Central effects of angiotensins on drinking and blood pressure: Structure-activity relationships

The dipsogenic and the pressor effect following intracerebroventricular injection of angiotensins and several C-terminal fragments were studied. Angiotensin I (ANG I), ANG II, ANG III and C-terminal hexa-, penta-, tetra- and tripeptide stimulated water intake in water-replete rats and induced significant pressor responses. In both paradigms the most active peptides (in the pmol range) were ANG II, ANG I and ANG III, in that order. Shorter C-terminal peptides appeared to be active, but had to be injected in the nmol range. Latencies to the onset of drinking were less than 45 s for all peptides tested. The C-terminal dipeptide and other dipeptide fragments did not possess detectable dipsogenic activity. The dipsogenic effect of ANG I was inhibited by pretreatment of the animals with the converting enzyme inhibitor SQ 14,225. Drinking induced by both ANG I and ANG (4–8) was antagonized by the ANG II-receptor blocking agent Sar¹-Ala⁸-ANG II.It is concluded that conversion of ANG I into ANG II is a prerequisite for the expression of the observed biological activity in the brain. Short C-terminal fragments are capable of stimulating the ANG II receptors, but a peptide chain of 7 amino acids appears necessary for maximal agonistic activity.     

Long term alterations in neuroimmune responses of female rats after neonatal exposure to lipopolysaccharide

Male and female rats display significant gender-associated differences in their responses to an immune challenge, and gender-specific alterations in many aspects of physiology are seen after a variety of interventions during the neonatal period. It is well-established that neonatal exposure to an immune challenge can alter centrally mediated inflammatory responses in adult male rats and yet little is known about female responses after a similar challenge. We therefore asked if neonatal exposure to lipopolysaccharide (LPS) would alter febrile and hypothalamic cyclooxygenase (COX)-2 responses to an adult immune challenge in female rats. Female Sprague-Dawley rats were administered a single injection of the bacterial endotoxin LPS at postnatal day 14 and were examined as adults for febrile, COX-2 and activity changes to LPS, as well as responses to interleukin (IL)-1beta. Adult female rat responses were similar to those we have seen previously for the males in that febrile and hypothalamic COX-2 responses to adult LPS were attenuated in neonatally LPS-treated animals. Responses to adult IL-1beta were unaffected. Interestingly, females did not display the elevated basal hypothalamic COX-2 that was previously seen in males. Thus we demonstrate that, like in the males, neonatal exposure to LPS has a powerful effect on adult responses to further LPS challenge in the female rats.     

Multiple neural mechanisms of fever

In rats, fevers induced by moderate-to-high doses of intravenous lipopolysaccharide consist of three phases (phases 1, 2 and 3) with body temperature peaks at approximately 1, 2, and 5 h postinjection, respectively. In this study, the effects of bilateral truncal subdiaphragmatic vagotomy and intraperitoneal capsaicin desensitization on febrile phases 1-3 were assessed in adult Wistar rats. Surgical vagotomy was performed approximately 30 d before the experiment; this procedure interrupts both afferent and efferent vagal fibers. Capsaicin was administered intraperitoneally in two consecutive injections (2 and 3 mg/kg, 3 h apart) 1 week prior to the experiment; this procedure desensitizes afferent fibers, primarily within the abdominal cavity, and does not lead to the known thermal effects of systemic capsaicin desensitization. At a neutral ambient temperature, the rats were given Escherichia coli lipopolysaccharide (10 microg/kg) through a preimplanted jugular catheter, and their colonic temperature wes measured by thermocouples for 7 h. The control rats exhibited the typical triphasic febrile responses. Confirming our earlier studies, subdiaphragmatic vagotomy did not affect phases 1 and 2; it did, however, result in a 2.5-fold reduction of phase 3. Capsaicin desensitization modified the febrile response differently: phases 2 and 3 were unaffected, but phase 1 disappeared. We suggest that neural afferent fibers (nonvagal but perhaps vagal as well) play an important role in the early febrile response (phase 1) by transducing peripheral pyrogenic signals to the brain. We also suggest that vagal efferent fibers are likely to participate in the later febrile response (phase 3) via an unknown mechanism.     

Metabolic mapping of the rat brain involved in thermoregulatory responses using the [C]2-deoxyglucose technique

The central nervous structures involved in thermoregulatory responses to thermal stimulation of the preoptic/anterior hypothalamic region were investigated in conscious, unrestrained rats by means of the 2-deoxy-d-[¹⁴C]glucose autoradiographic technique. Significant activation in metabolic activity was observed in the medial preoptic area, medial forebrain bundle, anterior part of ventromedial hypothalamus, anteroventral thalamus, dorsomedial thalamus, basal ganglia, pars compacta of substantia nigra, red nucleus and the reticular formation.     

The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity

Glossopharyngeal afferents may be the neural channel by which immune challenge of the posterior oral cavity conveys information to the brain. If this is the case, then bilateral transection of the glossopharyngeal nerves (GLOx) should disrupt this communication. Injection of lipopolysaccharide (LPS) or interleukin (IL)-1beta into the soft palate (ISP) of sham-operated rats induced a dose-related febrile response. GLOx significantly attenuated the febrile response induced by ISP injection of both LPS and IL-1beta. In contrast, GLOx did not affect the febrile response when LPS or IL-1beta were injected intraperitoneally, indicating that the effect of GLOx is not systemic. These results provide experimental evidence for a novel neural pathway for immune-to-brain communication.     

Activation of brain metabolism and fos during limbic seizures: the role of locus coeruleus

The noradrenergic nucleus Locus Coeruleus (LC) densely innervates limbic structures. In rats, the damage to LC by the neurotoxin DSP-4, converts episodic limbic seizures induced by bicuculline infusion in the anterior piriform cortex (APC) into self-sustaining status epilepticus (SE). SE induced by this approach is similar to SE induced by co-infusing cyclothiazide and bicuculline into APC in rats bearing an intact LC. As opposed to other commonly used rat SE models (e.g. systemic kainate or pilocarpine), this approach allows one to analyze the effects of SE on brain regions which are solely due to spreading of seizure activity, rather than to direct effect of systemic chemoconvulsant.We evaluated the expression of Fos protein (an immediate early gene product), and the local cerebral metabolic rates for [¹⁴C] 2-deoxyglucose (lCMRglc), in rats following SE induced either by cyclothiazide+bicuculline or by DSP-4+bicuculline.We demonstrated that regional Fos expression after SE does not parallel the increase in lCMRglc, in LC-lesioned rats. In DSP-4+bicuculline rats there is an overall lower expression of the protein as compared with the cyclothiazide+bicuculline or bicuculline alone groups; even more, such a difference co-exists with an higher lCMRglc in the DSP-4+bicuculline-treated rats in some regions, as compared with the other groups.These data show that LC neurons play an important role in determining immediate early genes expression even in conditions of strong pathological activation, such as limbic SE. This might have relevant effects in the plastic mechanisms related with epileptogenesis.     

Female Sex Hormones Influence the Febrile Response Induced by Lipopolysaccharide,Cytokines and Prostaglandins but not by Interleukin‐1β in Rats

There are differences in the immune response, and particularly fever, between males and females. In the present study, we investigated how the febrile responses induced by lipopolysaccharide (LPS) and different endogenous pyrogens were affected by female gonadal hormones. The febrile response to i.p. injection of LPS (50 μg/kg) was 40% lower in female rats compared to male or ovariectomised (OVX) female rats. Accordingly, oestrogen replacement in OVX animals reduced LPS‐induced fever. Treatment with the prostaglandin synthesis inhibitor indomethacin (2 mg/kg, i.p. 30 min before) reduced the febrile response induced by LPS in both OVX (88%) and sham‐operated (71%) rats. In line with the enhanced fever in OVX rats, there was increased expression of cyclooxygenase‐2 (COX‐2) in the hypothalamus and elevated levels of prostaglandin E₂ (PGE₂). In addition, OVX rats were hyper‐responsive to PGE₂ injected i.c.v. By contrast to the enhanced fever in response to LPS and PGE₂, the febrile response induced by i.c.v. injection of interleukin (IL)‐1β was unaffected by ovariectomy, whereas the responses induced by tumour necrosis factor (TNF)‐α and macrophage inflammatory protein (MIP)‐1α were completely abrogated. These results suggest that the mediators involved in the febrile response in females are similar to males, although the reduction of female hormones may decrease the responsiveness of some mediators such as TNF‐α and MIP‐1α. Compensatory mechanisms may be activated in females after ovariectomy such as an augmented synthesis of COX‐2 and PGE₂.     

Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat

The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces most of the features of human temporal lobe epilepsy. After having studied the metabolic changes occurring during the silent phase, in the present study, we explored the relationship between interictal metabolic changes and neuronal loss during the chronic phase following status epilepticus (SE) induced by Li-Pilo in 10-day-old (P10), 21-day-old (P21), and adult rats. Rats were observed and their EEG was recorded to detect the occurrence of spontaneous recurrent seizures (SRS). Local cerebral glucose utilization was measured during the interictal period of the chronic phase, between 2 and 7 months after SE, by the [(14)C]2-deoxyglucose method in rats subjected to SE at P10, P21, or as adults. Neuronal damage was assessed by cell counting on adjacent cresyl violet stained sections. When SE was induced at P10, rats did not become epileptic, did not develop lesions and cerebral glucose utilization was in the normal range 7 months later. When SE was induced in adult rats, they all became epileptic after a mean duration of 25 days and developed lesions in the forebrain limbic areas, which were hypometabolic during the interictal period of the chronic phase, 2 months after SE. When SE was induced in P21 rats, 24% developed SRS, and in 43% seizures could be triggered (TS) by handling, after a mean delay of 74 days in both cases. The remaining 33% did not become epileptic (NS). The three groups of P21 rats developed quite comparable lesions mainly in the hilus of the dentate gyrus, lateral thalamus, and entorhinal cortex; at 6 months after SE, the forebrain was hypometabolic in NS and TS rats while it was normo- to slightly hypermetabolic in SRS rats. These data show that interictal metabolic changes are age-dependent. Moreover, there is no obvious correlation, in this model, between interictal hypometabolism and neuronal loss, as reported previously in human temporal lobe epilepsy.     

Brain vasculature and mitochondrial responses to ischemia in gerbils II. Strain differences and statistical evaluation

The correlation between the anatomy of brain vasculature and the metabolic responses to ischemia was studied in two strains of the Mongolian gerbil as compared to the albino rat. Gerbils belonging to the Meriones unguiculatus obtained from Tumblebrook Farms and from the NY Institute for Basic Research were compared to two lines of the Meriones tristrami obtained from two different breeders in Israel. In all groups of gerbils and in the albino rats, a significant correlation was found between the anatomical patterns of the Circle of Willis and the metabolic responses to ischemia as evaluated by NADH redox state measurements, namely, that with a complete anterior anatomical Circle of Willis the metabolic response to unilateral occlusion was minimal. In the anterior part of the Circle of Willis the various groups of gerbils exhibited the entire range of ischemia levels, from 0-100%, depending upon the anatomical structure of the arteries. In M. tristrami, the anterior communications between the two hemispheres were very well developed as compared to the various degrees of connection found in the different individuals of M. unguiculatus. This anatomical pattern corresponds well to the metabolic response recorded under unilateral and bilateral occlusion. The best connection in the posterior part, was found in M. tristrami. This was less frequent (10-20% of the gerbils) in M. unguiculatus. A clear correlation was found between the size of the posterior communicating artery and the changes in NADH redox state measured during bilateral carotid artery ligation. The variation between gerbils of the same litter was significantly smaller than that of the general population of the same strain.(ABSTRACT TRUNCATED AT 250 WORDS)     

阿米洛利对复杂型热性惊厥的影响

目的观察阿米洛利对复杂型热性惊厥的作用及其可能机制。方法建立Sprague-Dawley(SD)幼鼠复杂型热性惊厥模型,将40只SD幼鼠分为正常对照组、热性惊厥组、阿米洛利两种剂量预处理组(1.3阿米洛利组和10阿米洛利组),每组10只。在热性惊厥发作过程中观察阿米洛利预处理对体温升高、发作潜伏期的影响,以及对热性惊厥后海马区星形胶质细胞数及白细胞介素1β(IL-1β)mRNA含量的影响。结果热性惊厥组于4.3~6.8 min体温达到39.5℃,1.3阿米洛利组和10阿米洛利组分别于8.3~10 min和9.3~11.6 min达到39.5℃,后两者体温达39.5℃的时间明显晚于热性惊厥组(P0.01),且1.3阿米-洛利组和10阿米洛利组间有显著性差异(P0.05)。1.3阿米洛利组发作潜伏期为10.67~14.50 min,体温阈值为41.3~42.1℃,10阿米洛利组潜伏期为12.33~16.60 min,体温阈值为41.4~42.1℃,而热性惊厥组潜伏期为7.67~9.50分钟,体温阈值为41.0~41.7℃,1.3和10阿米洛利两组潜伏期较热性惊厥组明显延长,并且全身强直发作的体温阈值明显高于热性惊厥组(P0.01),阿米洛利高低剂量组间有明显差异(P0.05)。阿米洛利预处理组星形胶质细胞较正常对照组增多,而较热性惊厥组明显减少(均P0.01)。阿米洛利预处理组IL-1βmRNA含量明显少于热性惊厥组(P0.01)。结论阿米洛利可抑制复杂型热性惊厥发作,具有一定的抗热性惊厥作用,这可能与抑制星形胶质细胞增殖、抑制炎性因子生成有关。     

Hyperpolarization and short-circuiting as mechanisms of seizure prevention following febrile convulsions

Though children with febrile convulsions only have seizures in the early stage of a febrile illness and not later, these seizures have been attributed to the fever. We studied the serum electrolyte and metabolite profiles in the later stage to see if there were fuel responses resulting in electrophysiological changes which prevented further seizure activity. On admission there was intracellular glucose starvation, as evidenced by increased ketones and lactate, and the possibility of the failure of some electrolyte pumps, as suggested by hyperuricaemia (energy crisis) and decreased serum Na+, Cl- and Ca2+. However, there was adaptive hyperglycemia and decreased serum K+. It seems likely that the hyperglycemia, induced the uptake of K+ by neurones, enabling their repolarization and hyperpolarization, which prevented further seizure activity, while Cl- influx short-circuited depolarizing currents produced by Na+ influx. Studies during recovery showed a gradual return of the metabolic and electrolyte aberrations to normality, suggesting that the provision of energy through adaptation to the stress, enabled recovery of the aforementioned pumps.     

Effect of ouabain on the afterhyperpolarization of slowly adapting pulmonary stretch receptors in the rat lung

In anesthetized, artificially ventilated rats with one vagus nerve section, the purposes of the present study were to investigate whether release from phasic consecutive hyperinflations (inflation volume=3 tidal volumes) results in the afterhyperpolarization (AHP) of the slowly adapting pulmonary stretch receptor (SAR) activity and whether the effect of ouabain, a Na+-K+ ATPase inhibitor, alters AHP of the SAR activity seen after release from maintained inflations. Release from 10 consecutive phasic hyperinflations did not cause any significant inhibition of SAR activity. Release from maintained inflations (for approximately 10 and 15 cmH2O) for 5 s produced the induction of disappearance of SAR activity, corresponding with the AHP. Intravenous administration of ouabain (20 and 40 microg/kg) had no significant effects on the responses of SAR activity and SAR adaptation index (AI) to maintained inflations, but ouabain treatment with at 40 microg/kg resulted in a significant increase in the SAR activity after stopping the respirator and significantly attenuated the AHP of the SAR activity. In the immunohistochemical study, we found Na+-K+ ATPase alpha3-subunit-isoforms-like immunoreactivity in SAR terminals, forming leaflike extensions in the intrapulmonary bronchioles at different diameters, and those terminals were buried in the smooth muscle. In the same sections, the alpha1 subunit immunoreactivity of SAR terminals was not found. These results suggest that the mechanism of generating the AHP of SARs is mainly mediated by the activation of Na+-K+ ATPase alpha3 subunit isoform.     

Repeated febrile convulsions impair hippocampal neurons and cause synaptic damage in immature rats： neuroprotective effect of fructose-1,6-diphosphate

Fructose-1,6-diphosphate is a metabolic intermediate that promotes cell metabolism. We hypothesize that fructose-1,6-diphosphate can protect against neuronal damage induced by febrile convulsions. Hot-water bathing was used to establish a repetitive febrile convulsion model in rats aged 21 days, equivalent to 3–5 years in humans. Ninety minutes before each seizure induction, rats received an intraperitoneal injection of low- or high-dose fructose-1,6-diphosphate(500 or 1,000 mg/kg, respectively). Low- and high-dose fructose-1,6-diphosphate prolonged the latency and shortened the duration of seizures. Furthermore, high-dose fructose-1,6-diphosphate effectively reduced seizure severity. Transmission electron microscopy revealed that 24 hours after the last seizure, high-dose fructose-1,6-diphosphate reduced mitochondrial swelling, rough endoplasmic reticulum degranulation, Golgi dilation and synaptic cleft size, and increased synaptic active zone length, postsynaptic density thickness, and synaptic interface curvature in the hippocampal CA1 area. The present findings suggest that fructose-1,6-diphosphate is a neuroprotectant against hippocampal neuron and synapse damage induced by repeated febrile convulsion in immature rats.     

Effects of MK-801 upon local cerebral glucose utilisation in conscious rats following unilateral lesion of caudal entorhinal cortex

Local cerebral glucose utilisation was examined in 62 discrete regions of conscious rats following unilateral ibotenic acid lesion of the caudal entorhinal cortex, and subsequent pharmacological challenge with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Fourteen days after unilateral lesion of the entorhinal cortex, there were no significant alterations in local cerebral glucose use except within the lesioned entorhinal cortex (reduced by 31% compared to sham-operated control animals). In sham-operated animals, systemic administration of MK-801 (0.5 mg/kg, i.v.) induced anatomically organised alterations in glucose use with increases in olfactory areas, subicular complex and some limbic areas (posterior cingulate cortex, mammillary body and anteroventral thalamic nucleus), and decreases in the inferior colliculus and neocortex (auditory, sensory-motor, somatosensory and frontal cortices). In animals with unilateral entorhinal cortex lesions, the metabolic response to MK-801 differed significantly from the response to the drug in sham-lesioned animals in a number of regions, viz. hippocampus, molecular layer (ipsilateral to lesion), entorhinal cortex (ipsilateral), dentate gyrus (ipsilateral), presubiculum (bilateral), parasubiculum (bilateral) and nucleus accumbens (bilateral). The ability of MK-801 to reduce glucose use in the neocortex was not altered by entorhinal cortex lesion. These data suggest that the functional consequences of non-competitive NMDA receptor blockade are dependent in some areas upon the integrity of the perforant pathway from the entorhinal cortex to the hippocampus.     

Long‐lasting modulation of synaptic plasticity in rat hippocampus after early‐life complex febrile seizures

A small fraction of children with febrile seizures appears to develop cognitive impairments. Recent studies in a rat model of hyperthermia‐induced febrile seizures indicate that prolonged febrile seizures early in life have long‐lasting effects on the hippocampus and induce cognitive deficits. However, data on network plasticity and the nature of cognitive deficits are conflicting. We examined three specific measures of hippocampal plasticity in adult rats with a prior history of experimental febrile seizures: (i) activity‐dependent synaptic plasticity (long‐term potentiation and depression) by electrophysiological recordings of Schaffer collateral/commissural‐evoked field excitatory synaptic potentials in CA1 of acute hippocampal slices; (ii) Morris water maze spatial learning and memory; and (iii) hippocampal mossy fiber plasticity by Timm histochemistry and quantification of terminal sprouting in CA3 and the dentate gyrus. We found enhanced hippocampal CA1 long‐term potentiation and reduced long‐term depression but normal spatial learning and memory in adult rats that were subjected to experimental febrile seizures on postnatal day 10. Furthermore, rats with experimental febrile seizures showed modest but significant sprouting of mossy fiber collaterals into the inner molecular layer of the dentate gyrus in adulthood. We conclude that enhanced CA1 long‐term potentiation and mild mossy fiber sprouting occur after experimental febrile seizures, without affecting spatial learning and memory in the Morris water maze. These long‐term functional and structural alterations in hippocampal plasticity are likely to play a role in the enhanced seizure susceptibility in this model of prolonged human febrile seizures but do not correlate with overt cognitive deficits.     

In vivo and in vitro effects of homocysteine on Na,K-ATPase activity in parietal, prefrontal and cingulate cortex of young rats

In the present study we determined the effect of chronic administration of homocysteine on Na+,K+-ATPase activity in synaptic membranes from parietal, prefrontal and cingulate cortex of young rats. We also studied the in vitro effect of homocysteine on this enzyme activity and on some oxidative stress parameters, namely thiobarbituric acid-reactive substances (TBA-RS) and total radical-trapping antioxidant potential (TRAP) in the same cerebral structures. For the in vivo studies, we induced elevated levels of homocysteine in blood (500 microM), comparable to those of human homocystinuria, and in brain (60 nmol/g wet tissue) of young rats by injecting subcutaneously homocysteine (0.3-0.6 micromol/g of body weight) twice a day at 8 h intervals from the 6th to the 28th postpartum day. Controls received saline in the same volumes. Rats were killed 12 h after the last injection. Chronic administration of homocysteine significantly decreased (50%) Na+,K+-ATPase activity in parietal, increased (36%) in prefrontal and did not alter in cingulate cortex of young rats. In vitro homocysteine decreased Na+,K+-ATPase activity and TRAP and increased TBA-RS in all cerebral structures studied. It is proposed that the alteration of Na+,K+-ATPase and induction of oxidative stress by homocysteine in cerebral cortex may be one of the mechanisms related to the neuronal dysfunction observed in human homocystinuria.     

Influence of lactate accumulation on Na,K-ATPase activity of ischemic and post-ischemic brain

In this study the cerebral Na+, K+-ATPase activity as well as selected parameters of oxidative metabolism and electrophysiological function were assessed in normoglycemic and hyperglycemic rats which were exposed to ischemia produced by electrocautery of the vertebral arteries and reversible occlusion of the carotid arteries. In hyperglycemic animals 0.5 h of ischemia was associated with massive accumulation of lactate (34 mumol X g-1) and enhanced Na+, K+-ATPase activity (116% control), whereas normoglycemic animals showed more moderate lactate accumulation (17 mumol X g-1) and normal Na+, K+-ATPase activity (102% control). In normoglycemic animals release of the carotid clamps and recirculation for 0.5-1.5 h was associated with a normalization of the lactate levels and a decrease in Na+, K+-ATPase activity (68-72% control). Restituted hyperglycemic animals showed metabolic changes which seemed related to the blood pressure, with hypotensive hyperglycemic animals showing continuing massive lactacidosis (30-35 mumol X g-1) and enhanced Na+, K+-ATPase activity (108-110% control), whereas normotensive hyperglycemic animals showed progressive decreases in lactate level (14-20 mumol X g-1) and normal or mildly suppressed Na+, K+-ATPase activity (88-97% control). These patterns of change suggest that the reperfusion of the post-ischemic hyperglycemic-hyperlactacidotic brain was inadequate or non-homogeneous.     

Evidence for the behavioral supersensitivity of dopamine D2 receptors without receptor up-regulation in morphine-abstinent rats

The effect of morphine tolerance-dependence and abstinence on the characteristics of dopamine D₂ receptors in brain regions and spinal cord was determined in the rat. Male Sprague-Dawley rats were implanted s.c. under light ether anesthesia with 6 morphine pellets for a 7-day period, each containing 75 mg of morphine free base. Rats implanted with placebo served as controls. This procedure resulted in the development of tolerance to morphine as evidenced by decreased analgesic response to a challenge dose of morphine. Similarly, the development of physical dependence was evidenced by a decreased in body weight and colonic temperature after morphine pellet removal (withdrawal). The binding characteristics (B_max andK_d values) of [³H]spiroperidol to dopamine D₂ receptors were determined in the tissues of morphine-tolerant and morphine-abstinent rats. In the tolerant rats, the pellets were left intact at the time of sacrificing, whereas, in the abstinent rats the pellets were removed 18 h prior to sacrificing. The binding of [³H]spiroperidol was determined in membranes prepared from brain regions (hypothalamus, hippocampus, cortex, pons and medulla, midbrain, corpus striatum and amygdala) and spinal cord of rats from various treatment groups. [³H]Spiroperidol bound to brain regions and spinal cord at a single high affinity site. TheB_max or theK_d values in brain regions and spinal cord of morphine-tolerant and -abstinent rats did not differ from their respective placebo controls. The behavioral responses to a selective dopamine D₂ receptor agonist, 2-bromo-α-ergocryptine were also determined in the morphine-abstinent rats. In morphine-abstinent rats, increased behavioral activity, such as total distance travelled, number of movements, and the number of stereotypic movements was seen as compared to placebo controls. The dose of 2-bromo-α-ergocryptine which by itself had no effect on any type of behavioral activity in placebo-treated rats, increased the total distance travelled, horizontal activity, number of movements, and movement time in morphine-abstinent rats. Although in morphine-tolerant or morphine-abstinent rats, the characteristics of [³H]spiroperidol binding to dopamine D₂ receptors in brain regions and spinal cord were unchanged, the supersensitivity was observed to behavioral responses of 2-bromo-α-ergocryptine, a selective dopamine D₂ receptor agonist. These results provide an evidence for behavioral responses of 2-bromo-α-ergocryptine, a selective up-regulation in morphine abstinent rats. Previously, we have show that dopamine D₁ receptors are unaffected in morphine tolerant rats but are modified in morphine-abstinent rats. Thus, in the morphine abstinent process a significant difference was noted in the biochemical characteristics of dopamine D₁ and D₂ receptors.     

Brain multiparametric responses to carbon monoxide exposure in the aging rat

The multiparametric monitoring system was applied to study the effects of 2000 ppm carbon monoxide (CO) on brain functions in vivo in the aging rat. The vasodilatory (non hypoxic) effects of CO on CBF in normal adult rats, which were shown in concentrations of 1000-2000 ppm involved the effect of nitric oxide (NO). Energy metabolism was evaluated by optical monitoring of CBF and mitochondrial function by fluorometry of NADH. Ionic homeostasis was evaluated by monitoring the extracellular level of K(+) and H(+) and the DC steady potential. Seven aging rats (24 months) were exposed to 2000 ppm for 60 min and 120 min of recovery, while five control rats were exposed to air under the same conditions. A comparison between the CO group and the control group showed that the changes in CBF, NADH and light reflectance were not statistically significant while extracellular K(+) was elevated and tissue pH became more acidic. Thus, the typical CO induced increase in CBF, was not recorded in the aging rats. We concluded that the brain vasodilatory response to CO was not active in the aging rat, while the ionic homeostasis responses were similar to those found in the adult rat.     

Stress-induced behaviour in juvenile rats: effects of neonatal asphyxia, body temperature and chelation of iron

Newborn mammals, showing reduced normal body temperature, might be protected against iron-mediated, delayed neurotoxicity of perinatal asphyxia. Therefore, we investigated the effects of (1) neonatal body temperature and neonatal critical anoxia as well as (2) postanoxic chelation of iron with deferoxamine, on open-field stress-induced behaviour in juvenile rats. The third aim of this study was to compare (after the above-mentioned treatments) circadian changes in spontaneous motor activity and body temperature in juvenile rats permanently protected from any stress. Neonatal anoxia at body temperature adjusted (both during anoxia and 2 h reoxygenation) to a level typical of healthy (37 degrees C) or febrile (39 degrees C) adults led to the stress-induced hyperactivity in juvenile (5-45 days old) rats. Both normal neonatal body temperature of 33 degrees C and chelation of iron prevented the hyperactivity in rats. Neither neonatal body temperature nor neonatal anoxia affected spontaneous motor activity or body temperature of juvenile rats, recorded in their home-cages with implantable transmitters. Circadian rhythmicity was also undisturbed. Presented data support the hypothesis that physiologically reduced neonatal body temperature can provide a protection against iron-mediated postanoxic disturbances of behavioural stress responses in juvenile rats.