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1.
Cereb Cortex ; 28(6): 1959-1979, 2018 06 01.
Article in English | MEDLINE | ID: mdl-28472227

ABSTRACT

Cholinergic (ACh) basal forebrain (BF) neurons are active during wakefulness and rapid eye movement (REM) sleep and are involved in sleep homeostasis. We have previously shown in adult animals that cortical neurons that express neuronal nitric oxide synthase (nNOS) and the receptor for Substance P (NK1R) are activated during non-REM (NREM) sleep in proportion to homeostatic sleep drive. Here, we show that BF neurons modulate cortical nNOS/NK1R cells. In vitro optogenetic stimulation of BF terminals both activated and inhibited nNOS/NK1R neurons. Pharmacological studies revealed cholinergic responses mediated by postsynaptic activation of muscarinic receptors (mAChRs; M3R > M2/4R > M1R) and that presynaptic M3R and M2R activation reduced glutamatergic input onto nNOS/NK1R neurons whereas nicotinic receptor (nAChR)-mediated responses of nNOS/NK1R neurons were mixed. Cholinergic responses of nNOS/NK1R neurons were largely unaffected by prolonged wakefulness. ACh release, including from BF cells, appears to largely excite cortical nNOS/NK1R cells while reducing glutamatergic inputs onto these neurons. We propose that cholinergic signaling onto cortical nNOS/NK1R neurons may contribute to the regulation of cortical activity across arousal states, but that this response is likely independent of the role of these neurons in sleep homeostasis.


Subject(s)
Arousal/physiology , Basal Forebrain/physiology , Cerebral Cortex/physiology , Neural Pathways/physiology , Neurons/physiology , Sleep/physiology , Animals , Basal Forebrain/cytology , Cerebral Cortex/metabolism , Cholinergic Neurons/cytology , Cholinergic Neurons/physiology , Mice , Neural Pathways/cytology , Neurons/cytology , Nitric Oxide Synthase Type I/metabolism , Receptors, Neurokinin-1/metabolism
2.
Brain Struct Funct ; 221(2): 923-40, 2016 Mar.
Article in English | MEDLINE | ID: mdl-25431268

ABSTRACT

Hypocretin/orexin (HCRT) neurons provide excitatory input to wake-promoting brain regions including the basal forebrain (BF). The dual HCRT receptor antagonist almorexant (ALM) decreases waking and increases sleep. We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals. To test this hypothesis, rats were given bilateral IgG-192-saporin injections, which predominantly targets cholinergic BF neurons. BFx and intact rats were then given oral ALM, the benzodiazepine agonist zolpidem (ZOL) or vehicle (VEH) at lights-out. ALM was less effective than ZOL at inducing sleep in BFx rats compared to controls. BF adenosine (ADO), γ-amino-butyric acid (GABA), and glutamate levels were then determined via microdialysis from intact, freely behaving rats following oral ALM, ZOL or VEH. ALM increased BF ADO and GABA levels during waking and mixed vigilance states, and preserved sleep-associated increases in GABA under low and high sleep pressure conditions. ALM infusion into the BF also enhanced cortical ADO release, demonstrating that HCRT input is critical for ADO signaling in the BF. In contrast, oral ZOL and BF-infused ZOL had no effect on ADO levels in either BF or cortex. ALM increased BF ADO (an endogenous sleep-promoting substance) and GABA (which is increased during normal sleep), and required an intact BF for maximal efficacy, whereas ZOL blocked sleep-associated BF GABA release, and required no functional contribution from the BF to induce sleep. ALM thus induces sleep by facilitating the neural mechanisms underlying the normal transition to sleep.


Subject(s)
Adenosine/metabolism , Basal Forebrain/physiology , Orexin Receptor Antagonists/pharmacology , Orexin Receptors/metabolism , Orexins/antagonists & inhibitors , Sleep/physiology , gamma-Aminobutyric Acid/metabolism , Acetamides/pharmacology , Animals , Antibodies, Monoclonal/pharmacology , Basal Forebrain/drug effects , Basal Forebrain/metabolism , Butyric Acid , Cholinergic Neurons/drug effects , Cholinergic Neurons/metabolism , Glutamic Acid , Intracellular Signaling Peptides and Proteins , Isoquinolines/pharmacology , Male , Neuropeptides/metabolism , Orexins/metabolism , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Ribosome Inactivating Proteins, Type 1/pharmacology , Saporins , Sleep/drug effects , Synaptic Transmission/drug effects , Wakefulness , Zolpidem
3.
Mol Genet Metab ; 111(2): 152-62, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24388731

ABSTRACT

Clinical, epidemiological and experimental studies confirm a connection between the common degenerative movement disorder Parkinson's disease (PD) that affects over 1 million individuals, and Gaucher disease, the most prevalent lysosomal storage disorder. Recently, human imaging studies have implicated impaired striatal dopaminergic neurotransmission in early PD pathogenesis in the context of Gaucher disease mutations, but the underlying mechanisms have yet to be characterized. In this report we describe and characterize two novel long-lived transgenic mouse models of Gba deficiency, along with a subchronic conduritol-ß-epoxide (CBE) exposure paradigm. All three murine models revealed striking glial activation within nigrostriatal pathways, accompanied by abnormal α-synuclein accumulation. Importantly, the CBE-induced, pharmacological Gaucher mouse model replicated this change in dopamine neurotransmission, revealing a markedly reduced evoked striatal dopamine release (approximately 2-fold) that indicates synaptic dysfunction. Other changes in synaptic plasticity markers, including microRNA profile and a 24.9% reduction in post-synaptic density size, were concomitant with diminished evoked dopamine release following CBE exposure. These studies afford new insights into the mechanisms underlying the Parkinson's-Gaucher disease connection, and into the physiological impact of related abnormal α-synuclein accumulation and neuroinflammation on nigrostriatal dopaminergic neurotransmission.


Subject(s)
Corpus Striatum/pathology , Gaucher Disease/pathology , Glucosylceramidase , Parkinson Disease/pathology , Synapses/pathology , alpha-Synuclein/metabolism , Animals , Corpus Striatum/enzymology , Corpus Striatum/physiopathology , Disease Models, Animal , Dopamine/metabolism , Evoked Potentials, Motor , Female , Gaucher Disease/enzymology , Gaucher Disease/genetics , Gaucher Disease/physiopathology , Humans , Inflammation , Inositol/administration & dosage , Inositol/analogs & derivatives , Male , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Mutation , Neuronal Plasticity , Parkinson Disease/enzymology , Parkinson Disease/genetics , Parkinson Disease/physiopathology , Synapses/enzymology , Synaptic Transmission , alpha-Synuclein/genetics
4.
Eur J Pharmacol ; 699(1-3): 200-6, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23219985

ABSTRACT

Nociceptin (N/OFQ) has been implicated in a variety of neurological disorders, most notably in reward processes and drug abuse. N/OFQ suppresses extracellular dopamine in the nucleus accumbens (NAc) after intracerebroventricular injection. This study sought to examine the effects of retrodialyzed N/OFQ on the cocaine-induced increase in extracellular dopamine levels in the NAc, as well as locomotor activity, in freely moving rats. 1.0µM, 10µM, and 1mM N/OFQ, in the NAc shell, significantly suppressed the cocaine-induced dopamine increase in the NAc, while N/OFQ alone had no significant effect on dopamine levels. Co-delivery of the selective NOP receptor antagonist SB612111 ([(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] reversed the N/OFQ suppression of cocaine-induced dopamine in the NAc, suggesting that this is an NOP receptor-mediated effect. Using a novel system to assess locomotion, we measured various motor activities of the animals with simultaneous microdialysis from the home cage. Cocaine produced an expected increase in total activity, including horizontal movement and rearing behavior. Retrodialysis of N/OFQ with cocaine administration affected all motor activities, initially showing no effect on behavior, but over time inhibiting cocaine-induced motor behaviors. These results suggest that N/OFQ can act directly in the NAc shell to block cocaine-induced increases in extracellular dopamine levels. Extracellular dopamine and locomotor activity can be dissociated within the NAc and may reflect motor output differences in shell versus core regions of the NAc. These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction.


Subject(s)
Cocaine/pharmacology , Dopamine/metabolism , Opioid Peptides/metabolism , Receptors, Opioid/metabolism , Animals , Behavior, Animal/drug effects , Cycloheptanes/pharmacology , Dose-Response Relationship, Drug , Locomotion/drug effects , Male , Microdialysis , Motor Activity/drug effects , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Opioid Peptides/administration & dosage , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Opioid/drug effects , Nociceptin Receptor , Nociceptin
5.
J Neurosurg ; 117(1): 162-75, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22577746

ABSTRACT

OBJECT: The authors evaluated the extent to which the Subdural Pharmacotherapy Device (SPD), chronically implanted over the frontal cortex to perform periodic, localized muscimol-delivery/CSF removal cycles, affects overall behavior, motor performance, electroencephalography (EEG) activity, and blood and CSF neurochemistry in macaque monkeys. METHODS: Two monkeys were used to adjust methodology and 4 monkeys were subjected to comprehensive testing. Prior to surgery, the animals' behavior in a large test chamber was monitored, and the motor skills required to remove food pellets from food ports located on the walls of the chamber were determined. The monkeys underwent implantation of the subdural and extracranial SPD units. The subdural unit, a silicone strip integrating EEG electrodes and fluid-exchange ports, was positioned over the right frontal cortex. The control unit included a battery-powered, microprocessor-regulated dual minipump and radiofrequency module secured to the cranium. After implantation, the SPD automatically performed periodic saline or muscimol (1.0 mM) deliveries at 12-hour intervals, alternating with local CSF removals at 6-hour intervals. The antiepileptic efficacy of this muscimol concentration was verified by demonstrating its ability to prevent focal acetylcholine-induced seizures. During SPD treatment, the monkeys' behavior and motor performance were again monitored, and the power spectrum of their radiofrequency-transmitted EEG recordings was analyzed. Serum and CSF muscimol levels were measured with high-performance liquid chromatography electrochemical detection, and CSF protein levels were measured with turbidimetry. RESULTS: The SPD was well tolerated in all monkeys for up to 11 months. The behavioral study revealed that during both saline and muscimol SPD treatment, the monkeys could achieve the maximum motor performance of 40 food-pellet removals per session, as before surgery. The EEG study showed that local EEG power spectra were not affected by muscimol treatment with SPD. The neurochemical study demonstrated that the administration of 1.0 mM muscimol into the neocortical subarachnoid space led to no detectable levels of this compound in the blood and cisternal CSF, as measured 1-125 minutes after delivery. Total protein levels were within the normal range in the cisternal CSF, but protein levels in the cortical-site CSF were significantly higher than normal: 361 ± 81.6 mg/dl. Abrupt discontinuation of 3-month, periodic, subdural muscimol treatments induced withdrawal seizures, which could be completely prevented by gradually tapering off the subdural muscimol concentration from 1.0 mM to 0.12-0.03 mM over a period of 2 weeks. The monkeys' general health and weight were maintained. Infection occurred only in one monkey 9 months after surgery. CONCLUSIONS: Long-term, periodic, transmeningeal muscimol delivery with the SPD is essentially a safe procedure. If further improved and successfully adapted for use in humans, the SPD can be used for the treatment of intractable focal neocortical epilepsy affecting approximately 150,000 patients in the US.


Subject(s)
Anticonvulsants/administration & dosage , Anticonvulsants/therapeutic use , Behavior, Animal/drug effects , GABA Agonists/administration & dosage , GABA Agonists/therapeutic use , Muscimol/administration & dosage , Muscimol/therapeutic use , Animals , Anticonvulsants/adverse effects , Body Weight/physiology , Cerebrospinal Fluid Proteins/analysis , Chromatography, High Pressure Liquid , Convulsants , Drug Implants , Electroencephalography , Electrophysiology , Epilepsy, Frontal Lobe/drug therapy , Frontal Lobe/surgery , GABA Agonists/adverse effects , Macaca radiata , Male , Muscimol/adverse effects , Neurosurgical Procedures/methods , Seizures/prevention & control , Software , Subdural Space/physiology , Subdural Space/surgery , Substance Withdrawal Syndrome
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