Ethanol Influences on Native T-Type Calcium Current in Thalamic Sleep Circuitry

Mu, Jian; Carden, W. Breckinridge; Kurukulasuriya, Nuwan; Alexander, Georgia M.; Godwin, Dwayne W.

doi:10.1124/jpet.103.053272

Cited by 28 publications

(18 citation statements)

References 36 publications

(47 reference statements)

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“…Using monkeys treated like our CI group, a recent study (44) found plasticity in I T with chronic ethanol in the lateral geniculate nucleus (LGN). Although the direction of plasticity was opposite to our finding in the IO, low doses of ethanol augmented I T in LGN neurons (45), and the monkeys in that study (44) consumed less ethanol per day than did our CI group. The different outcomes could be caused by different Ca V 3.1 splice variants (46).…”

Section: Discussioncontrasting

confidence: 96%

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Welsh¹,

Han

Rossi

et al. 2011

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

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The brain adapts to chronic ethanol intoxication by altering synaptic and ion-channel function to increase excitability, a homeostatic counterbalance to inhibition by alcohol. Delirium tremens occurs when those adaptations are unmasked during withdrawal, but little is known about whether the primate brain returns to normal with repeated bouts of ethanol abuse and abstinence. Here, we show a form of bidirectional plasticity of pacemaking currents induced by chronic heavy drinking within the inferior olive of cynomolgus monkeys. Intracellular recordings of inferior olive neurons demonstrated that ethanol inhibited the tail current triggered by release from hyperpolarization (I tail ). Both the slow deactivation of hyperpolarization-activated cyclic nucleotide-gated channels conducting the hyperpolarization-activated inward current and the activation of Ca v 3.1 channels conducting the T-type calcium current (I T ) contributed to I tail , but ethanol inhibited only the I T component of I tail . Recordings of inferior olive neurons obtained from chronically intoxicated monkeys revealed a significant up-regulation in I tail that was induced by 1 y of daily ethanol self-administration. The up-regulation was caused by a specific increase in I T which (i) greatly increased neurons' susceptibility for rebound excitation following hyperpolarization and (ii) may have accounted for intention tremors observed during ethanol withdrawal. In another set of monkeys, sustained abstinence produced the opposite effects: (i) a reduction in rebound excitability and (ii) a down-regulation of I tail caused by the down-regulation of both the hyperpolarizationactivated inward current and I T . Bidirectional plasticity of two hyperpolarization-sensitive currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.A cute ethanol withdrawal affects millions of people and can require management of a syndrome that consists of dysautonomia, seizures, cognitive disturbance, and tremor (1, 2). It generally is agreed that the washout of ethanol from the brain during acute withdrawal unmasks the physiological adaptations of neurons that allow them to function while they are bathed in ethanol (3, 4). It sometimes is assumed that once the symptoms of acute withdrawal are managed, long-term abstinence from ethanol gradually restores the brain to a preethanol state. Nevertheless, an alcoholic's drive to ingest ethanol can persist even after months or years of abstinence, and alcoholics can undergo multiple abstinences from alcohol in their lifetime.We tested the hypothesis that adaptations in the intrinsic electrical properties of inferior olive (IO) neurons are changed by chronic ethanol intake and by subsequent abstinence. We used patch-clamp recordings of IO neurons in acutely prepared brainstem slices from chronically intoxicated cynomolgus monkeys (5-7) to examine changes in intrinsic electrical properties with ethanol intake and repeated abstinences. We addressed two qu...

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Section: Discussioncontrasting

confidence: 96%

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Welsh¹,

Han

Rossi

et al. 2011

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

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“…In agreement with this suggestion, P-type channels were shown to be insensitive to EtOH concentrations as high as 200 mM in acutely dissociated rat cerebellar PNs (Hall et al, 1994;Walter and Messing, 1999). However, the effect of EtOH on T-type channel function in PNs has not been tested, and we cannot eliminate the possibility that EtOH modulates these channels in light of the recent demonstration that it potently regulates them in thalamic neurons (Mu et al, 2003). Voltage-clamp electrophysiological studies, which have faster temporal resolution than our Ca 2ϩ imaging studies, may reveal effects of ethanol on VGCCs in PNs.…”

Section: Etoh Does Not Affect the Camentioning

confidence: 55%

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Carta¹,

Mameli²,

Valenzuela³

2006

J. Neurosci.

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Consumption of alcoholic beverages produces alterations in motor coordination and equilibrium that are responsible for millions of accidental deaths. Studies indicate that ethanol produces these alterations by affecting the cerebellum, a brain region involved in the control of motor systems. Purkinje neurons of the cerebellar cortex have been shown to be particularly important targets of ethanol. However, its mechanism of action at these neurons is poorly understood. We hypothesized that ethanol could modulate Purkinje neuron function by altering the excitatory input provided by the climbing fiber from the inferior olive, which evokes a powerful all-or-none response denoted as the complex spike. To test this hypothesis, we performed whole-cell patch-clamp electrophysiological and Ca 2ϩ imaging experiments in acute slices from rat cerebella. We found that ethanol potently inhibits the late phase of the complex spike and that this effect is the result of inhibition of type-1 metabotropic glutamate receptor-dependent responses at the postsynaptic level. Moreover, ethanol inhibited climbing fiber long-term depression, a form of synaptic plasticity that also depends on activation of these metabotropic receptors. Our findings identify the climbing fiber3 Purkinje neuron synapse as an important target of ethanol in the cerebellar cortex and indicate that ethanol significantly affects cerebellar circuits even at concentrations as low as 10 mM (legal blood alcohol level in the United States is below 0.08 g/dl ϭ 17 mM).

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“…Our prior studies have shown significant effects of ethanol exposure and withdrawal on the physiology of T-type channels (Carden et al, 2006; Graef et al, 2011; Mu, Carden, Kurukulasuriya, Alexander, & Godwin, 2003; Shan, Hammarback, & Godwin, 2013; Wiggins, Graef, Huitt, & Godwin, 2013). Our current study extends these findings with the following observations: 1) ethanol withdrawal increased the incidence of seizure in DBA/2J mice; 2) ETX decreased ethanol withdrawal-induced seizures evident by reduced electrographical and behavioral measures of seizure; 3) ETX treatment rescued mice from seizures prior to withdrawal treatment.…”

Section: Discussionmentioning

confidence: 99%

Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

Riegle

Masicampo

Caulder

et al. 2014

Alcohol

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Chronic alcohol abuse depresses the nervous system and, upon cessation, rebound hyperexcitability can result in withdrawal seizure. Withdrawal symptoms, including seizures, may drive individuals to relapse, thus representing a significant barrier to recovery. Our lab previously identified an upregulation of the thalamic T-type calcium (T channel) isoform CaV3.2 as a potential contributor to the generation and propagation of seizures in a model of withdrawal. In the present study, we examined whether ethosuximide (ETX), a T-channel antagonist, could decrease the severity of ethanol withdrawal seizures by evaluating electrographical and behavioral correlates of seizure activity. DBA/2J mice were exposed to an intermittent ethanol exposure paradigm. Mice were treated with saline or ETX in each withdrawal period, and cortical EEG activity was recorded to determine seizure severity. We observed a progression in seizure activity with each successive withdrawal period. Treatment with ETX reduced ethanol withdrawal-induced spike and wave discharges (SWDs), in terms of absolute number, duration of events, and contribution to EEG power reduction in the 6–10 Hz frequency range. We also evaluated the effects of ETX on handling-induced convulsions. Overall, we observed a decrease in handling-induced convulsion severity in mice treated with ETX. Our findings suggest that ETX may be a useful pharmacological agent for studies of alcohol withdrawal and treatment of resulting seizures.

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Ethanol Influences on Native T-Type Calcium Current in Thalamic Sleep Circuitry

Cited by 28 publications

References 36 publications

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence

Alcohol Potently Modulates Climbing Fiber→Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors

Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

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