Effect of norethisterone acetate on serum lipid and lipoprotein parameters as well as on blood coagulation in female monkeys (M. fascicularis)

The effects of daily oral administration of a high dose of 10 mg norethisterone acetate (NET-Ac.)/kg/day over 14 weeks on serum lipid and lipoprotein parameters as well as on blood coagulation were investigated in female monkeys (M. fascicularis). Measurements of lipids and lipoprotein cholesterol were performed in weeks —5 and — 1 before treatment and in weeks 4, 8 and 12 after treatment. In addition, various blood coagulation and fibrinolytic parameters were determined in weeks 11–14 after treatment with NET-Ac. Furthermore, the serum levels of norethisterone (NET) were determined in order to monitor the real systemic compound exposure and revealed that C_max and AUC (0–3 h) values reached for norethisterone in this experiment in monkeys were about 25 times higher than those obtained after an oral contraceptive dose of NET-Ac. in women.

The results of lipid and lipoprotein cholesterol determinations showed decreases in serum total lipids, phospholipids, triglycerides and total cholesterol associated with similar decreases in HDL-, LDL- and VLDL-cholesterol fractions after NET-Ac.-treatment in monkeys. These effects were observed from week 4 onwards and maintained their magnitude up to week 12 after treatment. Since both HDL- and LDL-cholesterol fractions decreased, the HDL/LDL-ratio remained almost unchanged. Thus, the results obtained in this study after high-dose treatment with NET-Ac. in monkeys did not indicate any changes of lipid and lipoprotein parameters which in humans are supposed to be associated with an increased risk of cardiovascular lesions, namely a decrease in HDL- and increase in LDL-cholesterol fractions.

The results of blood coagulation and fibrinolytic parameters showed increased antithrombin-III and plasminogen levels besides minor changes in other parameters, thus indicating that NET-Ac. -treatment does not contribute to an increased risk of cardiovascular thrombotic events in the cynomolgus monkey.     

Figure-Ground Segregation at Contours: a Neural Mechanism in the Visual Cortex of the Alert Monkey

An important task of vision is the segregation of figure and ground in situations of spatial occlusion. Psychophysical evidence suggests that the depth order at contours is defined early in visual processing. We have analysed this process in the visual cortex of the alert monkey. The animals were trained on a visual fixation task which reinforced foveal viewing. During periods of active visual fixation, we recorded the responses of single neurons in striate and prestriate cortex (areas V1, V2, and V3/V3A). The stimuli mimicked situations of spatial occlusion, usually a uniform light (or dark) rectangle overlaying a grating texture of opposite contrast. The direction of figure and ground at the borders of these rectangles was defined by the direction of the terminating grating lines (occlusion cues). Neuronal responses were analysed with respect to figure-ground direction and contrast polarity at such contours. Striate neurons often failed to respond to such stimuli, or were selective for contrast polarity; others were non-selective. Some neurons preferred a certain combination of figure-ground direction and contrast polarity. These neurons were rare both in striate and prestriate cortex. The majority of neurons signalled figure-ground direction independent of contrast polarity. These neurons were only found in prestriate cortex. We explain these responses in terms of a model which also explains neuronal signals of illusory contours. These results suggest that occlusion cues are used at an early level of processing to segregate figure and ground at contours.     

猕猴对不同极化方向微波辐射能量吸收的研究

为提供微波辐射安全标准必要的数据，研究了不同极化方向微波辐射能量对猕猴的影响。实验在医学微波无反射室中进行，分为电场，磁场和微波传输方向极化组，辐射频率１ＧＨｚ，用红外热图技术，对暴露在三种极化方向电磁场中猕猴面部各解剖特片部位及胸部在辐射前后进行温度变化的定量分析。     

Pharmacokinetics of orally administered norethisterone enanthate in rabbit, monkey, and women

Norethisterone enanthate (NET-En), an established intramuscular long-acting contraceptive agent, has previously been shown to be effective in inhibiting fertility in two rodent species even 4 days after oral ingestion. Pharmacokinetics of NET and NET-En were studied after oral and intramuscular doses in two animal species and a few women. The results suggest that the NET-En was absorbed within a day in all the species after oral dose. The estimates of relative bioavailability ranged from 13 to 51% in rabbits, monkeys, and women. The elimination half-life was 5–10 days. The presence of the active component, NET, in the circulation over the experimental period of 15 days suggests that NET-En could be useful as a long-acting oral pill. The suppression of progesterone levels during the luteal phase of menstrual cycle in women also supports this finding.     

Pharmacological interactions between serotonin and dopamine on behavior in the squirrel monkey

 The behavioral effects of GBR 12909, a selective dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. Intermediate doses of GBR 12909 increased FI response rate markedly, and the highest dose decreased response rate below control values. The 5HT uptake inhibitors, alaproclate and fluoxetine, and the 5HT agonist, quipazine, attenuated the behavioral-stimulant effects of GBR 12909, whereas the 5HT_2A/2C antagonist, ritanserin, enhanced the behavioral-stimulant effects of the lowest dose. GBR 12909 reliably maintained self-administration, and ritanserin increased response rate maintained by the highest dose. The dopamine agonist, quinpirole, increased FI response rate in only one of three subjects, and ritanserin enhanced the behavioral-stimulant effects of quinpirole in that subject. The dopamine agonist, apomorphine, only decreased FI response rate, and ritanserin did not alter its behavioral effects. The pharmacological profile of GBR 12909 administered alone and in combination with selective 5HT drugs in the present study was similar to that obtained previously with cocaine, further demonstrating that 5HT can reliably modulate the behavioral effects of psychomotor stimulants with prominent dopaminergic actions. Received: 9 July 1996 / Final version: 22 November 1996     

Comparison of the Permeability Characteristics of a Human Colonic Epithelial (Caco-2) Cell Line to Colon of Rabbit,Monkey, and Dog Intestine and Human Drug Absorption

The in vitro permeabilities of Caco-2 monolayers and permeabilities in tissue sections from colon of monkey, rabbit, and dog were compared using a series of compounds. The selected compounds differed in their physicochemical properties, such as octanol/water partition coefficient, water solubility, and molecular weight. Their structure included steroids, carboxylic acids, xanthins, alcohols, and polyethylene glycols. A linear permeability relationship was established between Caco-2 and colon tissue from both rabbit and monkey. The results suggest that Caco-2 is twice as permeable as rabbit and five times as permeable as monkey colon. However, no clear relationship could be established between Caco-2 monolayers and dog colon permeability. A relationship between permeability in Caco-2 monolayers and human absorption was found. The results suggest that within certain limits, permeability of Caco-2 monolayers may be used as a predictive tool to estimate human drug absorption.     

Effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the dopaminergic and cholinergic receptors as evaluated by positron emission tomography in the Rhesus monkey

Summary The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) on the central cholinergic and dopaminergic systems in the Rhesus monkey brain were investigated by positron emission tomography (PET) with the muscarinic cholinergic receptor ligands (N-[¹¹C]methyl-benztropine) and dopaminergic receptor ligands selective for D₁ D₂, and D₃ subtypes ([¹¹C]SCH23390, N-[¹¹C]methyl-spiperone, and (+)[¹¹C]UH232, respectively). None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP used significantly affected the regional cerebral blood flow (rCBF as determined by Raichle's H₂ ¹⁵O method), and 10 mg/kg of R-THBP had little effect on the regional cerebral metabolic rate of glucose (rCMRglc) in the Rhesus monkey brain, as assessed by the graphical [¹⁸F]fluoro-deoxyglucose method. The effect of R-THBP on the muscarinic cholinergic system was dose dependent; while 3 mg/kg of R-THBP did not significantly alter the uptake ratio of N-[¹¹C]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP significantly reduced the uptake ratio in the thalamus, as well as in the frontal and temporal cortices. None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP tested affected [¹¹C]SCH23390 (dopamine D₁ receptor) binding. However, the k3 value for N-[¹¹C]methyl-spiperone (dopamine D₂ receptor) binding, which represents the association rate × B_max value, was significantly decreased in the striatum. The uptake ratio of (+)[¹¹C]UH232 (dopamine D₃ receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 30 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D₂ and D₃ receptors selectively without markedly affecting dopamine D₁ receptor binding. Furthermore, the changes in cholinergic and dopamine D₂ and D₃ receptors in vivo can not be attributed to a change in rCBF but may depend on the action of R-THBP.Abbreviations R-THBP 6R-L-erythro-5,6,7,8-tetrahydrobiopterin - PET positron emission tomography - rCBF regional cerebral blood flow - rCMRglc regional cerebral metabolic rate of glucose     

Visual recognition impairment follows ventromedial but not dorsolateral prefrontal lesions in monkeys

Visual recognition in monkeys appears to involve the participation of two limbothalamic pathways, one including the amygdala and the magnocellular portion of the medial dorsal nucleus (MDmc) and the other, the hippocampus and the anterior nuclei of the thalamus (Ant N). Both MDmc and Ant N project, in turn, to the prefrontal cortex, mainly to its ventral and medial portions. To test whether the prefrontal projection targets of the two limbothalamic pathways also participate in memory functions, performance on a variety of learning and memory tasks was assessed in monkeys with lesions of the ventromedial prefrontal cortex (Group VM). Normal monkeys and monkeys with lesions of dorsolateral prefrontal cortex (Group DL) served as controls. Group VM was severely impaired on a test of object recognition, whereas Group DL did not differ appreciably from normal animals. Conversely, the animals in Group VM were able to learn a spatial delayed response task, whereas 2 of the 3 animals in Group DL could not. Neither group was impaired in the acquisition of visual discrimination habits, even though the successive trials on a given discrimination were separated by 24-h intervals. The patterns of deficit suggest that ventromedial prefrontal cortex constitutes another station in the limbothalamic system underlying cognitive memory processes, whereas the dorsolateral prefrontal cortex lies outside this system. The results support the view that the classical delayed-response deficit observed after dorsolateral prefrontal lesions represents a perceptuo-mnemonic impairment in spatial functions selectively rather than a memory loss of a more general nature.     

Regional distribution of cholecystokinin receptors in primate cerebral cortex determined by in vitro receptor autoradiography

Cholecystokinin (CCK) is a putative peptide neurotransmitter present in high concentration in the cerebral cortex. By using techniques of in vitro receptor autoradiography, CCK binding sites in primate cortex were labeled with 125I-Bolton-Hunter-labeled CCK-33 (the 33-amino-acid C-terminal peptide) and 3H-CCK-8 (the C-terminal octapeptide). Biochemical studies performed on homogenized and slide-mounted tissue sections showed that the two ligands labeled a high-affinity, apparently single, saturable site. Autoradiography revealed that binding sites labeled by both ligands were anatomically indistinguishable and were distributed in two basic patterns. A faint and diffuse label characterized portions of medial prefrontal cortex, premotor and motor cortices, the superior parietal lobule, and the temporal pole. In other cortical areas the pattern of binding was layer-specific; i.e., binding sites were concentrated within particular cortical layers and were superimposed upon the background of diffuse label. Layer-specific label was found in the prefrontal cortex, anterior and posterior cingulate gyrus, somatosensory cortex, inferior parietal lobule, retrosplenial cortex, insula, temporal lobe cortices, and in the primary visual and adjacent visual association cortices. The areal and laminar localization of layer-specific CCK binding sites consistently coincided with the cortical projections of thalamic nuclei. In prefrontal cortex, CCK binding sites were present in layers III and IV, precisely paralleling the terminal fields of thalamocortical projections from the mediodorsal and medial pulvinar nucleus of the thalamus. In somatosensory cortex, the pattern of CCK binding in layer IV coincided with thalamic inputs arising from the ventrobasal complex, while in the posterior cingulate gyrus, insular cortex, and retrosplenial cortex, layer IV and lower III binding mirrored the laminar distribution of cortical afferents of the medial pulvinar. CCK binding in layers IVa, IVc alpha, IVc beta, and VI of primary visual cortex corresponded to the terminal field disposition of lateral geniculate neurons, whereas in adjacent visual association cortex, binding in layers III, IV, and VI faithfully followed the cortical distribution of projections from the inferior and lateral divisions of the pulvinar nucleus of the thalamus. We interpret the diffusely labeled binding sites in primate cortex as being associated with the intrinsic system of CCK-containing interneurons that are distributed throughout all layers and areas of the cortex. The stratified binding sites, however, appear to be associated with specific extrinsic peptidergic projections.(ABSTRACT TRUNCATED AT 400 WORDS)     

Variability in hand surface representations in areas 3b and 1 in adult owl and squirrel monkeys

Detailed microelectrode maps of the hand representation were derived in cortical areas 3b and 1 from a series of normal adult owl and squirrel monkeys. While overlap relationships were maintained, and all maps were internally topographic, many map features varied significantly when examined in detail. Variable features of the hand representations among different monkeys included a) the overall shapes and sizes of hand surface representations; b) the actual and proportional areas of representations of different skin surfaces and the cortical magnifications of representations of specific skin surfaces, which commonly varied severalfold in area 3b and manyfold in area 1; c) the topographic relationships among skin surface representations, with skin surfaces that were represented adjacently in some monkeys represented in locations many hundreds of microns apart in others; d) the internal orderliness of representations; e) the completeness of representations of the dorsal hand surfaces; and f) the skin surfaces represented along the borders of the hand representation. Owl monkey maps were, in general, internally more strictly topographic than squirrel monkey maps. In both species, area 3b was more strictly topographic and less variable than was area 1. The degree of individual variability revealed in these experiments is difficult to reconcile with the hypothesis that details of cortical maps are ontogenetically specified during a period in early life. Instead, we propose that differences in the details of cortical map structure are the consequence of individual differences in lifelong use of the hands. This conclusion is consistent with earlier studies of the consequences of peripheral nerve transection and digital amputation, which revealed that cortical maps are dynamically maintained and are alterable as a function of use or nerve injury in these monkeys (Merzenich et al., '83a,b, '84a; Merzenich, '86; Jenkins et al., '84; Jenkins and Merzenich, '87).