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P Bickford-Wimer

Publications and source records attributed to P Bickford-Wimer.

9 recordsLinked to original sources
PubMed1991

Effects of locally applied D1 and D2 agonists on striatal neurons with 6-OHDA and pertussis toxin lesions.

Electrophysiological recordings were performed on caudate neurons in rats with dopamine (DA) depleted striatum in combination with pertussis toxin (PT) lesions. Pertussis toxin inactivates the G protein coupled to D2 receptors. DA depletions were performed by unilateral injections of 6-hydroxydopamine (6-OHDA). After the 6-OHDA lesion, rats were challenged with low doses of apomorphine. When a double peak rotational pattern was stable over repeated rotational tests, PT was injected into striatum ipsilateral to the DA depleted side. Two days after the PT injections extracellular recordings with local applications of the D1 agonist SKF 38393 and the D2 agonist N-0437 were performed. Spontaneous firing rates, measured before drug application, were elevated in animals with both 6-OHDA and 6-OHDA/PT combination of lesions. In rats with only 6-OHDA lesions, a supersensitivity to N-0437 was observed, while no significant change in response to the D1 agonist was detected. Recordings from caudate neurons in rats with a combination of 6-OHDA and PT resulted in no response to the D2 agonist. However, a subsensitivity to the D1 agonist was detected and only 60% of neurons were inhibited by SKF 38393. Taken together, these data suggest an interaction between the D1 and D2 receptors, which is revealed only after an upregulation of the D2 receptors and subsequent blockade of D2 mediated effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Electrically-evoked release of norepinephrine in the rat cerebellum: an in vivo electrochemical and electrophysiological study.

Norepinephrine (NE) release from the locus coeruleus (LC) afferents to the cerebellar cortex of urethane anesthetized rats was achieved by electrical stimulation of the locus coeruleus or by local administration of potassium into the cerebellum. Both methods evoked an overflow of NE-like electroactive species. Electrically-evoked and potassium-induced overflow of NE-like responses were found to be reversible and reproducible. Releases were not observed in cerebellar white matter, an area which is relatively devoid of monoamine containing terminals. Systemic administration of desipramine, a potent and selective norepinephrine re-uptake blocker, significantly augmented the electrically-evoked electrochemical responses. Measurements of evoked release taken using high-speed chronoamperometry support the idea that a predominant contributor to electrically-induced signals was NE. Electrophysiological recordings of single Purkinje cells were performed with the same Nafion-coated single carbon fiber electrodes used for electrochemical recordings. Electrical stimulation of the LC was seen to depress Purkinje cell firing rates; an increase in electroactive species was detected at the same site that paralleled the time course of the electrophysiological response. These studies provide further direct evidence that the LC norepinephrine-containing cells have a direct inhibitory effect on Purkinje cells in the cerebellum, and that both pre- and postsynaptic events can be measured with the same recording sensor.

Animals↗
PubMed1990

Effects of pertussis toxin on caudate neuron electrophysiology: studies with dopamine D1 and D2 agonists.

The selective D1 and D2-agonists SKF-38393 and N-0437 respectively, were tested in caudate pretreated with PT. A paired recording paradigm was used where the contralateral untreated caudate served as a control. Micropipettes were used to locally apply SKF-38393 and N-0437 onto neurons in both control and PT-pretreated caudate. A significant attenuation of the responses to the D2 agonist were observed after PT administration. Only 1 out of 12 cells tested on the PT side demonstrated any response to locally applied N-0437, whereas 90% of the neurons responded to the drug on the control side. Neurons from both the PT-pretreated and control caudates responded to locally applied SKF-38393. In addition to the specific D1 and D2 receptor agonists, DA and the indirect dopamine agonist PCP were tested for changes in responsiveness. Dopamine was equally efficacious at both control and PT-pretreated caudate neurons, which suggest that dopamine locally applied from the micropipette can interact with the unperturbed D1 receptors in the PT-pretreated caudate. On the other hand, the response to PCP was significantly attenuated after PT administration, which suggest that endogenously released DA preferentially interacts with the D2 receptor subtype. Taken together these data suggest an important role for the D2 receptor in the physiology of dopamine responsiveness in the caudate nucleus.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Pertussis toxin lesioning of the nucleus caudate-putamen attenuates adenylate cyclase inhibition and alters neuronal electrophysiological activity.

Receptor-mediated inhibition of brain adenylate cyclase activity has been well characterized at the biochemical level. However, less understood is how these, typically modest, inhibitory effects on cyclase activity correlate with the electrophysiological activity of brain preparations. In addressing this question, we injected pertussis toxin (PT) into the nucleus caudate-putamen of intact rats, and observed a subsequent attenuated inhibition of adenylate cyclase activity in caudate membranes, which correlated with altered electrophysiological activity in this nucleus. PT completely abolished and electrophysiological activity in this nucleus. PT completely abolished and significantly reduced, respectively, dopamine D2 and opioid receptor-mediated inhibition of adenylate cyclase. In addition, pretreatment of rat caudate nuclei with PT attenuated the amount of in vitro ADP-ribosylation of 41,000 and 39,000 Da PT substrates measured in caudate membranes. Extracellular recording of the spontaneous activity of caudate neurons revealed that PT pretreatment significantly increased firing rates above those of cells recorded from sham-operated and unoperated controls. Furthermore, a significantly greater number of cells pretreated with PT displayed interspike intervals less than 50 ms, reflecting 'burst-like' activity. In short, the inactivation of G-proteins serving as PT substrates in rat caudate-putamen renders caudate cells more likely to fire spontaneously, and to fire in bursting, rather than uniform, patterns of activity. These observations suggest that PT substrates identical or similar to those which regulate adenylate cyclase, play a significant role in governing the electrophysiological behavior of intact caudate neurons.

Action Potentials↗
PubMed1987

Human fetal cerebellar and cortical tissue transplanted to the anterior eye chamber of athymic rats: electrophysiological and structural studies.

Human fetal tissue fragments from cortex cerebri and cerebellum were grafted to the anterior chamber of the eye of adult athymic nude rats. The grafts were obtained from tissue fragments recovered after elective routine abortions, performed in weeks 8-11 of gestation. Both cerebellar and cortex cerebri grafts survived and developed in the anterior chamber of the eye for 1-4 months. The transplants slowly became vascularized from the host iris. The grafts developed blood vessels with laminin-immunoreactive walls and contained relatively high amounts of glial fibrillary acidic protein- and neurofilament-immunoreactivity in the neuropil after 4 months in oculo. Recordings of extracellular action potentials from the grafts revealed spontaneously active neurons with action-potential waveforms similar to those observed in immature rodents. Morphologically, the grafts showed no signs of rejection. Clusters and bands of large neurons resembling Purkinje cells and dense aggregates of smaller granule-like cells could be found in the cerebellar grafts. Large neurons were also seen in the cortex grafts. Taken together, these data suggest that the athymic rat may serve as a useful tool for studies of central nervous system tissue from otherwise immunologically incompatible species.

Action Potentials↗
PubMed1987

Neurobiological studies of sensory gating in schizophrenia.

The sensory disturbance in schizophrenia is often described as an inability to filter out extraneous noise from meaningful sensory inputs. The neurobiological basis of this inability to filter has been examined using auditory evoked potentials, which are computerized averages of the brain's electrical response to sound. The sounds are presented in pairs to test the ability of the brain to inhibit, or gate, its response to a repeated stimulus. Schizophrenic patients lack the ability to gate the neuronal response shown by a particular wave, the P50 wave. The measurement of this deficit in human subjects and the exploration of its neurobiology in animals has produced evidence about several issues in the pathophysiology of schizophrenia: (1) the role of dopamine in improvement of sensory function in schizophrenic patients treated with neuroleptic drugs, (2) the interaction between familial or genetic deficits in sensory functioning in schizophrenic patients and possible abnormalities in dopamine metabolism, and (3) a mechanism by which noradrenergic hyperactivity in mania and other psychiatric illnesses might mimic some pathophysiological deficits in schizophrenia.

Antipsychotic Agents↗
PubMedDate not supplied

Age-related subsensitivity of cerebellar Purkinje neurons to locally applied beta 1-selective adrenergic agonist.

Previous electrophysiological studies in aged rats have revealed a number of deficits in noradrenergic neurotransmission in the central nervous system. Such deficits include subsensitivity to the depressant effects of norepinephrine on cerebellar Purkinje neurons, which has been attributed specifically to altered beta adrenergic receptor-mediated processes. The objective of this study was to determine which beta adrenergic receptor subtype, beta 1 or beta 2, is responsible for this age-related subsensitivity. The effects of beta 1 and beta 2 agonists on spontaneous activity of Purkinje neurons was first examined in young rats and the selectivity of these agents was validated using selective beta 1 and beta 2 antagonists. The effects of the selective beta 1 and beta 2 agonists were then compared in young (3-month-old) and aged (18- and 26-month-old) Fischer 344 rats. These agents were applied to Purkinje neurons by pressure microejection from multibarreled micropipettes and the change in neuronal action potential discharge rate was recorded. Both dobutamine, a beta 1-selective agonist, and zinterol, a beta 2-selective agonist, induced dose-dependent inhibitions of Purkinje cell firing rate. Dobutamine-induced inhibitions were blocked by the selective beta 1 antagonist, ICI 89406 and not by the beta 2-selective antagonist, ICI 118551; conversely, zinterol-induced inhibitions were not blocked by ICI 89406 but were blocked by the presence of ICI 118551. Purkinje neurons of both groups of aged rats were significantly less sensitive to locally applied dobutamine than Purkinje cells of young rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMedDate not supplied

Elementary neuronal dysfunctions in schizophrenia.

This paper describes an elementary deficit in sensory processing in people with schizophrenia. If paired sounds are presented to normal subjects, the response to the first sound, as measured by the P50 wave of the auditory-evoked potential, is much greater than the response to the second sound. The diminished response to the second sound is an example of a sensory gating mechanism that enables people to regulate their vigilance so that they can either detect all sounds in the environment or ignore most of them, in favor of narrowing the focus of their concentration. In schizophrenia, this mechanism is usually deficient; patients are in a state of hypervigilance and have diminished abilities to focus their attention. The deficiency appears to be genetically determined and to involve the brainstem control of sensory input to the hippocampus. Such sensory gating deficits may underlie more complex psychotic symptoms, such as hallucinations and delusions. Further studies of their neurobiology could lead to increased understanding of the pathophysiology of schizophrenia.

Arousal↗