Early postnatal administration of 5,7-DHT: Effects on serotonergic neurons and terminals

Serotonergic neurons throughout the brain were destroyed by early postnatal treatment of rats with an intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT), as demonstrated with biochemical measurements of serotonin and immunocytochemical localization of serotonin-containing neurons. Using these methods, it was shown that approximately 75–98% of serotonergic nuerons underwent cell death in rats which were treated on day 3. In contrast, intracisternal administration of 5,7-DHT in adult rats led to the loss of distal serotonergic terminals without apparent loss the cell bodies. Desipramine prevented significant effects of 5,7-DHT on noradrenergic neurons.     

Effects of neocortical ablations on eating elicited by hypothalamic stimulation

Unilateral and two-stage bilateral ablations had marked effects on stimulation-bound feeding. These included temporary or permanent failure to feed, increase in current thresholds, and reduction in the persistence of feeding during stimulation. Analysis of the data by a multiple regression technique indicated that the failure to feed was related to the amount of unilateral and bilateral damage to the frontal, but not other cortical regions. Changes in threshold were not related to frontal damage as such; rather, these changes appeared to be a function of an interaction between the sites of stimulation and amount of cortical damage. Persistence changes were related to the degree of frontal damage. Failure to feed appeared to reflect disorganization of food-seeking rather than consummatory responses.     

5,7-DHT facilitated lordosis: effects of 5-HT agonists.

The role of 5-HT (serotonin) in regulating lordosis was investigated by combining peripheral administration of the 5-HT agonists 8-OH-DPAT (8-hydroxy-2-[di-N-propylamino]tetralin) or TFMPP (1-[m-trifluoromethylphenyl]piperazine), with intrahypothalamic application of the 5-HT neurotoxin 5,7-DHT (5,7-dihydroxytryptamine). The 5-HT1A agonist, 8-OH-DPAT, significantly inhibited lordosis in 5,7-DHT-treated and non-treated rats. TFMPP, an agonist at 5-HT1B and 5-HT1C receptors, significantly facilitated lordosis in 5,7-DHT-treated and non-treated rats. Our results show that both inhibitory and facilitatory influences of hypothalamic 5-HT on lordosis, are modulated via postsynaptic receptors.     

Treatment of canine fucosidosis by intracisternal enzyme infusion

The blood brain barrier is the major obstacle to treating lysosomal storage disorders of the central nervous system such as canine fucosidosis. This barrier was overcome by three, monthly injections of recombinant canine α-l-fucosidase enzyme were given intracisternally. In dogs treated from 8 weeks of age enzyme reached all areas of central nervous system as well as the cervical lymph node, bone marrow and liver. Brainstem and spinal cord samples from regions adjacent to the injection site had highest enzyme levels (39–73% of normal). Substantial enzyme activity (8.5–20% of normal controls) was found in the superficial brain compared to deeper regions (2.6–5.5% of normal). Treatment significantly reduced the fucosyl-linked oligosaccharide accumulation in most areas of CNS, liver and lymph node. In the surface and deep areas of lumbar spinal cord, oligosaccharide accumulation was corrected (79–80% reduction) to near normal levels (p < 0.05). In the spinal meninges (thoracic and lumbar) enzyme activity (35–39% of normal control) and substrate reduction (58–63% affected vehicle treated samples) reached levels similar to those seen in phenotypically normal carriers (p < 0.05).The procedure was safe and well-tolerated, treated (average 16%) dogs gained more weight (p < 0.05) and there was no antibody formation or inflammatory reaction in plasma and CSF following treatments. The capacity of early ERT to modify progression of biochemical storage in fucosidosis is promising as this disease is currently only amenable to treatment by bone marrow transplantation which entails unacceptably high risks for many patients.     

经腰穿注入尿激酶治疗脑池血肿

目的探讨腰穿注入尿激酶治疗脑池血肿的疗效。方法将67例创伤性蛛网膜下腔出血并脑池血肿的病人,随机分成两组:A组,35例,单纯腰穿放脑脊液治疗;B组,32例,在腰穿放脑脊液基础上注入尿激酶治疗。疗效比较:(1)在伤后第7天、第15天复查头颅CT,分别比较两组病例的恢复例数,并行χ2检验;(2)比较两组病例治愈所行腰穿次数,并行t检验。结果经腰穿放液注入尿激酶疗效明显优于单纯腰穿放液,统计学检验均存在显著性差异(P<0.01)。结论该方法是一种简单有效且安全的治疗脑池内血肿的新方法。     

Destruction of the hamster serotonergic system by 5,7-DHT: effects on circadian rhythm phase, entrainment and response to triazolam

The role of the serotonergic system in the regulation of hamster circadian rhythms was analyzed using intraventricular injection of the selective neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Sixty days after 5,7-DHT administration, immunoreactive serotonin in the forebrain, particularly the suprachiasmatic nuclei and intergeniculate leaflets, was severely depleted in 16 animals, moderately depleted in four and only slightly affected in four. 5,7-DHT produced an immediate and sustained advance of the onset of running wheel activity relative to the 24 h light-dark (LD) cycle. Activity onset occurred 0.7 +/- 0.07 h before lights out among 5,7-DHT-treated animals compared with 0.18 +/- 0.04 h after lights out for vehicle-infused controls. This new, advanced phase angle of entrainment was maintained throughout the 60-day period of the study while the animals remained in a LD cycle, including after an 8-h phase advance of the light cycle. 5,7-DHT treatment also delayed the offset of wheelrunning in 16 of 24 animals and reduced the likelihood of a smooth pattern of reentrainment to the shifted LD cycle. The drug treatment did not affect circadian period in constant darkness, the rate of reentrainment to an 8-h phase advance or the amount of wheelrunning activity per day. In addition, 5,7-DHT treatment had no effect on the ability of triazolam, a short-acting benzodiazepine, to accelerate the rate of reentrainment to an 8-h phase advance. These observations show that ascending projections of midbrain raphe serotonin neurons participate in the regulation of the circadian activity phase but are not required for triazolam-induced acceleration of reentrainment to a phase-advanced LD cycle.     

Inhibition of lordosis behavior by intrahypothalamic infusion of a protein kinase G antagonist

Previous experiments demonstrated that intracerebroventricular infusion of the protein kinase G inhibitor KT5823 inhibits lordosis behavior in hormone-treated female rats. Present studies show that KT5823 attenuates lordosis in a dose-dependent manner when infused bilaterally into the ventromedial hypothalamus. Thus, activation of protein kinase G in the ventromedial hypothalamus is necessary for the expression of hormone-dependent lordosis behavior in female rats.     

Effects of intragastric water infusion and gastric distension on hypothalamic neuronal activity

The effects of gastric water infusion and distension were examined in neurons from various parts of the rat brain. Neurons in the lateral preoptic-lateral hypothalamic-medial forebrain bundle (LPA-LH-MFB) neuropil were sensitive to gastric water infusion and distension. Cells randomly selected and examined in other brain areas were less sensitive to the same stimulation which indicated that the effects were relatively specific. The results, in terms of changes in neuronal discharge frequency from an established baseline, indicate that many cells in the lateral preoptic-lateral hypothalamic-medial forebrain bundle area are affected by intragastric water infusion and gastric distension within a time period during which changes in drinking would normally occur. These neurons were also affected differentially by acute water deprivation. LPA-LH-MFB neurons in 24 hr water deprived animals were significantly more sensitive to water infusions and less sensitive to stomach distension when compared to cells recorded in animals maintained on ad lib eating and drinking. Some of these same neurons were also sensitive to changes in the extracellular concentrations of sodium and glucose. The results are discussed in terms of the involvement of the lateral preoptic-lateral hypothalamic-medial forebrain bundle neuropil in ingestive behavior.     

脑池内局部应用尼卡地平多聚体缓释微球治疗脑血管痉挛的实验研究

目的 研究脑池内注入NC -PLGA缓释微球对脑血管痉挛的治疗作用.方法 采用枕大池二次注血法制作兔蛛网膜下腔出血模型.分别采用脑池内注入NC -PLGA微球和尼卡地平的方法治疗脑血管痉挛.应用经颅多普勒技术测基底动脉的血流速度,脑血管造影测量基底动脉直径,光镜和电镜行病理检查,观察基底动脉的形态学变化,评价脑血管痉挛的严重程度.结果 脑池内注入NC - PLGA微球和尼卡地平都能降低基底动脉的血流速度(P＜0.01),基底动脉的直径明显升高(P＜0.01),并能明显改善血管壁的病理改变,但前者只需一次性注入后者总量的1/4既可达到同样的疗效.结论 经脑池内注入NC -PLGA缓释微球能明显减轻脑血管痉挛的严重程度,并可减轻痉挛血管壁的病理学变化.     

Blockade of progesterone-induced increase in hypothalamic luteinizing hormone-releasing hormone levels and serum gonadotropins by intrahypothalamic implantation of 6-hydroxydopamine.

The present study was undertaken to identify the hypothalamic locus where norepinephrine (NE) nerve terminals communicate with luteinizing hormone-releasing hormone (LH-RH)-containing neurons involved in the stimulatory feedback action of gonadal steroids on LH and FSH release. Ovariectomized rats received estradiol benzoate (10 microgram/rat s.c.) on day 0. Intracranial implants containing either 6-hydroxydopamine (6-OHDA), to destroy NE terminals, or cocoa butter (controls) were placed bilaterally in the suprachiasmatic nucleus (SCN), medial basal hypothalamus (MBH) or olfactory tubercle (OT) on day 1. Progesterone (P, 5 mg/rat s.c.) was administered at 10.00 h on day 2 to elicit increases in serum LH and FSH and the MBH LH-RH levels in the afternoon. Implantation of 6-OHDA in the SCN resulted in a marked depletion of NE in and around the region of the SCN in the preoptic-anterior hypothalamic area (POA-AH) without adversely affecting dopamine (DA) concentrations, and blocked the P-induced afternoon increase in the MBH LH-RH and serum gonadotropin levels. Similar reduction in the MBH NE concentrations occurred following placement of 6-OHDA in the MBH; however, these as well as implants in the OT were ineffective in suppressing the P-induced effects. These studies show that functional integrity of the SCN regions is critical in manifestation of the P-induced rise in the MBH LH-RH activity, and this region in the POA-AH, therefore, may be the primary locus of synaptic communication between NE terminals and LH-RH neurons.     

Feeding and drinking elicited by low and high frequencies of hypothalamic stimulation

Rats had chronic, stimulating electrodes implanted in the hypothalamus. Feeding and drinking were elicited in a number of the animals and the occurrence of these consummatory behaviors was shown to be related to the frequency of the hypothalamic stimulation. When the frequency of square wave pulses was 20–40 c/sec feeding was induced more frequently than drinking. As the frequency of the hypothalamic stimulation was raised the occurrence of drinking increased and feeding declined. When the frequencies of stimulation were 100–200 c/sec, drinking was elicited a greater number of times than feeding. It is suggested that signals for water deficit and energy deficit are integrated by neurons in the hypothalamus and other parts of the brain and that these integrative systems are activated differentially by low and high frequencies of electrical stimulation.     

Effect of hypothalamic injections of 5,7-dihydroxytryptamine on elicitation of mouse-killing in rats

An overall and marked serotonin (5-HT) depletion of the brain was found to facilitate initiation of mouse-killing behavior in the rat, whereas more selective 5-HT depletions within forebrain structures such as the septum, hippocampus, cingular cortex and amygdala, did not have such an effect. In order to further investigate the topography of the 5-HT pathways and terminals thought to be involved in an inhibitory control over this behavior, localized lesions of the serotonergic system(s) were performed by means of bilateral 5,7-dihydroxytryptamine (5,7-DHT) injections (5 μg/μl) into the hypothalamus in naive rats. 5,7-DHT injections into the medial hypothalamus did not affect the initiation of mouse-killing behavior, whereas the reflexive startle responses to air puffs were increased. The animals' open-field behavior remained unchanged. Forebrain 5-HT content was reduced by 50% in this group. 5,7-DHT injections into the lateral hypothalamus increased the proportion of killers to 46% as compared to 10% in the control group, in spite of a reduced activity in the open-field and unchanged startle responses. Forebrain 5-HT content was reduced by 88%. As the lateral hypothalamus contains afferents from both the dorsal and the median raphe nuclei, it is likely that 5-HT terminals modulate some hypothalamic mechanism involved in the control of mouse-killing behavior.     

Effects of stimulus intensity on elicited ponto-geniculo-occipital waves.

Waves similar to spontaneous ponto-geniculo-occipital (PGO) waves of paradoxical sleep (PS) in cats are elicited by tones and can be considered a form of evoked potential termed PGOE. The aims of the present experiment were to determine: (1) the effects of tone intensity on the probability of producing PGOE; (2) the effects of intensity on the amplitude and latency of PGOE across slow-wave sleep (SWS) and PS; (3) whether the effects of intensity on PGOE are similar to those on a particular form of auditory evoked potential known as the mid-latency response (MLR). Increasing the intensity of the stimulus from 60 to 100 in 10 dB increments resulted in increased probability, increased amplitude, and decreased latency of PGOE in both SWS and PS. This pattern was similar to published findings with MLR, and latencies of PGOE (roughly 60-100 msec) fell within the range of 'C wave' type of MLR recorded in intralaminar nuclei of the thalamus of cats. The possibility that PGOE and MLR share underlying mechanisms and represent the same phenomenon is discussed with particular attention to the function of the mechanisms during alerting and orienting.     

Blockade of progresterone-induced increase in hypothalamic luteinizing hormone-releasing hormone levels and serum gonadotropins by intrahypothalamic implantation of 6-hydroxydopamine

The present study was undertaken to identify the hypothalamic locus where norepinephrine (NE) nerve terminals communicate with leteinizing hormone-releasing hormone (LH-RH)-containing neurons involved in the stimulatory feedback action of gonadal steroids on LH and FSH release. Ovariectomized rats received estradiol benzoate (10 μg/rat s.c.) on day 0. Intracranial implants containing either 6-hydroxydopamine (6-OHDA), to destroy NE terminals, or cocoa butter (controls) were placed bilaterally in the suprachiasmatic nucleus (SCN), medial basal hypothalamus (MBH) or olfactory tubercle (OT) on day 1. Progesterone (P, 5 mg/rat s.c.) was administered at 10.00 h on day 2 to elicit increases in serum LH and FSH and the MBH LH-RH levels in the afternoon. Implantation of 6-OHDA in the SCN resulted in a marked depletion of NE in and around the region of the SCN in the preoptic-anterior hypothalamic area (POA-AH) without adversely affecting dopamine (DA) concentrations, and blocked the P-induced afternoon increase in the MBH LH-RH and serum gonadotropin levels. Similar reduction in the MBH NE concentrations occurred following placement of 6-OHDA in the MBH; however, these as well as implants in the OT were ineffective in suppressing the P-induced effects. These studies show that functional integrity of the SCN regions is critical in manifestation of the P-induced rise in the MBH LH-RH activity, and this region in the POA-AH, therefore, may be the primary locus of synaptic communication between NE terminals and LH-RH neurons.     

Alterations in body temperature elicited by intrahypothalamic administration of tetrodotoxin, ouabain and A23187 ionophore in the conscious cat

Ouabain, tetrodotoxin, and calcium selective ionophore (A23187) were administered bilaterally into the hypothalamus of the unrestrained, fully conscious cat, while body temperature and other indicators of thermoregulatory responses were monitored continuously. Posterior hypothalamic microinjection of 2.0 to 10.0 ng or tissue perfusion with 1.1 X 10(-7) to 1.1 X 10(-8) M ouabain elicited dose dependent increases in body temperature accompanied by pinnae vasoconstriction, shivering and postural changes consistent with heat conservation. Tetrodotoxin, microinjected in doses of 0.5 and 5.0 ng or tissue perfusions with 7.8 X 10(-9) to 7.8 X 10(-7) M in the posterior hypothalamus elicited dose dependent falls in body temperature. However, tetrodotoxin microinjected into the anterior hypothalamic region elicited only increases in temperature. The calcium selective ionophore, A23187, at least at the concentrations used in this study, did not appear to produce any consistent effects on thermoregulation. These data support the hypothesis that the ionic milieu of the posterior hypothalamic region is essential in the maintenance of body temperature. Further, they suggest that increasing the [Ca++]/[Na+] acts in a manner similar to a depression in the firing frequency of a distinct population of cells, which may in turn determine in some way the "set-point" for body temperature. There is no evidence to support the concept that increasing the [Ca++]/[Na+] causes an increased release of the synaptic contents of the region.