Old age and cognition: Enhancement of recent memory in aged rats by the calcium channel blocker nimodipine

LeVere, T. E.; Walker, A.

doi:10.1016/0197-4580(92)90010-u

Cited by 62 publications

(35 citation statements)

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“…In healthy animals, nimodipine may impair learning (Maurice et al 1995). However, nootropic effects of nimodipine have been previously demonstrated in other neuropsychiatric disorders (Pantoni et al 1996;Sze et al 1998), aged animals (Levere andWalker 1992;Sandin et al 1990) and animals with anticholinergic impairments in learning (Balakrishnan and Pandhi 1997). In preclinical studies, sustained nimodipine administration enhanced spatial learning without promoting long-term potentiation (Kane and Robinson 1999).…”

Section: Discussionmentioning

confidence: 97%

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Krupitsky

2001

Neuropsychopharmacology

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Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/ kg/hr) (Krystal et al. 1999c). In addition, these drugs produce effects in healthy human subjects that resemble aspects of the signs and symptoms of schizophrenia or dissociative disorders (Krystal et al. 25 , NO . 6 Nimodipine-Ketamine Interactions 937 1999a). As a result, ketamine administration may provide a laboratory-based approach that may contribute to the characterization of NMDA receptor contributions to cognitive function and the development of novel pharmacotherapeutic approaches that might ameliorate the consequences of NMDA receptor dysfunction. NMDA receptor antagonists also have ethanol-like behavioral effects in animals and humans (Grant and Colombo 1993;Krystal et al. 1998b;Petrakis et al. 2001). In ethanol dependent patients, ketamine effects were deemed more similar to ethanol effects than they were to the effects of marijuana or cocaine (Krystal et al. 1998b). This observation is consistent with studies indicating that NMDA receptors are among the highest affinity targets of ethanol in the brain, where it produces dose-related uncompetitive antagonism of receptor function (Grant and Lovinger 1995;Lovinger 1997). In animals, the behavioral effects of ethanol have a complex neurobiology, reflecting the interaction of the many component dose-related actions of ethanol in the brain (Green and Grant 1998).Ethanol, relative to the uncompetitive NMDA receptor antagonists phencyclidine and ketamine, has less propensity to produce psychotic symptoms in healthy humans or recovering ethanol-dependent patients (Krystal et al. 1994a;Krystal et al. 1998b;Luby et al. 1959). The limited psychotogenic propensity of ethanol at doses typically associated with human intoxication may reflect the capacity of ethanol facilitation of GABA A receptor function to moderate its NMDA antagonist effects (Grant and Lovinger 1995). Consistent with this hypothesis, some reduction in the perceptual effects of ketamine in healthy human subjects was produced by lorazepam pretreatment (Krystal et al. 1998a). However, preclinical data suggest that the capacity of ethanol to block L-type VSCCs (Crews et al. 1996) may also protect against its psychotogenic potential. In animals, components of the behavioral and discriminative stimulus effects of NMDA antagonists are attenuated by pretreatment with L-type VSCC antagonists (Green and Grant 1999;Green-Jordan and Grant 2000;Popoli et al. 1992;Sukhotina et al. 1999).The current ...

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Section: Discussionmentioning

confidence: 97%

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Krupitsky

2001

Neuropsychopharmacology

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“…The L-type channel antagonist nimodipine reverses learning deficits in rodents (8,(57)(58)(59)(60)(61)(62)(63). Influx of Ca 2ϩ through L-type Ca 2ϩ channels is robustly increased in old rodents (9,64).…”

Section: Discussionmentioning

confidence: 99%

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Davare

Hell

2003

Proc. Natl. Acad. Sci. U.S.A.

110

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An increase in Ca 2؉ influx through L-type Ca 2؉ channels is thought to contribute to neuronal dysfunctions that underlie senile symptoms and Alzheimer's disease. The molecular basis of the agedependent up-regulation in neuronal L-type Ca 2؉ channel activity is largely unknown. We show that phosphorylation of the L-type channel Ca v1.2 by cAMP-dependent protein kinase is increased >2-fold in the hippocampus of aged rats. The hippocampus is critical for learning and is one of the first brain regions to be affected in Alzheimer's disease. Phosphorylation of Ca v1.2 by cAMP-dependent protein kinase strongly enhances its activity. Therefore, increased Ca v1.2 phosphorylation may account for a substantial portion of the age-related rise in neuronal Ca 2؉ influx and its neuropathological consequences. C a 2ϩ regulates a variety of signaling pathways (1-3). Acute uncontrolled Ca 2ϩ influx can cause neuronal death by overstimulation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (4, 5). Chronic elevation of Ca 2ϩ influx has been implicated in age-associated neuronal loss and Alzheimer's disease (6, 7). The age-related learning impairment in rabbits is reversed by the specific L-type Ca 2ϩ channel blocker nimodipine (8). These observations indicate that elevation of L-type channel activity causes neuronal dysfunction during aging. Ca 2ϩ influx through L-type channels is up-regulated Ͼ2-fold in hippocampal neurons of old versus adult rats (9). The hippocampus is crucial for learning and memory; however, the molecular basis for the increase in L-type channel activity during aging is not well defined, except for an Ϸ20% increase in Ca v 1.3 protein (10, 11). We now show that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of the L-type channel Ca v 1.2 increases Ͼ2-fold during aging and that it may underlie a substantial portion of the age-related increase in L-type channel activity.PKA increases L-type channel activity in neurons (13-16) and in the heart, where PKA-dependent stimulation of the cardiac L-type channel is crucial for the up-regulation of the heartbeat after adrenergic stimulation (17, 18 (19), and the auxiliary subunits ␣ 2 -␦, -␤, and -␥ (22). Only ␣ 1 1.2, and none of the auxiliary subunits, is required for the PKA-mediated increase in channel activity (23). ␣ 1 1.2 is phosphorylated in intact hippocampal neurons by PKA (24). The main phosphorylation site on ␣ 1 1.2 is serine 1928 (25, 26), which is important for the up-regulation of the channel activity by PKA (27). This site is close to the C terminus of ␣ 1 1.2, is present only in the full-length form of ␣ 1 1.2 (21), and is removed by the Ca 2ϩ -activated protease calpain after Ca 2ϩ influx through NMDA receptors (28). Calpain cleaves ␣ 1 1.2 Ϸ300 residues upstream of the C terminus in vitro (28). Deletion of the last 300-400 residues of ␣ 1 1.2 increases channel activity when expressed in Xenopus oocytes (29); therefore, calpain-mediated cleavage may permanently elevate Ca v 1.2 activity in vivo. Because calpain has been impli...

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“…By facilitating and inhibiting LTD and LTP induction, respectively, the overall effect of increased L-channel activity during aging would favor the weakening of synaptic efficacy , which is a primary electrophysiological marker for age-related cognitive deficits (Barnes et al, 1992(Barnes et al, , 1996. Thus, the current study provides a plausible mechanistic link between age-related memory deficits and L-channel activity in the aging brain (Deyo et al, 1989;Straube et al, 1990;Levere and Walker, 1992;Ingram et al, 1994;Kowalska and Disterhoft, 1994;Soloman et al, 1995;Thibault and Landfield, 1996). Moreover, the results continue to support the examination of L-channel blockers in the early therapeutic intervention of age-related neurodegenerative diseases such as Alzheimer's (Fischhof, 1993;Grobe-Einsler, 1993;Parnetti et al, 1993;Fritze and Walden, 1995).…”

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confidence: 92%

Reversal of Age-Related Alterations in Synaptic Plasticity by Blockade of L-Type Ca²⁺Channels

1998

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The role of L-type Ca 2ϩ channels in the induction of synaptic plasticity in hippocampal slices of aged (22-24 months) and young adult (4-6 months) male Fischer 344 rats was investigated. Prolonged 1 Hz stimulation (900 pulses) of Schaffer collaterals, which normally depresses CA3/CA1 synaptic strength in aged rat slices, failed to induce long-term depression (LTD) during bath application of the L-channel antagonist nifedipine (10 M). When 5 Hz stimulation (900 pulses) was used to modify synaptic strength, nifedipine facilitated synaptic enhancement in slices from aged, but not young, adult rats. This enhancement was pathway-specific, reversible, and impaired by the NMDA receptor (NMDAR) antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Induction of long-term potentiation (LTP) in aged rats, using 100 Hz stimulation, occluded subsequent synaptic enhancement by 5 Hz stimulation, suggesting that nifedipine-facilitated enhancement shares mechanisms in common with conventional LTP. Facilitation of synaptic enhancement by nifedipine likely was attributable to a reduction (ϳ30%) in the Ca 2ϩ -dependent K ϩ -mediated afterhyperpolarization (AHP), because the K ϩ channel blocker apamin (1 M) similarly reduced the AHP and promoted synaptic enhancement by 5 Hz stimulation. In contrast, apamin did not block LTD induction using 1 Hz stimulation, suggesting that, in aged rats, the AHP does not influence LTD and LTP induction in a similar way. The results indicate that, during aging, L-channels can (1) facilitate LTD induction during low rates of synaptic activity and (2) impair LTP induction during higher levels of synaptic activation via an increase in the Ca 2ϩ -dependent AHP.

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Old age and cognition: Enhancement of recent memory in aged rats by the calcium channel blocker nimodipine

Cited by 62 publications

References 5 publications

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Reversal of Age-Related Alterations in Synaptic Plasticity by Blockade of L-Type Ca²⁺Channels

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Old age and cognition: Enhancement of recent memory in aged rats by the calcium channel blocker nimodipine

Cited by 62 publications

References 5 publications

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Increased phosphorylation of the neuronal L-type Ca 2+ channel Ca v 1.2 during aging

Reversal of Age-Related Alterations in Synaptic Plasticity by Blockade of L-Type Ca2+Channels

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Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Reversal of Age-Related Alterations in Synaptic Plasticity by Blockade of L-Type Ca²⁺Channels