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1.
Neuropsychopharmacology ; 40(10): 2357-67, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25801502

ABSTRACT

There is considerable interest in NMDAR modulators to enhance memory and treat neuropsychiatric disorders such as addiction, depression, and schizophrenia. D-serine and D-cycloserine, the NMDAR activators at the glycine site, are of particular interest because they have been used in humans without serious adverse effects. Interestingly, D-serine also inhibits some NMDARs active at hyperpolarized potentials (HA-NMDARs), and we previously found that HA-NMDARs within the nucleus accumbens core (NAcore) are critical for promoting compulsion-like alcohol drinking, where rats consume alcohol despite pairing with an aversive stimulus such as quinine, a paradigm considered to model compulsive aspects of human alcohol use disorders (AUDs). Here, we examined the impact of D-serine and D-cycloserine on this aversion-resistant alcohol intake (that persists despite adulteration with quinine) and consumption of quinine-free alcohol. Systemic D-serine reduced aversion-resistant alcohol drinking, without altering consumption of quinine-free alcohol or saccharin with or without quinine. Importantly, D-serine within the NAcore but not the dorsolateral striatum also selectively reduced aversion-resistant alcohol drinking. In addition, D-serine inhibited EPSCs evoked at -70 mV in vitro by optogenetic stimulation of mPFC-NAcore terminals in alcohol-drinking rats, similar to reported effects of the NMDAR blocker AP5. Further, D-serine preexposure occluded AP5 inhibition of mPFC-evoked EPSCs, suggesting that D-serine reduced EPSCs by inhibiting HA-NMDARs. Systemic D-cycloserine also selectively reduced intake of quinine-adulterated alcohol, and D-cycloserine inhibited NAcore HA-NMDARs in vitro. Our results indicate that HA-NMDAR modulators can reduce aversion-resistant alcohol drinking, and support testing of D-serine and D-cycloserine as immediately accessible, FDA-approved drugs to treat AUDs.


Subject(s)
Alcohol Drinking/drug therapy , Alcohol Drinking/physiopathology , Compulsive Behavior/drug therapy , Compulsive Behavior/etiology , Cycloserine/therapeutic use , Serine/therapeutic use , Animals , Ethanol/adverse effects , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Hippocampus/cytology , In Vitro Techniques , Male , Prefrontal Cortex/cytology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Rats, Wistar , Saccharin/metabolism , Valine/analogs & derivatives , Valine/pharmacology
2.
Nat Neurosci ; 16(8): 1094-100, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23817545

ABSTRACT

Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats. Aversion-resistant intake was associated with a new type of NMDA receptor adaptation, in which hyperpolarization-active NMDA receptors were present at mPFC and insula but not amygdalar inputs in the NAcore. Accordingly, inhibition of Grin2c NMDA receptor subunits in the NAcore reduced aversion-resistant alcohol intake. None of these manipulations altered intake when alcohol was not paired with an aversive consequence. Our results identify a mechanism by which hyperpolarization-active NMDA receptors under mPFC- and insula-to-NAcore inputs sustain aversion-resistant alcohol intake.


Subject(s)
Alcohol Deterrents/pharmacology , Alcohol Drinking/physiopathology , Avoidance Learning/physiology , Cerebral Cortex/physiopathology , Drug Resistance/physiology , Nerve Tissue Proteins/physiology , Nucleus Accumbens/physiopathology , Prefrontal Cortex/physiopathology , Quinine/pharmacology , Receptors, N-Methyl-D-Aspartate/physiology , Alcohol Drinking/blood , Alcohol Drinking/drug therapy , Amygdala/chemistry , Animals , Bacterial Proteins/analysis , Cerebral Cortex/chemistry , Conditioning, Operant , Ethanol/blood , Excitatory Amino Acid Antagonists/pharmacology , Halorhodopsins/analysis , Luminescent Proteins/analysis , Male , Optogenetics , Patch-Clamp Techniques , Piperidines/pharmacology , Prefrontal Cortex/chemistry , RNA Interference , RNA, Small Interfering/pharmacology , Random Allocation , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/genetics , Valine/analogs & derivatives , Valine/pharmacology
3.
PeerJ ; 1: e61, 2013.
Article in English | MEDLINE | ID: mdl-23646281

ABSTRACT

The MCH and dopamine receptor systems have been shown to modulate a number of behaviors related to reward processing, addiction, and neuropsychiatric conditions such as schizophrenia and depression. In addition, MCH and dopamine receptors can interact in a positive manner, for example in the expression of cocaine self-administration. A recent report (Chung et al., 2011a) showed that the DA1/DA2 dopamine receptor activator apomorphine suppresses pre-pulse inhibition, a preclinical model for some aspects of schizophrenia. Importantly, MCH can enhance the effects of lower doses of apomorphine, suggesting that co-modulation of dopamine and MCH receptors might alleviate some symptoms of schizophrenia with a lower dose of dopamine receptor modulator and thus fewer potential side effects. Here, we investigated whether MCH and apomorphine could enhance action potential firing in vitro in the nucleus accumbens shell (NAshell), a region which has previously been shown to mediate some behavioral effects of MCH. Using whole-cell patch-clamp electrophysiology, we found that MCH, which has no effect on firing on its own, was able to increase NAshell firing when combined with a subthreshold dose of apomorphine. Further, this MCH/apomorphine increase in firing was prevented by an antagonist of either a DA1 or a DA2 receptor, suggesting that apomorphine acts through both receptor types to enhance NAshell firing. The MCH/apomorphine-mediated firing increase was also prevented by an MCH receptor antagonist or a PKA inhibitor. Taken together, our results suggest that MCH can interact with lower doses of apomorphine to enhance NAshell firing, and thus that MCH and apomorphine might interact in vivo within the NAshell to suppress pre-pulse inhibition.

4.
Neuron ; 71(2): 278-90, 2011 Jul 28.
Article in English | MEDLINE | ID: mdl-21791287

ABSTRACT

D(1) dopamine receptors are primary mediators of dopaminergic signaling in the CNS. These receptors internalize rapidly following agonist-induced activation, but the functional significance of this process is unknown. We investigated D(1) receptor endocytosis and signaling in HEK293 cells and cultured striatal neurons using real-time fluorescence imaging and cAMP biosensor technology. Agonist-induced activation of D(1) receptors promoted endocytosis of receptors with a time course overlapping that of acute cAMP accumulation. Inhibiting receptor endocytosis blunted acute D(1) receptor-mediated signaling in both dissociated cells and striatal slice preparations. Although endocytic inhibition markedly attenuated acute cAMP accumulation, inhibiting the subsequent recycling of receptors had no effect. Further, D(1) receptors localized in close proximity to endomembrane-associated trimeric G protein and adenylyl cyclase immediately after endocytosis. Together, these results suggest a previously unanticipated role of endocytosis, and the early endocytic pathway, in supporting rapid dopaminergic neurotransmission.


Subject(s)
Dopamine/metabolism , Endocytosis/physiology , Neurons/physiology , Signal Transduction/physiology , Action Potentials/drug effects , Action Potentials/genetics , Adenylyl Cyclases/pharmacology , Animals , Benzazepines/pharmacology , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/genetics , Cells, Cultured , Corpus Striatum/cytology , Cyclic AMP/pharmacology , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Dose-Response Relationship, Drug , Embryo, Mammalian , Endocytosis/drug effects , Flow Cytometry/methods , Guanine Nucleotide Exchange Factors/metabolism , Humans , Hydrazones/pharmacology , Microscopy, Fluorescence/methods , Neurons/drug effects , Protein Transport/drug effects , RNA, Small Interfering/pharmacology , Rats , Receptors, Dopamine D1/genetics , Time Factors , Transfection/methods
5.
Channels (Austin) ; 5(4): 289-92, 2011.
Article in English | MEDLINE | ID: mdl-21712648

ABSTRACT

We recently described the SK-type potassium channel as a novel target for treatment of excessive alcohol intake.1 SK channel function is reduced in the nucleus accumbens (NAcb) core in rats consuming alcohol under intermittent (IAA) but not continuous (CAA) access, and the FDA-approved SK activator chlorzoxazone reduces the excessive alcohol intake in IAA rats but not the more moderate intake in CAA rats. Here, we discuss the implications of these and related findings for SK as a treatment for alcohol use disorders. In addition, we report that many NAcb core electrophysiological parameters related to action potential waveform or basal parameters were not altered in alcohol-drinking rats. These results are in strong contrast to those reported for cocaine, where several NAcb ion channels show adaptations after cocaine exposure. These results suggest that alcohol intake is associated with only limited ion channel neuro-adaptations in the NAcb relative to cocaine, and support the hypothesis that SK represents a selective and potent intervention to reduce excessive alcohol intake.


Subject(s)
Alcohol Drinking/drug therapy , Alcohols/administration & dosage , Calcium Channel Agonists/pharmacology , Small-Conductance Calcium-Activated Potassium Channels/metabolism , Animals , Male
6.
Biol Psychiatry ; 69(7): 618-24, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21195386

ABSTRACT

BACKGROUND: Alcoholism imposes a tremendous social and economic burden. There are relatively few pharmacological treatments for alcoholism, with only moderate efficacy, and there is considerable interest in identifying additional therapeutic options. Alcohol exposure alters SK-type potassium channel (SK) function in limbic brain regions. Thus, positive SK modulators such as chlorzoxazone (CZX), a US Food and Drug Administration-approved centrally acting myorelaxant, might enhance SK function and decrease neuronal activity, resulting in reduced alcohol intake. METHODS: We examined whether CZX reduced alcohol consumption under two-bottle choice (20% alcohol and water) in rats with intermittent access to alcohol (IAA) or continuous access to alcohol (CAA). In addition, we used ex vivo electrophysiology to determine whether SK inhibition and activation can alter firing of nucleus accumbens (NAcb) core medium spiny neurons. RESULTS: Chlorzoxazone significantly and dose-dependently decreased alcohol but not water intake in IAA rats, with no effects in CAA rats. Chlorzoxazone also reduced alcohol preference in IAA but not CAA rats and reduced the tendency for rapid initial alcohol consumption in IAA rats. Chlorzoxazone reduction of IAA drinking was not explained by locomotor effects. Finally, NAcb core neurons ex vivo showed enhanced firing, reduced SK regulation of firing, and greater CZX inhibition of firing in IAA versus CAA rats. CONCLUSIONS: The potent CZX-induced reduction of excessive IAA alcohol intake, with no effect on the more moderate intake in CAA rats, might reflect the greater CZX reduction in IAA NAcb core firing observed ex vivo. Thus, CZX could represent a novel and immediately accessible pharmacotherapeutic intervention for human alcoholism.


Subject(s)
Alcohol Drinking/drug therapy , Alcohols/administration & dosage , Calcium Channel Agonists/pharmacology , Small-Conductance Calcium-Activated Potassium Channels/metabolism , Action Potentials/drug effects , Alcohol Drinking/psychology , Animals , Apamin/pharmacology , Behavior, Animal/drug effects , Calcium Channel Agonists/therapeutic use , Chlorzoxazone/pharmacology , Chlorzoxazone/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Neurons/drug effects , Nucleus Accumbens/pathology , Patch-Clamp Techniques , Rats , Rats, Wistar , Self Administration
7.
J Neurosci ; 30(26): 8830-40, 2010 Jun 30.
Article in English | MEDLINE | ID: mdl-20592205

ABSTRACT

There is considerable interest in the regulation of sensorimotor gating, since deficits in this process could play a critical role in the symptoms of schizophrenia and other psychiatric disorders. Sensorimotor gating is often studied in humans and rodents using the prepulse inhibition of the acoustic startle response (PPI) model, in which an acoustic prepulse suppresses behavioral output to a startle-inducing stimulus. However, the molecular and neural mechanisms underlying PPI are poorly understood. Here, we show that a regulatory pathway involving protein phosphatase 2A (PP2A), glycogen synthase kinase 3 beta (GSK3beta), and their downstream target, the M-type potassium channel, regulates PPI. Mice (Mus musculus) carrying a hypomorphic allele of Ppp2r5delta, encoding a regulatory subunit of PP2A, show attenuated PPI. This PPP2R5delta reduction increases the phosphorylation of GSK3beta at serine 9, which inactivates GSK3beta, indicating that PPP2R5delta positively regulates GSK3beta activity in the brain. Consistently, genetic and pharmacological manipulations that reduce GSK3beta function attenuate PPI. The M-type potassium channel subunit, KCNQ2, is a putative GSK3beta substrate. Genetic reduction of Kcnq2 also reduces PPI, as does systemic inhibition of M-channels with linopirdine. Importantly, both the GSK3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)1H-pyrrole-2,5-dione (SB216763) and linopirdine reduce PPI when directly infused into the medial prefrontal cortex (mPFC). Whole-cell electrophysiological recordings of mPFC neurons show that SB216763 and linopirdine have similar effects on firing, and GSK3 inhibition occludes the effects of M-channel inhibition. These data support a previously uncharacterized mechanism by which PP2A/GSK3beta signaling regulates M-type potassium channel activity in the mPFC to modulate sensorimotor gating.


Subject(s)
Auditory Perception/physiology , Brain/physiology , Glycogen Synthase Kinase 3/metabolism , Inhibition, Psychological , Potassium Channels/metabolism , Protein Phosphatase 2/metabolism , Amino Acid Sequence , Animals , Auditory Perception/drug effects , Brain/drug effects , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta , KCNQ2 Potassium Channel/genetics , KCNQ2 Potassium Channel/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Neurological , Neurons/drug effects , Neurons/physiology , Phosphorylation , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Protein Phosphatase 2/genetics , Reflex, Startle/drug effects , Reflex, Startle/physiology , Signal Transduction
8.
Eur J Neurosci ; 31(11): 1946-59, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20497469

ABSTRACT

The striatum is considered to be critical for the control of goal-directed action, with the lateral dorsal striatum (latDS) being implicated in modulation of habits and the nucleus accumbens thought to represent a limbic-motor interface. Although medium spiny neurons from different striatal subregions exhibit many similar properties, differential firing and synaptic plasticity could contribute to the varied behavioral roles across subregions. Here, we examined the contribution of small-conductance calcium-activated potassium channels (SKs) to action potential generation and synaptic plasticity in adult rat latDS and nucleus accumbens shell (NAS) projection neurons in vitro. The SK-selective antagonist apamin exerted a prominent effect on latDS firing, significantly decreasing the interspike interval. Furthermore, prolonged latDS depolarization increased the interspike interval and reduced firing, and this enhancement was reversed by apamin. In contrast, NAS neurons exhibited greater basal firing rates and less regulation of firing by SK inhibition and prolonged depolarization. LatDS neurons also had greater SK currents than NAS neurons under voltage-clamp. Importantly, SK inhibition with apamin facilitated long-term depression (LTD) induction in the latDS but not the NAS, without alterations in glutamate release. In addition, SK activation in the latDS prevented LTD induction. Greater SK function in the latDS than in the NAS was not secondary to differences in sodium or inwardly rectifying potassium channel function, and apamin enhancement of firing did not reflect indirect action through cholinergic interneurons. Thus, these data demonstrate that SKs are potent modulators of action potential generation and LTD in the dorsal striatum, and could represent a fundamental cellular mechanism through which habits are regulated.


Subject(s)
Action Potentials/physiology , Corpus Striatum/metabolism , Long-Term Synaptic Depression/physiology , Small-Conductance Calcium-Activated Potassium Channels/metabolism , Action Potentials/drug effects , Animals , Apamin/pharmacology , Corpus Striatum/cytology , Long-Term Synaptic Depression/drug effects , Male , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Neurons/drug effects , Neurons/physiology , Patch-Clamp Techniques , Rats , Rats, Long-Evans
9.
Neuron ; 65(5): 682-94, 2010 Mar 11.
Article in English | MEDLINE | ID: mdl-20223203

ABSTRACT

The cellular mechanisms underlying pathological alcohol seeking remain poorly understood. Here, we show an enhancement of nucleus accumbens (NAcb) core action potential firing ex vivo after protracted abstinence from alcohol but not sucrose self-administration. Increased firing is associated with reduced small-conductance calcium-activated potassium channel (SK) currents and decreased SK3 but not SK2 subunit protein expression. Furthermore, SK activation ex vivo produces greater firing suppression in NAcb core neurons from alcohol- versus sucrose-abstinent rats. Accordingly, SK activation in the NAcb core significantly reduces alcohol but not sucrose seeking after abstinence. In contrast, NAcb shell and lateral dorsal striatal firing ex vivo are not altered after abstinence from alcohol, and SK activation in these regions has little effect on alcohol seeking. Thus, decreased NAcb core SK currents and increased excitability represents a critical mechanism that facilitates motivation to seek alcohol after abstinence.


Subject(s)
Conditioning, Operant/physiology , Potassium Channels, Calcium-Activated/metabolism , Protein Serine-Threonine Kinases/metabolism , Small-Conductance Calcium-Activated Potassium Channels/metabolism , Action Potentials/drug effects , Analysis of Variance , Animals , Apamin/pharmacology , Behavior, Animal/drug effects , Benzimidazoles/pharmacology , Calcium Channel Agonists/pharmacology , Central Nervous System Depressants/administration & dosage , Conditioning, Operant/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Food Preferences/drug effects , Germinal Center Kinases , In Vitro Techniques , Male , Neurons/drug effects , Nucleus Accumbens/cytology , Nucleus Accumbens/drug effects , Nucleus Accumbens/physiopathology , Rats , Rats, Wistar , Reinforcement Schedule , Self Administration/methods , Sucrose/administration & dosage , Sweetening Agents/administration & dosage
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