Improvement to the Hargreaves paw flick method.
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Animals↗
Biomedical subjects
G M Alexander
Publications and source records attributed to G M Alexander.
Testosterone and sexual behavior in oral contraceptive users and nonusers: a prospective study.
The relationship between plasma testosterone (T) secretion and patterns of sexual behavior was examined in 18 women using oral contraceptives (OCs) and 13 nonusers matched for partner availability. Retrospective assessments of perimenstrual symptoms, sexual attitudes, and sexual experience were obtained and women completed daily ratings of the frequency of sexual activities and the level of well-being for 1 month. Plasma levels of sex hormone binding globulin (SHBG), progesterone, Total T, Free T, and non-SHBG bound T were determined by radioimmunoassay at four phases of the pill or menstrual cycle. Overall, women not using OCs had higher plasma levels of Total, Free, and non-SHBG bound T and lower plasma levels of SHBG than those of OC users. Further, only nonusers had perimenstrual decreases in plasma levels of Total and Free T. The two groups were comparable on most retrospective measures. However, OC users reported more satisfaction with their sexual partners than did nonusers and prospective monitoring revealed that they engaged in sexual interactions more frequently than did nonusers across the cycle. In contrast, both groups reported a similar frequency of autosexual activities across the cycle. There were no correlations between average levels of T and levels of sexual desire, sexual interactions, or autosexuality. Moreover, only nonusers reported a decrease in levels of sexual desire during the perimenstrual period that was associated with the changes in Free T over the menstrual cycle.
Adolescent↗
Local cerebral glucose metabolism after global ischemia: treatment by ventriculocisternal perfusion with a fluorocarbon emulsion.
The local cerebral metabolic rate for glucose (LCMRg) was measured in cats subjected to global cerebral ischemia (GCI). Control (nonperfused) cats showed decreased LCMRg (P less than 0.01) in the frontal, temporal, parietal, and occipital cortex 9.5 hours after a 10-minute exposure to GCI. Cats perfused ventriculocisternally with oxygenated nutrient solution (ONS) for 8 hours showed significant increases in the LCMRg (p less than 0.05) at 9.5 hours postischemia in the parietal and occipital areas over the levels found in untreated ischemic cats. Supplementing the ONS perfusion medium with fluorocarbon (OFNS) increased the LCMRg (P less than 0.05) in the frontal, as well as the parietal and occipital areas, over that seen in untreated ischemic brains. The increase of LCMRg in three (rather than only two) cortical areas may be a result of the ability of the fluorocarbon in OFNS to deliver greater quantities of oxygen to the brain than ONS without fluorocarbon. Perfusion with OFNS without glucose, or with low (50 mg%) glucose, was more effective than OFNS with high (200 mg%) glucose in restoring LCMRg to normal in all four cortical areas affected by GCI. In five brain areas not affected by GCI, perfusion with OFNS having no glucose significantly increased LCMRg as compared to normal animals. This study demonstrates that OFNS perfused by the ventriculocisternal route can restore toward normal the LCMRg following GCI and that different concentrations of glucose in the perfusing fluid will have variable effects on LCMRg in certain brain areas.
Animals↗
Comparison of the effects of intracerebrally administered MPP+ (1-methyl-4-phenylpyridinium) in three species: microdialysis of dopamine and metabolites in mouse, rat and monkey striatum.
Intracerebral microdialysis in 3 awake species allowed the measurement of the basal output of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) from rat and mouse striatum and monkey caudate in vivo. The DOPAC/HVA ratios in dialysates from mouse and rat striatum were about 1 and 2 respectively, but only 0.09 in monkey caudate dialysates. The extracellular levels of the metabolites correlated well with reported tissue levels, while extracellular DA levels were 3 orders of magnitude lower than tissue concentrations. The effects of the intracerebrally administered dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) were essentially similar in the 3 species. In all cases an immediate, massive release of DA was accompanied by a pronounced decrease in the output of the metabolites. Basal DA release was no longer detectable 5-12 h after MPP+ administration and a second MPP+ perfusion failed to increase the release of DA.
1-Methyl-4-phenylpyridinium↗
Cerebral metabolism of parkinsonian primates 21 days after MPTP.
This study evaluates the changes in the local cerebral metabolic rate for glucose (LCMRg) in primates exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The LCMRg was evaluated 21 days following the last dose of MPTP. At this time, all MPTP-injected animals demonstrated parkinsonism and striatal dopamine was reduced to less than 3% of control values. The structures whose LCMRg was most affected were the motor cortex, the intermediate zone of the putamen, the external segment of the globus pallidus, the medial part of the ventrolateral nucleus of the thalamus (VLm), visual cortex, locus ceruleus, and the dorsolateral segment of the substantia nigra pars compacta. The structure whose increase in LCMRg correlated most closely to the clinical severity of parkinsonism was the external segment of the globus pallidus.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Flow dependent changes in the effective surface area of microdialysis probes.
The relative efficiencies of microdialysis probes were determined both in vitro and in vivo using tritiated water. Tritiated water (THO) freely distributes throughout the fluid spaces of an experimental animal and, at equilibrium, the brain extracellular concentration of THO is the same as the plasma concentration. Microdialysis probes were inserted into the right caudoputamen of anesthetized rats. The rats were injected with THO and after one hour microdialysis samples were collected at flow rates between 0.2 and 10.0 ul/min. The in vitro relative efficiency for THO was computed as the ratio of the THO concentration in the dialysate to that of the solution the probe was immersed in. The in vivo relative efficiency was computed as the ratio of the concentration of THO in the brain dialysate to that measured in the plasma of the rat. Both the in vitro and in vivo relative efficiencies for THO decrease with increasing flow rates, but they differ from each other except at very low flow rates (less than 0.25 ul/min). The in vitro relative efficiency at a given probe flow is the maximum efficiency that can be attained in vivo at that flow. The surface of effective exchange (Se) is the fraction of that maximum which is attained in vivo. This study also demonstrates how the effective surface area can be computed at any probe flow rate and how it can be used as a correction factor.
3,4-Dihydroxyphenylacetic Acid↗
Quantitative autoradiographic maps of local cerebral glucose metabolism in awake rats: I. Septal region and anterior hypothalamus.
Quantitative 14C-2-deoxyglucose autoradiography was used to determine the local cerebral glucose metabolic rate (lCMRG) of nuclei in the septal region and anterior hypothalamus of awake, unanesthetized rats. The lCMRG of the medial and lateral septal areas, preoptic areas, medial preoptic nuclei, suprachiasmatic nuclei, supraoptic nuclei, anterior hypothalamic nuclei, and paraventricular nuclei were measured. The lCMRG of each nucleus was mapped at successive rostral-caudal levels to determine significant internuclear and intranuclear variations. These data provide a detailed neuroanatomic map of cerebral energy metabolism of the septal and anterior hypothalamic regions in animals under standardized conditions.
Animals↗
Neuromelanin: a role in MPTP-induced neurotoxicity.
Methylphenyltetrahydropyridine (MPTP) selectively destroys melanin-containing neurons in the substantia nigra of humans and other primates. Methylphenylpyridine (MPP+), an active metabolite of MPTP, which is accumulated intraneuronally by the catecholamine uptake system, binds with high affinity to neuromelanin. MPP+ bound intracellularly to neuromelanin may be released gradually, resulting in damage to the neurons of the substantia nigra. Chloroquine, a drug which blocks MPP+ binding to neuromelanin, can protect monkeys from MPTP neurotoxicity.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Measurements of regional glucose metabolism in studies of motor control.
We used the incorporation of tracer quantities of radiolabeled glucose analogues into muscle and CNS tissues to determine, first, whether unilateral dorsal root deafferentation affects hindlimb flexor and extensor muscles of that side equally. For this we compared the incorporation of [3H]fluorodeoxyglucose into selected muscles in the intact and the deafferented side. The muscles were dissected out after exercise on a treadmill, and tracer incorporation was measured by scintillation counting. Second, we used the [14C]2-DG radioautographic method of Sokoloff to seek confirmation of the involvement of certain CNS structures in locomotor control. We found fascinating side to side asymmetries in glucose metabolism, in the cervical spinal cord, motor cortex, and caudate nucleus. There is still debate about the manner in which "neuronal function", regional blood flow, and glucose metabolism, may be coupled (or even on the existence of such coupling). However, these methods can be useful by their anatomical resolution, and the possibility of making multiple regional measurements from a single subject.
Animals↗
Changes in the local cerebral metabolic rate for glucose in the MPTP primate model of Parkinson's disease.
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Asymmetrical regional changes in energy metabolism of the central nervous system during walking.
Cats were injected with 2-deoxy- [14C]glucose (2-DG) while walking on a moving treadmill (experimental group), or sitting down on a stationary one (controls). After a 45-min equilibration period they were anesthetized, and their central nervous system (CNS) was removed rapidly and frozen. The tissue blocks were sectioned serially, and X-ray film exposed to the sections was used for quantitative densitometric analysis by Sokoloff's method. The utilization of glucose in a CNS region (LCMRg) was regarded as a measure of that region's energy metabolic activity and--indirectly--of its functional status. The walking cats exhibited significantly higher LCMRg in many but not all places of the neuraxis, compared to the control group. Also, LCMRg was symmetrical (side to side) in the control group but significantly asymmetrical in certain regions of the CNS in the experimental group. In all but one of these cats the LCMRg was greater in the right side of the gray matter of the cervical spinal cord and in the left visual and motor cortices and caudate nucleus. The finding that the motor cortex and other supraspinal regions become more active during walking suggests they may contribute to the control of locomotion and/or processing of related sensory data. The side to side asymmetry in the spinal cord and hemispheres during walking may be related to the phenomenon of lateral dominance.
Animals↗
Changes in the local cerebral metabolic rate for glucose in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease.
Nine adult monkeys (Macaca fascicularis) were used in this study. Five animals were used as controls. Three animals were injected intravenously daily with 0.5 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over a 4-day period; one animal was injected weekly over a 4-week period. Neurological examination of the MPTP-treated animals revealed a flexed posture of trunk and extremities, bradykinesia, increased tone without cogwheel rigidity, loss of vestibular righting reflexes, decreased vocalization and swallowing, failure of upgaze and abnormal pursuit eye movements. Reflexes were hyperactive. The compound 2-deoxy-D-[14C]glucose (2-DG) was utilized for the determination of the local cerebral metabolic rate for glucose (lCMRg). A generalized decrease in lCMRg was noted in all cerebral cortical areas as compared to control values. The cerebellar cortex demonstrated no change in lCMRg. Areas that demonstrated a significant increase in lCMRg were: the internal and external segments of the globus pallidus (P less than 0.01), the pars compacta and the pars reticulata of the substantia nigra (P less than 0.05). Areas that demonstrated a significant decrease in lCMRg were: the head of the caudate nucleus (P less than 0.05), the anterior dorsomedial putamen (P less than 0.05) and the anterior segment of the subthalamic nucleus (P less than 0.05). The 2-DG analysis of the MPTP primate model of Parkinson's disease is particularly suited to demonstrate areas in the central nervous system that are affected by this neurotoxin. Further studies of these areas may lead to a better understanding of the mechanisms that underlie the clinical symptomatology of Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Spinal cord metabolism of the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkey.
Nine monkeys (Macaca fascicularis) were used in this study. Four monkeys were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 0.5 mg/kg intravenously. Three animals were injected once daily for 4 days, and one animal once weekly for 4 weeks. Five animals were used as controls. All MPTP-treated animals demonstrated the same clinical features which included akinesia, bradykinesia, a flexed posture of the trunk and all extremities, decreased initiation of the threat response, decreased vocalization and difficulty in swallowing. An increase in rigidity and reflexes was noted in all extremities. Tremor was present in all animals. Determination of the local spinal metabolic rate of glucose (LSMRg) utilization revealed an increase (P less than 0.05) in LSMRg in Rexed layer I in all cord segments and in Rexed layer II in both cervical and lumbar segments. Rexed layer X demonstrated a significant (P less than 0.05) increase in LSMRg at the cervical cord. The LSMRg in the animal that received weekly injections was similar to the daily injected animals.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Quantitative computer analysis of autoradiographs utilizing a charge-coupled device solid-state camera.
A computerized image-processing system that employs a high resolution Datacopy Corporation charge-coupled device (CCD) camera is described. The CCD camera generates 327,680 pixels (512 horizontal axis by 640 vertical axis), eight bits per pixel (256 grey levels). The image is then processed by a Digital Graphics TKS-400 imaging computer system. The computer image corresponds to the optical density information contained in the autoradiograms. Depending on the autoradiographic information, the image can be displayed as functional maps, i.e. maps of cerebral metabolism, blood flow, neurotransmitter receptor densities, etc. This system provides quantitative computer analysis of autoradiograms in a relatively inexpensive manner.
Animals↗
Diastolic coronary artery pressure-flow velocity relationships in conscious man.
We characterised the diastolic pressure-flow velocity relationship in the normal left coronary artery of conscious man before and after vasodilatation with angiographic contrast medium. Phasic coronary artery pressure and flow velocity were measured in ten patients during individual diastoles (0.5 to 1.0 s) using a 20 MHz catheter-tipped, pulsed Doppler transducer. All pressure-flow velocity curves were linear over the diastolic pressure range of 110 +/- 15 (SD) mmHg to 71 +/- 7 mmHg (r = 0.97 +/- 0.01). In the basal state, values for slope and extrapolated zero flow pressure intercept averaged 0.35 +/- 0.12 cm X s-1 X mmHg-1 and 51.7 +/- 8.6 mmHg, respectively. Vasodilatation resulted in a 2.5 +/- 0.5 fold increase in mean flow velocity. The diastolic pressure-flow velocity relationship obtained during peak vasodilatation compared to that during basal conditions was characterised by a steeper slope (0.80 +/- 0.48 cm X s-1 X mmHg-1, p less than 0.001) and lower extrapolated zero flow pressure intercept (37.9 +/- 9.8 mmHg, p less than 0.05). Mean right atrial pressure for the group averaged 4.4 +/- 1.7 mmHg, while left ventricular end-diastolic pressure averaged 8.7 +/- 2.8 mmHg. These observations in man are similar to data reported in the canine coronary circulation which are consistent with a vascular waterfall model of diastolic flow regulation. In this model, coronary blood flow may be regulated by changes in diastolic zero flow pressure as well as in coronary resistance.
Adult↗
Interpretation and physiological significance of diastolic coronary artery pressure-flow relationships in the canine coronary bed.
We analyzed the relationship between diastolic coronary artery pressure and flow in the canine coronary bed, using an electrical analog model of the coronary circulation based on the theory of critical closure. The model contains a voltage-dependent nonlinear resistance and capacitance. The behavior of the resistive element was described using experimental diastolic pressure-flow curves obtained in the absence of compliance effects. Compliance free zero flow pressure intercepts (Pf0) exceeded coronary venous pressure (Pv) by 2- to 5-fold and were related to initial diastolic coronary artery pressure Pa(0) and flow F(0), and Pv by: Pf0 = 14.3 [(Pa(0) - Pv)/F(0)] + Pv + 4.0 (r = 0.93). When coronary artery pressure was suddenly lowered to values less than or equal to the compliance-free Pf0, diastolic flow abruptly decreased and, after a transient reversal, remained at zero for up to 8 seconds. In the model, zero flow pressure represents critical closing pressure and the resistance regulating flow is the difference between coronary artery and venous pressure divided by flow. Theoretically predicted pressure-flow curves were in good agreement with existing experimental data, including the effects of elevating coronary venous pressure on zero flow pressure. Differences between compliance-free pressure-flow curves and those obtained with pressure gradually decreasing were explained by a coronary arterial compliance whose magnitude varies inversely with pressure and is dependent on vasomotor tone. In conclusion, the results of this study demonstrate the existence of a diastolic pressure gradient across the canine coronary bed at zero flow which is dependent on coronary vasomotor tone. A theoretical model of the coronary circulation based on the concept of critical closure describes the observed relationship between diastolic coronary artery pressure and flow during various experimental conditions.
Animals↗
Regional metabolic changes in the spinal cord related to spinal shock and later hyperreflexia in monkeys.
The regional metabolic rate for glucose (rMRglu) was studied in macaque monkeys after spinal cord transection at T10, both during spinal shock and after reflexes had returned. The rMRglu was measured in all Rexed layers in cord segments both caudal and rostral to the level of the transection utilizing the quantitative [14C]deoxyglucose technique. The monkeys in spinal shock exhibited a significant increase in rMRglu in Rexed layer I and a significant reduction in layers VI to IX of the lumbosacral cord. In contrast, after reflexes had returned the rMRglu was increased in all Rexed layers of the lumbosacral cord; this increase was significant in layers I, V, and VI.
Animals↗
Methylphenidate decreases local glucose metabolism in the motor cortex.
The local cerebral metabolism on glucose (l-CMRg) was evaluated in animals given methylphenidate (15 mg/kg) in order to investigate possible mechanisms of action of the drug. Significant increases in l-CMRg (p greater than 0.05) were found in the globus pallidus, entopeduncular nucleus, substantia nigra, subthalamic nucleus, inferior olive, red nucleus, lateral cerebellar cortex, ventral lateral nucleus of the thalamus and the midbrain reticular formation. Significant decreases (p greater than 0.05) in l-CMRg were found in the motor cortex. These results suggest possible mechanisms for methylphenidate's action in attention deficit disorders.
Animals↗