Biomedical subjects

Anthony R West

Publications and source records attributed to Anthony R West.

11 recordsLinked to original sources

PubMed2007

Dopamine D2 receptor-dependent modulation of striatal NO synthase activity.

RATIONALE: Striatal nitric oxide (NO)-producing interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and are regulated by phasic DA transmission. Classic antipsychotic drugs elevate neuronal NO synthase (NOS) expression in the rat striatum. Given that NO signaling potently modulates the membrane excitability of striatal projection neurons, it is plausible that up-regulation of NOS activity after DA D2 receptor blockade contributes to the therapeutic efficacy and/or motor side effects associated with antipsychotic drugs. OBJECTIVES: This study assessed the impact of DA D(2) receptor activation on striatal NOS activity in vivo. Characterization of the dopaminergic regulation of striatal NO signaling will be relevant for understanding the mechanism(s) of action of antipsychotic drugs. MATERIALS AND METHODS: Striatal NO efflux, evoked via electrical stimulation of the substantia nigra (SN) or systemic administration of the DA D(1) receptor agonist SKF 81297, was assessed in anesthetized rats using an NO-selective amperometric microsensor. RESULTS: The facilitatory effect of SN stimulation on striatal NO efflux was attenuated by systemic administration of the DA D(2) receptor agonist quinpirole. Conversely, administration of the DA D(2) receptor antagonist eticlopride augmented evoked NO efflux. NO efflux induced by systemic administration of SKF 81297 was attenuated by quinpirole and restored by co-administration of quinpirole and eticlopride. The facilitatory effect of SKF 81297 on NO efflux was also significantly attenuated after pretreatment with the non-specific NOS inhibitor methylene blue. CONCLUSIONS: Activation of NO synthesis by phasic DA transmission is down-regulated via a DA D2 receptor-dependent mechanism. DA D(2) receptor activation opposes DA D(1) receptor activation of NO synthesis at a site postsynaptic to the DA terminal. Further studies examining NO-DA dynamics may have potential to reveal novel therapeutic strategies to treat various brain disorders.

Animals↗

PubMed2006

EELS characterisation of bulk CaCu3Ti4O12 ceramics.

CaCu3Ti4O12 (CCTO) is a cubic perovskite phase and sintered ceramics exhibit high permittivity at room temperature. Electron energy-loss spectroscopy (EELS) and energy dispersive X-ray spectrometry (EDS) data have been collected from samples of CCTO to relate the observed electrical properties to the microstructure and chemistry on the nanoscale. CCTO ceramics were sintered for 24h at 1115 degrees C in air, giving a grain size of 50-300 microm. Ti L(2,3)-, Cu L(2,3)- and O K-edge EEL data were collected for bulk CCTO (within grain) and compared with well characterised Ti-oxides, CaTiO3 and BaTiO3 perovskites. The bulk metal L(2,3)-edge data for CCTO suggest that Cu is divalent and Ti is present as Ti4+. The O K-edge of CCTO shows increased near-edge structure (NES) compared to those of the simple perovskites.

Journal Article↗

PubMed2006

Inorganic functional materials: optimization of properties by structural and compositional control.

A review is given of the strategies used to dope inorganic solids and the consequences for properties such as ionic and electronic conductivity. Doping mechanisms involve either substitution of foreign ions onto lattice sites, creation of vacancies on either cation or anion sites, or population of normally empty interstitial sites by either anions or cations. Mechanisms for charge compensation associated with aliovalent doping are reviewed and examples are given in the fields of solid state ionics and high-temperature superconductivity. The strategies used for targeting materials with new properties are reviewed, including a surprising number of cases where startling new properties are encountered in well-known materials. Specific examples discussed include MgB2 superconductor, Na beta-alumina sodium ion conductor, Ca12Al14O33 oxide ion conductor, LiCoMnO4 lithium battery cathode, doped Li4SiO4 tunable lithium ion conductor, and La-doped BaTiO3 ferroelectric, which can be either semiconducting or insulating. Examples are also given of a curious observation that extraordinary properties are often encountered in materials that are on the edge of stability, either structurally or compositionally or at the crossover between different property types.

Journal Article↗

PubMed2006

Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D(1/5) receptor-dependent mechanism.

Dysfunctional neurotransmission within striatal networks is believed to underlie the pathophysiology of several neurological and psychiatric disorders. Nitric oxide (NO)-producing interneurons have been shown to play a critical role in modulating striatal synaptic transmission. These interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and may be regulated by DA receptor activation. In the current study, striatal NO efflux was measured in anesthetized male rats using an NO-selective electrochemical microsensor and the role of DA in modulating NO synthase (NOS) activity was assessed during electrical or chemical (bicuculline) stimulation of the substantia nigra (SN). Electrical stimuli were patterned to approximate the natural single spike or burst firing activity of midbrain DA neurons. Electrical stimulation of the SN at low frequencies induced modest increases in striatal NO efflux. In contrast, train stimulation of the SN robustly increased NO efflux in a stimulus intensity-dependent manner. NO efflux evoked by SN stimulation was similar in chloral hydrate- and urethane-anesthetized rats. The facilitatory effect of train stimulation on striatal NO efflux was transient and attenuated by systemic administration of the neuronal NOS inhibitor 7-nitroindazole and the nonselective NOS inhibitor methylene blue. Moreover, the increase in NO efflux observed during chemical and train stimulation of the SN was attenuated following systemic administration of the DA D(1/5) receptor antagonist SCH 23390. SCH 23390 also blocked NO efflux induced by systemic administration of the D(1/5) agonist SKF 81297. These results indicate that neuronal NOS is activated in vivo by nigrostriatal DA cell burst firing via a DA D(1/5)-like receptor-dependent mechanism.

Anesthesia↗

PubMed2004

Li(+) ion conductivity in rock salt-structured nickel-doped Li(3)NbO(4).

Two mechanisms of doping Li(3)NbO(4), which has an ordered, rock salt superstructure, have been established. In the "stoichiometric mechanism", the overall cation-to-anion ratio is maintained at 1:1 by means of the substitution 3Li(+) + Nb(5+) --> 4Ni(2+). In the "vacancy mechanism", Li(+) ion vacancies are created by means of the substitution 2Li(+) --> Ni(2+). Solid solution ranges have been determined for both mechanisms and a partial phase diagram constructed for the stoichiometric join. On the vacancy join, the substitution mechanism has been confirmed by powder neutron diffraction; associated with lithium vacancy creation, a dramatic increase in Li(+) ion conductivity occurs with increasing Ni content, reaching a value of 5 x 10(-4) Omega(-1) cm(-1) at 300 degrees C for composition x= 0.1 in the formula Li(3-2x)Ni(x)NbO(4). This is the first example of high Li(+) ion conductivity in complex oxides with rock salt-related structures.

Journal Article↗

PubMed2004

The nitric oxide-guanylyl cyclase signaling pathway modulates membrane activity States and electrophysiological properties of striatal medium spiny neurons recorded in vivo.

Nitric oxide (NO)-releasing interneurons are believed to regulate the activity of striatal medium spiny neurons (MSNs) that contain the NO effector enzyme guanylyl cyclase (GC). The involvement of NO-GC signaling in modulating steady-state membrane activity of striatal MSNs was examined using in vivo intracellular recordings in rats. Intrastriatal infusion of a neuronal NO synthase inhibitor or a NO scavenger via reverse microdialysis consistently decreased the amplitude of spontaneously occurring depolarized plateau potentials (up events). Intrastriatal infusion of a NO scavenger also decreased the amplitude of EPSPs evoked during electrical stimulation of the orbital prefrontal cortex. The effect of the NO scavenger on spontaneous up events was partially reversed by coperfusion with a cell-permeable cGMP analog. Intracellular injection of MSNs with a soluble GC inhibitor resulted in large decreases in the following: (1) spontaneous up-event amplitude, (2) responsiveness to depolarizing current, (3) action potential amplitude, and (4) input resistance. These effects were partially reversed by coinjection of cGMP. Conversely, intracellular injection of a phosphodiesterase inhibitor increased MSN neuron membrane excitability. These results indicate that, in the intact animal, the NO signaling pathway exerts a powerful tonic modulatory influence over the membrane activity of striatal MSNs via the activation of GC and stimulation of cGMP production.

Animals↗

PubMed2003

Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission.

The mesolimbic dopamine system is centrally involved in reward and goal-directed behavior, and it has been implicated in multiple psychiatric disorders. Understanding the mechanism by which dopamine participates in these activities requires comprehension of the dynamics of dopamine release. Here we report dissociable regulation of dopamine neuron discharge by two separate afferent systems in rats; inhibition of pallidal afferents selectively increased the population activity of dopamine neurons, whereas activation of pedunculopontine inputs increased burst firing. Only the increase in population activity increased ventral striatal dopamine efflux. After blockade of dopamine reuptake, however, enhanced bursting increased dopamine efflux three times more than did enhanced population activity. These results provide insight into multiple regulatory systems that modulate dopamine system function: burst firing induces massive synaptic dopamine release, which is rapidly removed by reuptake before escaping the synaptic cleft, whereas increased population activity modulates tonic extrasynaptic dopamine levels that are less influenced by reuptake.

Afferent Pathways↗

PubMed2003

Electrophysiological interactions between striatal glutamatergic and dopaminergic systems.

Glutamatergic and dopaminergic systems play a primary role in frontal-subcortical circuits involved in motor and cognitive functions. Considerable evidence has emerged indicating that the complex interaction between these neurotransmitter systems within the dorsal striatum and nucleus accumbens is critically involved in the gating of information flow in these highly integrative brain regions. As a result, disruptions of the interaction between glutamate and dopamine has been proposed as a pathological basis for a number of disorders, including the pathophysiology of schizophrenia. In this chapter, we discuss recent studies that have significantly advanced our understanding of the reciprocal interactions between glutamatergic and dopaminergic systems within the striatal complex in the normal brain and in pathological states.

Animals↗

PubMed2002

Regulation of striatal dopamine neurotransmission by nitric oxide: effector pathways and signaling mechanisms.

An important role for the reactive gas nitric oxide (NO) in regulating striatal dopaminergic neurotransmission was identified shortly after initial observations indicated that this unorthodox neurotransmitter mediates many of the influences of glutamatergic neurotransmission in the cerebellum, cortex, and hippocampus. While the precise actions of NO on striatal presynaptic and postsynaptic elements remain to be fully characterized, the recent application of sophisticated anatomical, neurochemical, and electrophysiological approaches to the study of nitrergic signaling has revealed that NO exerts a powerful influence both on tonic extracellular dopamine (DA) levels and phasic DA neuron spike activity via the modulation of intrinsic striatal mechanisms and striatonigral feedback loops. Although the nature of the NO-mediated modulatory influence on DA neurotransmission was initially clouded by seemingly conflicting neurochemical observations, a growing body of literature and understanding of the diverse signaling mechanisms and effector pathways utilized by NO indicates that NO exerts a primary facilitatory influence over tonic and phasic dopaminergic neurotransmission under physiological conditions. A review of neurochemical and electrophysiological studies examining the influence of endogenous and exogenous NO on DA neurotransmission indicates that NO signaling exerts multiple effects on local striatal circuits and projection neurons involved in regulating basal ganglia output and nigrostriatal DA neuron activity. In addition to summarizing these influences, the current review focuses on the mechanisms utilized by striatal NO signaling pathways involved in modulating DA transmission at the level of the terminal and cell body and attempts to integrate these observations into a functional model of NO-dependent regulation of basal ganglia systems.

Animals↗

PubMed2002

Opposite influences of endogenous dopamine D1 and D2 receptor activation on activity states and electrophysiological properties of striatal neurons: studies combining in vivo intracellular recordings and reverse microdialysis.

The tonic influence of dopamine D1 and D2 receptors on the activity of striatal neurons in vivo was investigated by performing intracellular recordings concurrently with reverse microdialysis in chloral hydrate-anesthetized rats. Striatal neurons were recorded in the vicinity of the microdialysis probe to assess their activity during infusions of artificial CSF (aCSF), the D1 receptor antagonist SCH 23390 (10 microm), or the D2 receptor antagonist eticlopride (20 microm). SCH 23390 perfusion decreased the excitability of striatal neurons exhibiting electrophysiological characteristics of spiny projection cells as evidenced by a decrease in the maximal depolarized membrane potential, a decrease in the amplitude of up-state events, and an increase in the intracellular current injection amplitude required to elicit an action potential. Conversely, a marked depolarization of up- and down-state membrane potential modes, a decrease in the amplitude of intracellular current injection required to elicit an action potential, and an increase in the number of spikes evoked by depolarizing current steps were observed in striatal neurons after local eticlopride infusion. A significant increase in maximal EPSP amplitude evoked by electrical stimulation of the prefrontal cortex was also observed during local eticlopride but not SCH 23390 infusion. These results indicate that in intact systems, ongoing dopaminergic neurotransmission exerts a powerful tonic modulatory influence on the up- and down-state membrane properties of striatal neurons and controls their excitability differentially via both D1- and D2-like receptors. Moreover, a significant component of D2 receptor-mediated inhibition of striatal neuron activity in vivo occurs via suppression of excitatory synaptic transmission.

Action Potentials↗

PubMed2002

Direct examination of local regulation of membrane activity in striatal and prefrontal cortical neurons in vivo using simultaneous intracellular recording and microdialysis.

Slice preparations are typically used to study the effects of pharmacological manipulations on the electrophysiological activity of mature neurons. However, the severing of afferent inputs is known to significantly change the natural membrane activity of the neuron. To study the effects of local pharmacological manipulations on neurons in the intact brain, we combined the methods of microdialysis and intracellular recording in vivo. After implantation of a microdialysis probe into the prefrontal cortex (PFC) or striatum, intracellular recordings were conducted within approximately 500 microm of the active surface of the probe. The spontaneous membrane activity, passive membrane properties, and intracellularly and synaptically evoked responses of striatal and cortical neurons recorded during perfusion of artificial cerebral spinal fluid were not different from that of neurons recorded in intact animals. Moreover, in the PFC, local perfusion with glutamate or N-methyl-D-aspartate depolarized neurons and increased spike activity. Conversely, local perfusion of tetrodotoxin hyperpolarized neurons while markedly reducing spontaneous membrane depolarizations and eliminating spike activity. In the striatum, local perfusion of the gamma-aminobutyric acid(A) receptor antagonist bicuculline rapidly depolarized neurons and increased spontaneous spike activity. Given that striatal and PFC neurons recorded in animals undergoing microdialysis in the current study exhibited electrophysiological properties similar to those recorded in intact controls, it is likely that the effects of local microdialysis on ongoing synaptic activity, neuronal excitability, and endogenous neurotransmitter levels are minimal. We conclude that the use of local microdialysis with intracellular recording is a powerful method for studying local receptor regulation of synaptic activity in vivo.

Action Potentials↗