Dihydropyridine Calcium Antagonists in Mice: Blood and Brain Pharmacokinetics and Efficacy Against Pentylenetetrazol Seizures

Larkin, John G.; Thompson, George G.; Scobie, G; Forrest, Gerard; Drennan, J. E.; Brodie, Martin J.

doi:10.1111/j.1528-1157.1992.tb02358.x

Cited by 48 publications

(44 citation statements)

References 56 publications

(41 reference statements)

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“…As no effect on extinction was noted at this concentration, we increased the dose up to 1 mg/kg to reach nifedipine brain concentrations that should be within the range of those reached after i.p. injections (see Materials and Methods) at the beginning of the experiment (Larkin et al 1992). Proper cannula placement was confirmed both histologically and functionally, by applying BayK (70 µg/µL) at the end of the experiment, resulting in dystonic behavior within 1-2 min after injection.…”

Section: Discussionmentioning

confidence: 99%

“…Doses were adjusted to reach CNS concentrations within a range similar to i.p. injections based on previously determined pharmacokinetic parameters (Larkin et al 1992). Figure 5, B, D, and F, illustrates that fear acquisition prior to injection was similar in the two groups, later assigned to vehicle and the drug group.…”

Section: Effect Of Intracerebroventricular (Icv) Nifedipine Adminimentioning

confidence: 98%

“…injection whether the nifedipine-induced impairment of extinction is centrally mediated. Nifedipine can easily cross the blood brain barrier due to its high lipophilicity (Larkin et al 1992). We investigated the effect of nifedipine at concentrations calculated to be at the lower and higher end of the expected brain concentrations reached after i.p.…”

Section: Discussionmentioning

confidence: 99%

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Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

Busquet

Hetzenauer²,

Sinnegger-Brauns³

et al. 2008

Learn. Mem.

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Dihydropyridine (DHP) L-type Ca2+ channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the treatment of specific anxiety disorders. Ca V 1.2 and Ca V 1.3 are the predominant LTCCs in the mammalian brain. However, since no isoform-selective DHP blockers are available, their individual contribution to fear memory extinction is unknown. We used a novel mouse model expressing DHP-insensitive Ca V 1.2 LTCCs (Ca V 1.2DHP −/− mice) to address this question. In line with previous studies, wild-type (WT) mice treated with systemic nifedipine displayed markedly impaired fear extinction. This DHP effect was completely abolished in Ca V 1.2DHP −/− mice, indicating that it is mediated by Ca V 1.2, but not by Ca V 1.3 LTCCs. Supporting this conclusion, Ca V 1.3-deficient mice (Ca V 1.3 −/− ) showed extinction identical to the respective WT mice. The inhibition of fear extinction was not observed after intracerebroventricular (i.c.v.) application of different doses of nifedipine, suggesting that this effect is secondary to inhibition of peripheral Ca V 1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in Ca V 1.2DHP −/− mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the Ca V 1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly Ca V 1.3) is not sufficient to accelerate extinction of conditioned fear in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Intracerebroventricular (Icv) Nifedipine Adminimentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

Busquet

Hetzenauer²,

Sinnegger-Brauns³

et al. 2008

Learn. Mem.

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“…Mice were injected subcutaneously 50 min prior to behavioral testing (10 mL/kg). Drug dose and pretreatment time were chosen based on studies conducted in our laboratory (Cain et al 2002;Barad et al 2004) and on previous reports of systemic administration in rodents (Janicki 1988;Larkin 1992). …”

Section: Drugmentioning

confidence: 99%

The L-type calcium channel blocker nifedipine impairs extinction, but not reduced contingency effects, in mice

Cain

Godsil²,

Jami³

et al. 2005

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We recently reported that fear extinction, a form of inhibitory learning, is selectively blocked by systemic administration of L-type voltage-gated calcium channel (LVGCC) antagonists, including nifedipine, in mice. We here replicate this finding and examine three reduced contingency effects after vehicle or nifedipine (40 mg/kg) administration. In the first experiment, contingency reduction was achieved by adding USs to the training protocol (degraded contingency), a phenomenon thought to be independent of behavioral inhibition. In the second experiment, contingency reduction was achieved by varying the percentage of CS-US pairing, a phenomenon thought to be weakly dependent on behavioral inhibition. In the third and fourth experiments, contingency reduction was achieved by adding CSs to the training protocol (partial reinforcement), a phenomenon thought to be completely dependent on behavioral inhibition. We found that none of these reduced contingency effects was impaired by nifedipine. In a final experiment, we found that extinction conducted 1 or 3 h post-acquisition, but not immediately, was LVGCC-dependent. Taken together, the results suggest that reduced contingency effects and extinction depend on different molecular mechanisms and that LVGCC dependence of behavioral inhibition develops with time after associative CS-US learning.Pavlovian fear conditioning in rodents has been widely used in the laboratory setting to model human fear and anxiety, as well as excitatory learning and memory processes (Fendt and Fanselow 1999;Maren 2001;Ohman and Mineka 2001;Fanselow and Gale 2003;LeDoux 2003). Fear conditioning is achieved by temporally pairing an initially neutral conditional stimulus (CS), such as a tone, with an aversive unconditional stimulus (US), usually a mild footshock. Rats show robust fear responding to a CS with as little as one CS-US pairing (Fanselow 1990). Extinction of conditional fear, the progressive weakening of the fear response by repeated presentations of the CS alone, has been an important model in the development of behavior therapy for human anxiety disorders (Wolpe 1969;Wolpe and Rowan 1988;Craske 1999;Myers and Davis 2002) and is the prototypical procedure for inducing inhibitory learning (Davis et al. 2003;Delamater 2004).While the molecular and cellular mechanisms of fear acquisition have been intensely studied for decades, the mechanisms of fear extinction are only beginning to be unraveled. For instance, lesion and local infusion studies suggest that the amygdala (Falls et al. 1992;Quirk et al. 1997;Lu et al. 2001;Marsicano et al. 2002;Royer and Pare 2002;Walker et al. 2002;Davis et al. 2003;Ledgerwood et al. 2003; Lin et al. 2003a,b,c) and prefrontal cortex (Morgan et al. 1993;Quirk et al. 2000;Herry and Garcia 2002;Milad and Quirk 2002;Santini et al. 2004;Shah et al. 2004) participate in the learning and retention of fear extinction. Additionally, both local infusion and systemic behavioral pharmacology studies have identified important roles in extinction for the NMDA-type ...

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“…In addition to these, clinical studies have also been performed in epileptic patients to investigate the effects of nifedipine. They have failed to confirm its efficacy in epilepsy, but EEGs suggested a small improvement with higher dose nifedipine (26,27).…”

Section: Yilmaz I Et Al: Nifedipine and Hippocampal Neuron Numbermentioning

confidence: 99%

Effect of nifedipine on hippocampal neuron number in penicillin-induced epileptic rats

Yılmaz

Akdogan²,

Kaya³

et al. 2013

Turkish Neurosurgery

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AIm: Epileptic seizures lead to neuronal loss in the hippocampus. Experimental epilepsy can be induced by direct application of various chemicals to cerebral cortex. Nifedipine is an L-type voltage-dependent calcium channel blocker. In spite of several studies that show the seizure-suppressing effects of nifedipine, it has been shown that nifedipine does not suppress but conversely increases epileptic seizures. Similarly, contradictory effects of nifedipine have been reported, such as neuroprotection, failed neuroprotection and neurotoxicity. We therefore aimed to investigate the effect of nifedipine on hippocampal neuronal loss in penicillin induced epileptic rats in this study. mATeRIAL and meTHods:The effect of nifedipine on total hippocampal neuron number was estimated by using the optical fractionator method (an unbiased stereological method) in penicillin-G induced epileptic rats. ResuLTs:The total number of hippocampal neurons in the control group was 183687 ± 3184. In the penicillin-induced group, the total neuron number significantly decreased to 146318 ± 3042 compared to the control group. In the nifedipine group, the neuron number significantly decreased to 128873 ± 1157 compared to both control and penicillin-induced groups.CoNCLusIoN: Nifedipine increased neuronal loss and did not suppress epileptic seizures in penicillin-induced epileptic rats. Nifedipine could not protect against hippocampal neuronal loss in penicillin-induced epileptic rats.KeywoRds: Penicillin epilepsy model, Nifedipine, Hippocampus, Neuron number, The optical fractionator method, Rat, Epilepsy, Seizure ÖZ AmAÇ: Epileptik nöbetler hipokampusta nöron kaybına yol açmaktadır. Çeşitli kimyasalların beyin korteksine direkt olarak uygulanmasıyla deneysel epilepsi oluşturulabilir. Nifedipin, L-tipi voltaj bağımlı kalsiyum kanal blokörüdür. Nifedipinin nöbet baskılayıcı etkilerini gösteren çeşitli çalışmalar bulunduğu gibi, epileptik nöbetleri baskılamadığı tam tersine arttırdığı da gösterilmiştir. Benzer şekilde, nifedipinin çelişkili etkileri bildirilmiştir; olumlu -olumsuz nöroprotektif (nöron koruyucu) ve nörotoksisite gibi. Bu nedenle, bu çalışmada, penisilin ile deneysel epilepsi oluşturulan sıçanlarda nifedipinin hipokampal nöron kaybı üzerine etkisini araştırmayı amaçladık. yÖNTem ve GeReÇLeR: Nifedipinin penisilin G ile deneysel epilepsi oluşturulan sıçanlarda toplam hipokampal nöron sayısına etkisi tarafsız (objektif ) bir stereolojik metot olan optik parçalama yöntemi ile değerlendirildi.BuLGuLAR: Kontrol grubunun toplam hipokampal nöron sayısı 183687 ± 3184 idi. Penisilin grubunun toplam nöron sayısı kontrol grubuna göre anlamlı olarak düşüktü (146318 ± 3042). Penisilin+nifedipin grubunun toplam nöron sayısı (128873 ± 1157) hem kontrol hem de penisilin grubuna göre istatistiksel olarak anlamlı olarak azalmış bulundu. soNuÇ: Nifedipinin epileptik sıçanlarda nöron kaybını arttırdığı ve epileptik nöbetleri baskılamadığı ortaya kondu. Nifedipin, penisilin ile deneysel epilepsi oluşturulan sıçanlarda ortaya çıkan nöron ka...

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Dihydropyridine Calcium Antagonists in Mice: Blood and Brain Pharmacokinetics and Efficacy Against Pentylenetetrazol Seizures

Cited by 48 publications

References 56 publications

Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

The L-type calcium channel blocker nifedipine impairs extinction, but not reduced contingency effects, in mice

Effect of nifedipine on hippocampal neuron number in penicillin-induced epileptic rats

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Dihydropyridine Calcium Antagonists in Mice: Blood and Brain Pharmacokinetics and Efficacy Against Pentylenetetrazol Seizures

Cited by 48 publications

References 56 publications

Role of L-type Ca2+channel isoforms in the extinction of conditioned fear

Role of L-type Ca2+channel isoforms in the extinction of conditioned fear

The L-type calcium channel blocker nifedipine impairs extinction, but not reduced contingency effects, in mice

Effect of nifedipine on hippocampal neuron number in penicillin-induced epileptic rats

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Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear

Role of L-type Ca²⁺channel isoforms in the extinction of conditioned fear