Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

Kong, Xiang; Earl, Damien E.; Davis, Kathleen; Giovannucci, David R.; Greenfield, Lazar J.; Tietz, Elizabeth I.

doi:10.1124/jpet.108.144444

Cited by 28 publications

(28 citation statements)

References 45 publications

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“…Long-term BZ administration up-regulates L-type high voltage-gated calcium channels in the cerebral cortex (Katsura et al, 2007) and potentiates high voltagegated calcium channel currents in the hippocampal CA1 neurons (Xiang et al, 2008).…”

Section: Conclusion On Effects Of Long-term Benzodiazepine Administrmentioning

confidence: 99%

Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

2010

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Section: Conclusion On Effects Of Long-term Benzodiazepine Administrmentioning

confidence: 99%

Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

2010

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“…The clinical effects of BDZs are attributed to their ability to allosterically enhance the inhibitory action of GABA A receptors (GABA A R). However, there is also evidence that BDZs directly inhibit L-type voltage-gated calcium channels (L-VGCCs) in muscle and nerve cells at low micromolar concentrations (Yamakage et al, 1999;Xiang et al, 2008). Other GABA A R modulators, such as the neurosteroid allopregnanolone (3␣-hydroxy-5␣-pregnan-20-one), the barbiturate pentobarbital, and ethanol, can also inhibit neuronal L-VGCCs ffrenchMullen et al, 1993;Hu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Recombinant L-Type Voltage-Gated Calcium Channels by Positive Allosteric Modulators of GABA_A Receptors

Earl¹,

Tietz²

2011

J Pharmacol Exp Ther

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Benzodiazepines (BDZs) depress neuronal excitability via positive allosteric modulation of inhibitory GABA A receptors (GABA A R). BDZs and other positive GABA A R modulators, including barbiturates, ethanol, and neurosteroids, can also inhibit L-type voltage-gated calcium channels (L-VGCCs), which could contribute to reduced neuronal excitability. Because neuronal L-VGCC function is up-regulated after long-term GABA A R modulator exposure, an interaction with L-VGCCs may also play a role in physical dependence. The current studies assessed the effects of BDZs (diazepam, flurazepam, and desalkylflurazepam), allopregnanolone, pentobarbital, and ethanol on whole-cell Ba 2ϩ currents through recombinant neuronal Ca v 1.2 and Ca v 1.3 L-VGCCs expressed with ␤ 3 and ␣ 2 ␦-1 in HEK293T cells. Allopregnanolone was the most potent inhibitor (IC 50 , ϳ10 M), followed by BDZs (IC 50 , ϳ50 M), pentobarbital (IC 50 , 0.3-1 mM), and ethanol (IC 50 , ϳ300 mM). Ca v 1.3 channels were less sensitive to pentobarbital inhibition than Ca v 1.2 channels, similar to dihydropyridine (DHP) L-VGCC antagonists. All GABA A R modulators induced a negative shift in the steady-state inactivation curve of Ca v 1.3 channels, but only BDZs and pentobarbital induced a negative shift in Ca v 1.2 channel inactivation. Mutation of the high-affinity DHP binding site (T1039Y and Q1043M) in Ca v 1.2 channels reduced pentobarbital potency. Despite the structural similarity between benzothiazepines and BDZs, mutation of an amino acid important for diltiazem potency (I1150A) did not affect diazepam potency. Although L-VGCC inhibition by BDZs occurred at concentrations that are possibly too high to be clinically relevant and is not likely to play a role in the up-regulation of L-VGCCs during long-term treatment, pentobarbital and ethanol inhibited L-VGCCs at clinically relevant concentrations.

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“…However, Ca 2ϩ influx in benzodiazepine-withdrawn rats was mediated via L-type voltage-gated calcium channels (Xiang et al, 2008) and CaMKII was not autophosphorylated (Shen et al, 2010). Thus, although we identified numerous mechanistic similarities, we identified some important differences between druginduced glutamatergic plasticity and the postsynaptic signaling mechanisms associated with e.g., hippocampal long-term potentiation (LTP).…”

Section: Introductionmentioning

confidence: 76%

“…at ASPET Journals on May 12, 2018 jpet.aspetjournals.org Downloaded from increase in voltage-gated Ca 2ϩ channel-mediated current density emerged upon withdrawal from 1-week FZP treatment and lasted up to 2 days (Xiang et al, 2008).…”

Section: Regulation Of Nmdar During Benzodiazepine Withdrawal 271mentioning

confidence: 99%

Down-Regulation of Synaptic GluN2B Subunit-Containing N-methyl-d-aspartate Receptors: A Physiological Brake on CA1 Neuron α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Hyperexcitability during Benzodiazepine Withdrawal

Shen

Tietz²

2010

J Pharmacol Exp Ther

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A significant link was previously established between benzodiazepine withdrawal anxiety and a progressive increase in ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) potentiation in hippocampal CA1 neurons from rats withdrawn up to 2 days from 1-week oral administration of the benzodiazepine flurazepam (FZP). Despite AMPAR current potentiation, withdrawal anxiety was masked by a 2-fold reduction in CA1 neuron N-methyl-D-aspartate receptor (NMDAR) currents since preinjection of an NMDA antagonist restored NMDAR currents and unmasked anxiety in 2-day FZP-withdrawn rats. In the current study, GluN subunit levels in postsynaptic density (PSD)-enriched subfractions of CA1 minislices were compared with GluN2B-mediated whole-cell currents evoked in CA1 neurons in hippocampal slices from 1-and 2-day FZP-withdrawn rats. GluN1 and GluN2B, although not the phosphoSer1303-GluN2B ratio or GluN2A subunit levels, were decreased in PSD subfractions from 2-day, but not 1-day, FZP-withdrawn rats. Consistent with immunoblot analyses, GluN2B-mediated NMDAR currents evoked in slices from 2-day FZP-withdrawn rats were decreased in the absence, but not the presence, of the GluN2B subunit-selective antagonist ifenprodil. In contrast, ifenprodil-sensitive NMDAR currents were unchanged in slices from 1-day withdrawn rats. Because AMPA (1 M) preincubation of slices from 1-day FZP-withdrawn rats induced depression of GluN2B subunit-mediated currents, depression of NMDAR currents was probably secondary to AMPAR potentiation. CA1 neuron NMDAR currents were depressed ϳ50% after 2-day withdrawal and offset potentiation of AMPAR-mediated currents, leaving total charge transfer unchanged between groups. Collectively, these findings suggest that a reduction of GluN2B-containing NMDAR may serve as a homeostatic feedback mechanism to modulate glutamatergic synaptic strength during FZP withdrawal to alleviate benzodiazepine withdrawal symptoms.

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Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

Cited by 28 publications

References 45 publications

Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

Inhibition of Recombinant L-Type Voltage-Gated Calcium Channels by Positive Allosteric Modulators of GABA_A Receptors

Down-Regulation of Synaptic GluN2B Subunit-Containing N-methyl-d-aspartate Receptors: A Physiological Brake on CA1 Neuron α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Hyperexcitability during Benzodiazepine Withdrawal

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Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

Cited by 28 publications

References 45 publications

Regulation of GABAAReceptor Subunit Expression by Pharmacological Agents

Regulation of GABAAReceptor Subunit Expression by Pharmacological Agents

Inhibition of Recombinant L-Type Voltage-Gated Calcium Channels by Positive Allosteric Modulators of GABAA Receptors

Down-Regulation of Synaptic GluN2B Subunit-Containing N-methyl-d-aspartate Receptors: A Physiological Brake on CA1 Neuron α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Hyperexcitability during Benzodiazepine Withdrawal

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Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

Inhibition of Recombinant L-Type Voltage-Gated Calcium Channels by Positive Allosteric Modulators of GABA_A Receptors