Biomedical subjects

A R West

Publications and source records attributed to A R West.

10 recordsLinked to original sources

PubMed2000

Dopamine-mediated regulation of striatal neuronal and network interactions.

The dopaminergic system exerts dynamic modulation of glutamatergic afferent drive that is dependent on the temporal pattern of the dopaminergic input and the subtypes of striatal neurons affected. The differences in feedforward inhibition between striatal neurons comprising the direct and indirect output pathway confer distinct response-pattern differences in their respective targets,supporting brief bursts of activity in Type-I neurons but attenuating repetitive activity in Type-II cells. This temporal patterning is further modulated by NO-mediated signaling, and by tonic and phasic dopamine-mediated stimulation, which exerts preferential actions on indirect and direct output neurons, respectively. As a result,the striatal network is forced into state-dependent patterns of activity that differentially regulate muscle tone and voluntary motor activity via distinct output projections from the striatum.

Animals↗

PubMed2000

Striatal nitric oxide signaling regulates the neuronal activity of midbrain dopamine neurons in vivo.

A major component of the cortical regulation of the nigrostriatal dopamine (DA) system is known to occur via activation of striatal efferent systems projecting to the substantia nigra. The potential intermediary role of striatal nitric oxide synthase (NOS)-containing interneurons in modulating the efferent regulation of DA neuron activity was examined using single-unit recordings of DA neurons performed concurrently with striatal microdialysis in anesthetized rats. The response of DA neurons recorded in the substantia nigra to intrastriatal artificial cerebrospinal fluid (ACSF) or drug infusion was examined in terms of mean firing rate, percent of spikes fired in bursts, cells/track, and response to electrical stimulation of the orbital prefrontal cortex (oPFC) and striatum. Intrastriatal infusion of NOS substrate concurrently with intermittent periods of striatal and cortical stimulation increased the mean DA cell population firing rate as compared with ACSF controls. This effect was reproduced via intrastriatal infusion of a NO generator. Infusion of either a NOS inhibitor or NO chelator via reverse microdialysis did not affect basal firing rate but increased the percentage of DA neurons responding to striatal stimulation with an initial inhibition followed by a rebound excitation (IE response) from 40 to 74%. NO scavenger infusion also markedly decreased the stimulation intensity required to elicit an IE response to electrical stimulation of the striatum. In single neurons in which the effects of electrical stimulation were observed before and after drug delivery, NO antagonist infusion was observed to decrease the onset latency and extend the duration of the initial inhibitory phase induced by either oPFC or striatal stimulation. This is the first report showing that striatal NO tone regulates the basal activity and responsiveness of DA neurons to cortical and striatal inputs. These studies also indicate that striatal NO signaling may play an important role in the integration of information transmitted to basal ganglia output centers via corticostriatal and striatal efferent pathways.

Animals↗

PubMed1999

The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia.

Since the discovery that the therapeutic efficacy of antipsychotic drugs was significantly correlated to their ability to block dopamine D2 receptors, abnormal dopamine transmission in the forebrain has been postulated to underlie psychosis in schizophrenia. In the past 15 years, an impressive amount of clinical and basic research aimed at the study of schizophrenia has indicated that prefrontal and temporal cortical abnormalities may be more important in the etiology of many of the symptoms of schizophrenia, including psychosis. However, the cortical systems that appear to have structural and/or metabolic abnormalities in schizophrenia patients potently regulate forebrain dopamine transmission through a number of mechanisms. In turn, dopamine modulates excitatory transmission mediated by frontal and temporal cortical projections to the basal ganglia and other regions. The present review summarizes the multiple interactions between forebrain DA systems and frontal and temporal corticostriatal transmission. It then examines the role of these interactions in normal behaviors and the psychopathology of schizophrenia.

Basal Ganglia↗

PubMed1998

Nitric oxide and potassium chloride-facilitated striatal dopamine efflux in vivo: role of calcium-dependent release mechanisms.

Previous studies investigating the calcium-dependency of nitric oxide-facilitated striatal dopamine efflux have produced conflicting results. In the current study, we have investigated the role of extracellular calcium in nitric oxide and potassium chloride-evoked striatal dopamine efflux in vivo using microdialysis. Dialysis probes were implanted in the anterior dorsal striatum of chloral hydrate-anesthetized rats. Intrastriatal infusion (20 min fraction) of the nitric oxide generators sodium nitroprusside (200 microM, 500 microM, or 1 mM) and 3-morpholinosydnonimine (1 mM) increased extracellular dopamine levels. The facilitatory effects of 3-morpholinosydnonimine and potassium chloride on dopamine efflux were attenuated following pretreatment (100 min) and co-infusion of calcium free artificial cerebral spinal fluid containing magnesium chloride. Local potassium chloride infusion (100 mM) administered alone elevated striatal dopamine efflux to a similar degree as potassium chloride (100 mM) delivered 60 min after 3-morpholinosydnonimine infusion. These results demonstrate that like potassium chloride, nitric oxide facilitates striatal dopamine efflux in vivo via a mechanism largely dependent on extracellular calcium. Also, as intrastriatal potassium chloride infusion evoked similar increases in extracellular dopamine levels in controls and subjects receiving pretreatment with the NO-generator 3-morpholinosydnonimine, it is unlikely that the functional integrity of DA nerve terminals is compromised via a neurotoxic disruption of plasma membrane potential following enhanced striatal NO production.

Animals↗

PubMed1997

Inhibition of glutamate reuptake potentiates endogenous nitric oxide-facilitated dopamine efflux in the rat striatum: an in vivo microdialysis study.

The current study investigated the effects of the nitric oxide synthase (NOS) substrate, N(G)-hydroxy-L-arginine (H-ARG) and the selective glutamate (GLU) reuptake inhibitor (2S)-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) on striatal dopamine (DA) and glutamate (GLU) efflux in vivo. Concentric microdialysis probes were stereotaxically implanted in the anterior-medial striatum of chloral hydrate-anesthetized rats. Intra-striatal infusion of PDC (200 microM) elevated extracellular (EC) DA and GLU levels concurrently over a 10 fraction collecting period without affecting EC asparagine levels. Infusion of H-ARG (200 microM) for six 20-min fractions, also significantly elevated EC DA levels. In the presence of PDC (200 microM), co-perfusion of H-ARG (200 microM) resulted in supra-additive increases in EC DA levels. The synergistic effect of PDC and H-ARG infusion on DA efflux was attenuated by co-infusion of the NOS inhibitor, 7-nitroindazole (100-200 microM). These results suggest that while both endogenous NO and GLU regulate striatal DA efflux via facilitatory influences, enhanced glutamatergic tone on striatal NOS-containing neurons may potentiate NO-synthesis and subsequently NO-induced DA efflux.

Animals↗

PubMed1996

Desensitization of 5-hydroxytryptamine-facilitated dopamine release in vivo.

Desensitization to serotonin (5-hydroxytryptamine, 5-HT)-facilitated dopamine release in vivo develops following either continuous or repeated pulses of 5-HT. For instance, an initial 20 min pulse of 5-HT (10 microM) produced a 715 +/- 150% increase in basal dopamine, an effect which steadily declined over 5 subsequent fractions to 222 +/- 80%. Also, secondary pulses (s2) of 5-HT administered 40 min following the primary pulse (s1), elicited a 327 +/- 16% increase in dopamine levels, significantly decreased from the primary s1 pulse. Augmentation of either protein kinase A or protein kinase C systems attenuated 5-HT-facilitated dopamine release, suggesting a role for protein kinases in regulating the desensitization process.

Animals↗

PubMed1996

Regulation of serotonin-facilitated dopamine release in vivo: the role of protein kinase A activating transduction mechanisms.

Recent neuroanatomical, biochemical, and electrophysiological studies suggest that serotonin (5HT) can modulate dopaminergic function at the level of the cell body and the nerve terminal. The receptor subtypes, regulatory processes, and intracellular transduction mechanisms mediating these interactions remain to be characterized. The potential involvement of cAMP in mediating 5HT-facilitated increases in extracellular levels of striatal dopamine (DA) was assessed using in vivo microdialysis. Local infusion of 0.4 nmol 5HT delivered via probes located in the anterior striata of chloral hydrate-anesthetized male rats significantly increased extracellular DA levels to approximately 700% of basal control levels. Local, intrastriatal infusion of either 2 nmol forskolin, 2 nmol rolipram, 100 nmol isobutylmethylxanthine, or 200 nmol dibutyryl cAMP significantly increased basal DA levels to 28 +/- 3%, 143 +/- 5%, 56 +/- 7%, and 52 +/- 3% above control levels, respectively. Additionally, coperfusion of any of these agents with 5HT significantly decreased the 5HT-facilitory effect on DA release to approximately 50% of observed 5HT controls. The current results suggest a role for the cAMP second-messenger systems in modulating 5HT-facilitated DA release.

Animals↗

PubMed1996

Intrastriatal infusion of (+/-)-S-nitroso-N-acetylpenicillamine releases vesicular dopamine via an ionotropic glutamate receptor-mediated mechanism: an in vivo microdialysis study in chloral hydrate-anesthetized rats.

The existence of both nitric oxide synthase (NOS) immunoreactive interneurons and amino acid neurotransmitter-mediated nitric oxide (NO) release in the striatum suggests a role for NO in modulating striatal function. To explore the potential interaction between NO and dopaminergic neurotransmission, the NO-releasing agent (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) was administered locally into the anterior medial striatum of chloral hydrate-anesthetized rats. SNAP, at 0.5, 1, and 2 mM concentrations, elevated striatal extracellular (EC) dopamine (DA) to 200 +/- 42, 472 +/- 120, and 2,084 +/- 496%, respectively, above baseline levels. Perfusion with (+/-)-penicillamine (PEN, 1 mM), the non-NO-containing carrier component of SNAP, was ineffective, indicating that PEN is not responsible for SNAP-mediated DA release. Additional microdialysis experiments suggest SNAP-mediated DA release is not due to NO-induced neurotoxicity or blockade of the DA transporter. The DA-releasing effect of SNAP was attenuated under calcium-free conditions and abolished in rats pretreated with reserpine (5 mg/kg), implicating a calcium-sensitive vesicular-dependent release process. To determine the mechanism of SNAP-mediated DA release, the guanylyl cyclase (GC) inhibitor LY 83583 (100 microM) was administered 100 min before and during the SNAP pulse. LY 83583 elevated EC DA levels approximately fivefold and potentiated the DA-releasing effect of SNAP to 2,598 +/- 551% above basal DA levels. Similar pretreatments with both the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 (10 microM) and the competitive NMDA-receptor antagonist (+/-)-3-(carboxypiperazin-4-yl) propyl-1-phosphonic acid [(+/-)-CPP, 100 microM] blocked SNAP-mediated DA release. SNAP-mediated DA release was also significantly blunted by pretreatment and coperfusion with MgSO4 (10 mM) and 6,7-dinitroquinoxaline-2,3-dione (DNQX, 10 microM) but not (+)-2-amino-3-phosphonopropionic acid (AP-3, 10 microM). These results suggest that NO releases DA via a calcium-sensitive vesicular-dependent process that is independent of GC activation. In addition, NMDA and kainate/ (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated mechanisms are implicated in NO-induced DA release.

Anesthesia↗

PubMedDate not supplied

Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: role of ionotropic glutamate receptor-dependent mechanisms.

We have investigated the influence of the nitric oxide synthase (NOS) substrate, NG-hydroxy-L-arginine (H-ARG) on dopamine (DA) and glutamate (GLU) efflux in vivo using concentric microdialysis probes implanted in the anterior-medial striatum of chloral hydrate-anesthetized rats. Intrastriatal infusion of H-ARG (100 microM, 200 microM, or 1 mM for 120 min) increased DA efflux in a dose-dependent fashion. The facilitatory effect of H-ARG (1 mM) on DA efflux was abolished following pretreatment (80 min) with the constitutive NOS inhibitor 7-nitroindazole (7-NI, 10 microM) but unaffected by L-NG(1-iminoethyl) lysine (100 microM) infusion. As both H-ARG (1 mM) and the NO-generator (+/-)-S-nitroso-N-acetylpenicillamine (1 mM) were observed to increase GLU efflux concurrently with the effect on DA efflux, we evaluated the potential intermediary role of GLU in NO-facilitated DA efflux using ionotropic GLU receptor antagonists. Local infusion of dizocilpine maleate (10 microM) or (+/-)-2-amino-3-[3-(carboxymethoxy)-5-methyl-isoxazol-4-yl] propionic acid (100 microM), attenuated the H-ARG (1 mM)-induced elevation of extracellular DA levels. Conversely, similar treatment with the kainate receptor antagonist d-gamma-glutamyl-aminomethanesulfonic acid did not alter H-ARG-induced DA efflux. To evaluate the regulatory influence of striatal NO on NMDA receptor activation, NMDA (100 microM) was co-perfused with either H-ARG (2 mM) or 7-NI (10 microM). While co-perfusion with 7-NI potentiated NMDA-induced DA efflux, similar treatment with H-ARG (2 mM) abolished the effect. These results demonstrate that endogenous NO production, stimulated via H-ARG-dependent activation of type 1 NOS, enhances striatal DA efflux via an increase in glutamatergic tone on ionotropic GLU-receptors. At higher levels of NOS activation (following H-ARG (2 mM) or NMDA infusion), NO may block glutamatergic neurotransmission via inhibition of NMDA receptor function.

Animals↗

PubMedDate not supplied

Making a difference: immunizing infants and children.

Childhood immunizations, particularly for those under the age of two, is a major health issue. Since the measles epidemic in 1989-1991, the American Nurses Association/Foundation has collaborated with Every Child By Two (ECBT) to protect the nation's youngest from the ravages of vaccine preventable disease. Immunizations are the first line of prevention for infants and children. Healthy People 2000, together with the Presidential Administration's Childhood Immunization Initiative has mandated a goal of 90% immunizations for children under the age of two by the year 2000. As a nation, we are very close to meeting that goal.

Adolescent↗