were caused by local infusion of either ␣4␤2 or ␣7 antagonists. Ventral hippocampal ␣4␤2 blockade-induced working memory deficits are reversed by chronic systemic nicotine treatment, while ventral hippocampal ␣7 blockade-induced working memory deficits were not found to be reversed by the same nicotine regimen. Interestingly, ␣4␤2 and ␣7 induced deficits were not found to be additive in either the ventral hippocampus or the basolateral amygdala. In fact, in the amygdala, ␣7 antagonist cotreatment actually reversed the working memory impairment caused by ␣4␤2 antagonist administration. These studies of the neural nicotinic mechanisms underlying cognitive function are key for opening avenues for development of safe and effective nicotinic treatments for cognitive dysfunction.

show abstract

3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat α7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner

Cited by 154 publications

References 19 publications

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

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

Nicotinic receptor subtypes and cognitive function

Contact Info

Product

Resources

About