Respiratory complications and sleep disorders in children with chronic kidney disease: A correlation often underestimated.

Chronic Kidney Disease (CKD) is characterized by a progressive and irreversible loss of kidney function which gradually leads to end-stage kidney disease (ESKD). Virtually all the organs are damaged by the toxicity of uremic compounds. The lungs may be affected and the impaired pulmonary function may be the direct result of fluid retention and metabolic, endocrine and cardiovascular alterations, as well as systemic activation of the inflammation. An increased prevalence in sleep disorders (SD) is also reported in patients with CKD, leading to a further negative impact on overall health and quality of life. While these complex relationships are well documented in the adult population, these aspects remain relatively little investigated in children. The aim of this review is to provide a brief overview of the pathophysiology between lung and kidney and to summarize how CKD may affect respiratory function and sleep in children.

Blood pressure management in children on dialysis.

Hypertension is a leading cause of cardiovascular complications in children on dialysis. Volume overload and activation of the renin-angiotensin-aldosterone system play a major role in the pathophysiology of hypertension. The first step in managing blood pressure (BP) is the careful assessment of ambulatory BP monitoring. Volume control is essential and should start with the accurate identification of dry weight, based on a comprehensive assessment, including bioimpedance analysis and intradialytic blood volume monitoring (BVM). Reduction of interdialytic weight gain (IDWG) is critical, as higher IDWG is associated with a worse left ventricular mass index and poorer BP control: it can be obtained by means of salt restriction, reduced fluid intake, and optimized sodium removal in dialysis. Optimization of peritoneal dialysis and intensified hemodialysis or hemodiafiltration have been shown to improve both fluid and sodium management, leading to better BP levels. Studies comparing different antihypertensive agents in children are lacking. The pharmacokinetic properties of each drug should be considered. At present, BP control remains suboptimal in many patients and efforts are needed to improve the long-term outcomes of children on dialysis.

[Experience of a peripheral center in the surgical treatment of hepatic metastasis from colorectal cancer]. / Esperienza di un centro periferico nel trattamento chirurgico delle metastasi epatiche da cancro colorettale.

Surgical resection is still the first therapeutic option in patients with resectable colorectal cancer metastatic to the liver. Application of radiofrequency energy has been used in patients who did not meet the criteria for resectability and yet were candidates for a liver-directed procedure based upon the presence of liver-only disease. Hepatic resection has evolved in the last two or three decades from a procedure with associated mortality rate of up to 20% in the early 80s to usually less than 5% in patients undergoing liver resection thereafter. This improvement in morbidity and mortality is multifactorial; despite the increased safety of liver operations, hepatic resection still remains a complex surgical procedure with serious potential morbidity. The experience with liver resections and/or radiofrequency ablations, for colorectal cancer metastatic to the liver, performed at a medium-volume center (15 cases in 4 years) is presented. Some features of the metastatic disease, including the number, size and location of metastases are identified. The perioperative mortality is 0, morbidity for non surgical complications is 40%. In this series the reported overall 1-yr survival is 80%, 2-yr is 67%. This paper reviews the experienced factors that have defined the morbidity and mortality associated with liver surgery.

Parafascicular thalamic nucleus deafferentation reduces c-fos expression induced by dopamine D-1 receptor stimulation in rat striatum.

We investigated the role played by the parafascicular thalamostriatal pathway, one of the major excitatory inputs to the striatum, in the D-1 receptor induction of c-fos messenger RNA expression in the rat striatum. The full D-1 receptor agonist, SKF-82958 (0.05, 0.1, 0.5 and 1 mg/kg, s.c., 30 min), dose-dependently induced c-fos messenger RNA in naive rat striatum as determined by northern blot analysis. One day following electrolytic lesion of the parafascicular thalamostriatal nucleus, striatal c-fos signal by itself was not altered but the stimulated expression of c-fos was strongly decreased. Sections of sham-operated and acute-lesioned dorsal striata of vehicle- or SKF-82958-treated rats were processed for in situ hybridization histochemistry at the single-cell level with an RNA probe for c-fos. The basal expression of striatal c-fos was poorly detectable in sham and lesioned groups. Sections of dorsal striata from sham-operated rats treated with SKF-82958 showed two types of labeled neurons for c-fos: the lightly and the very densely labeled neurons which are few in number. Thalamic lesion strongly reduced SKF-82958 stimulated expression of c-fos RNA in both types of labeled cells. The frequency distribution of c-fos labeling per neuron in dorsal striata of lesioned rats treated with SKF-82958 was shifted to the left, and its median was lower than in the sham-operated striata treated with the D-1 receptor agonist. The results provide evidence that the excitatory projections from the parafascicular nucleus of the thalamus, thought to operate primarily through the N-methyl-D-aspartate receptors, exert a facilitatory control over D-1 receptor-induced c-fos gene expression specifically in the dorsal striatum.

Peritonectomy and hyperthermic antiblastic perfusion in the treatment of peritoneal carcinomatosis.

AIMS: Some low-grade malignant tumours arising in the abdomen tend to remain loco-regionally confined to peritoneal surfaces, without systemic dissemination. In these cases complete surgical tumour cytoreduction followed by intra- or post-operative regional chemotherapy has curative potential. The aim of this study was to evaluate the outcome for patients treated in this way. METHODS: Peritonectomy was performed, involving the complete removal of all the visceral and parietal peritoneum involved by disease. After peritonectomy, hyperthermic antiblastic perfusion was carried out throughout the abdominopelvic cavity for 90 min, at a temperature of 41.5-42.5 degrees C, with mitomycin C (3.3 mg/m2/l) and cisplatin (25 mg/m2/l) (for appendicular or colorectal primaries), or cisplatin alone (for ovarian primaries). Alternatively, the immediate post-operative regional chemotherapy was performed with 5-fluorouracil (13.5 mg/kg) and Lederfolin (125 mg/m2) (for colonic or appendicular tumours) or cisplatin (25 mg/m2) (for ovarian tumours), each day for 5 days. RESULTS: Thirty-five patients affected by extensive peritoneal carcinomatosis were submitted to peritonectomy, with no residual macroscopic disease in all cases except three. Twenty-six patients were able to undergo the combined treatment involving loco-regional chemotherapy. Complications were observed in 54% of the patients and led to death in four of them. At a mean follow-up of 17 months overall 2-year survival was 55.2%, with a median survival of 26 months. CONCLUSIONS: After a learning curve of 18 months the feasibility of the integrated treatment increased to more than 90%, while mortality decreased dramatically. The curative potential of the combined therapeutic approach seems high in selected patients with peritoneal carcinomatosis not responding to systemic chemotherapy. Careful selection of patients can minimize the surgical risk, but the treatment should currently be reserved for clinical trials.

Myocardial ischaemia in neonates with perinatal asphyxia. Electrocardiographic, echocardiographic and enzymatic correlations.

In asphyxiated neonates, hypoxia is often responsible for myocardial ischaemia. To evaluate cardiac involvement in neonates with respiratory distress, ECG and echocardiographic recordings were performed, and cardiac enzymes determined. These data were related to clinical presentation and patient outcome. Three groups of neonates were studied: 22 healthy newborn infants (group I) with 5 min Apgar scores > 9 and pH > 7.3; 15 neonates with moderate respiratory distress (group II) which had Apgar scores ranging between 7 and 9, and pH between 7.2 and 7.3; and 13 neonates with severe asphyxia, Apgar scores < 7, and pH < 7.2 (group III). The ECGs were evaluated according to the 4-grade classification proposed by Jedeikin et al. [8]. On the echocardiograms, fractional shortening and aortic flow curve parameters were taken into account. Serum creatine kinase (CK), creatine kinase-MB isoenzyme (CK-MB) and lactate dehydrogenase were determined. All of groups I and II survived, but 5 out of 13 in group III died within the 1st week. Grade 3 or 4 ECG changes were observed only in group III patients, while all group II and 3 patients of group I showed grade 2 ECG changes. Fractional shortening, peak aortic velocity and mean acceleration were significantly reduced in group III, whereas the only abnormality found in group II was a reduced fractional shortening. CK, CK-MB, CK-MB/CK ratio and lactate dehydrogenase were all increased in group III, while in group II only CK-MB and the CK-MB/CK ratio were abnormal. Severely asphyxiated newborn infants reflect relevant ischaemic electrocardiographic changes, depressed left ventricular function and marked cardiac enzyme increase. These alterations are far less pronounced in neonates with mild respiratory distress.

Increased striatal expression of glutamate decarboxylase 67 after priming of 6-hydroxydopamine-lesioned rats.

Previous single exposure (priming) to a dopamine receptor agonist greatly enhances the contralateral turning behaviour elicited by dopamine D1 receptor agonists in unilaterally 6-hydroxydopamine lesioned rats. In the present study we have investigated the levels of glutamate decarboxylase 67 and glutamate decarboxylase 65 messenger RNA in the striatum of 6-hydroxydopamine-lesioned rats primed with L-3,4-dihydroxyphenylalanine (L-DOPA) and challenged with the D1 receptor agonist SKF 38393, three days thereafter. As previously reported, levels of glutamate decarboxylase 67 messenger RNA increased in the striatum denervated by the 6-hydroxydopamine lesion as compared with the intact one. Striatal glutamate decarboxylase 67 messenger RNA levels, measured three days after priming with L-DOPA (50 mg/kg), further increased in the lesioned striatum while were not modified in the intact one. Administration of SKF 38393 (3 mg/kg) elicited a more intense contralateral turning behaviour in primed than in drug-naive 6-hydroxydopamine-lesioned rats but did not induce any change in striatal glutamate decarboxylase 67 messenger RNA. In contrast, striatal levels of glutamate decarboxylase 65 messenger RNA were not modified by either 6-hydroxydopamine lesions or priming with L-DOPA. The results show that priming with L-DOPA induces long-lasting changes in GABAergic neurons of the 6-hydroxydopamine-lesioned striatum. These changes might play a role in the increased behavioural response of striatal D1 receptors induced by priming.

Different sensitivity of in vivo acetylcholine transmission to D1 receptor stimulation in shell and core of nucleus accumbens.

We investigated whether D1 dopaminergic receptors modulate in vivo acetylcholine output in the shell and core areas of rat nucleus accumbens using the microdialysis technique. Subcutaneous injection (1, 2 and 3 mg/kg) of the D1 agonist SKF 82958 enhanced acetylcholine output in both areas of the nucleus accumbens while the selective D1 antagonist SCH 39166 (0.15 and 0.30 mg/kg, s.c.) lowered it. Both SKF 82958 and SCH 39166 were more effective in the shell than in the core region. The increase in acetylcholine release induced by SKF 82958 in the shell was tetrodotoxin-sensitive. The dopamine release inducer d-amphetamine (1 and 2mg/kg, s.c.) and the dopamine uptake inhibitor cocaine (10 and 20 mg/kg, i.p.) dose-dependently raised acetylcholine release in the shell and core areas. The dopaminergic stimulants, like the direct-acting D1 compounds, were more effective in the shell than in the core compartment of the nucleus accumbens. The acetylcholine increases in the shell induced by d-amphetamine (2 mg/kg), cocaine (20 mg/kg) and SKF 82958 (3 mg/kg) were antagonized by the D1 antagonists SCH 39166 (5 microM) and SCH 23390 (10 microM), applied locally by reverse dialysis. The results suggest that dopamine acting at the D1 receptors exerts a tonic stimulatory control over the cholinergic function of the shell and core compartments of the nucleus accumbens with the shell being more strongly influenced.

The parafascicular thalamic nucleus but not the prefrontal cortex facilitates the nitric oxide/cyclic GMP pathway in rat striatum.

We investigated whether the parafascicular thalamic nucleus and the prefrontal cortex, the two major excitatory inputs to the striatum, modulate the nitric oxide/cyclic GMP pathway in rat striatum. Electrical stimulation (10 pulses of 0.5 ms, 10 V applied at 10 Hz, 140 microA) delivered bilaterally to the parafascicular thalamic nucleus for a total of 4, 10 and 20 min, time-dependently facilitated cyclic GMP output in the dorsal striatum of freely moving rats, assessed by trans-striatal microdialysis. Electrical stimulation to the prefrontal cortex for a total duration of 20 min did not affect striatal cyclic GMP levels. The facilitatory effect observed after electrical stimulation of the parafascicular thalamic nucleus was blocked by co-perfusion with tetrodotoxin, suggesting that the effect is mediated by neuronal process(es). The non-competitive N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (30 microM infused into the dorsal striatum), and the competitive one, 3-[(R)-carboxypiperazin-4-yl]-propyl-phosphonic acid (50 microM infused), but not local perfusion of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid antagonist, 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (15 microM perfused locally), abolished the cyclic GMP response in the striatum. The nitric oxide synthase inhibitor, 7-nitroindazole, applied locally (1 mM), blocked the electrically evoked increase in striatal extracellular cyclic GMP. This increase was also prevented by local application (100 and 300 microM) of 1H-(1,2,4)-oxadiazolo-(4,3a)-quinoxalin-1-one, a selective inhibitor of soluble guanylyl cyclase. The results provide direct functional evidence of selective thalamic facilitation of the nitric oxide/cyclic GMP pathway in the dorsal striatum, through activation of N-methyl-D-aspartate receptors.

Chronic morphine induces long-lasting changes in acetylcholine release in rat nucleus accumbens core and shell: an in vivo microdialysis study.

Previously, only in vitro studies have shown that chronic administration of morphine provokes long-lasting enhanced activity of accumbal cholinergic neurons, which may contribute to the behavioural sensitization, positive reinforcement and aversive effects associated with enhanced drug-seeking. The present study was aimed at clarifying whether these adaptive changes would also be supported by in vivo microdialysis measurements in freely moving rats, distinguishing between the accumbal substructures shell and core, and observing behavioural changes simultaneously. Acute administration of morphine dose-dependently decreased acetylcholine (ACh) release in the nucleus accumbens (NAc), with 10 mg/kg s.c. being most effective, 5 mg/kg ineffective. On day 5 of spontaneous abstinence from chronic morphine treatment (10-40 mg/kg morphine dose once daily for 5 days), when withdrawal symptoms were still present, even a lower morphine dose (5 mg/kg) was effective in decreasing ACh release in the NAc. During the later phase of abstinence, when no withdrawal symptoms were detectable, the opposite effect, i.e. an increase of ACh release was found. This later effect may represent a long-lasting neuroadaptive effect of morphine. These adaptive effects seemed to be more prominent in the NAc shell. Concurrent with these changes in ACh release, morphine challenges produced marked behavioural stereotypes, possibly indicating behavioural sensitization.

5-HT1A receptors mediate inhibition of ethanol-induced ascorbic acid release in rat striatum studied by microdialysis.

Our previous study showed that the serotonergic system was involved in the ethanol-induced striatal ascorbic acid release in rat. In the present study, the 5-HT1A agonists and antagonists were used to analyze the possible mechanism of ethanol-induced ascorbic acid release in rat striatum. The results showed that ethanol (3.0 g/kg, i.p.) significantly increased striatal ascorbic acid release. Buspirone (5.0 mg/kg, s.c.), a partial agonist of 5-HT1A receptors, and 8-OH-DPAT (0.5 mg/kg, s.c.), a selective agonist of 5-HT1A receptors, showed no effect on basal ascorbic acid release in striatum, but both drugs significantly antagonized the ascorbic acid release induced by ethanol in striatum. WAY 100635 (0.5 mg/kg, s.c.), a selective antagonist of 5-HT1A receptors, affecting neither the basal nor the ethanol-induced ascorbic acid release per se, antagonized the suppressing effect of 8-OH-DPAT on ethanol-induced ascorbic acid release in striatum. This study gives the first evidence that activation of 5-HT1A receptors is involved in ethanol-induced ascorbic acid release in rat striatum.

Galanin stimulates the N-methyl-D-aspartate receptor/nitric oxide/cyclic GMP pathway in vivo in the rat ventral hippocampus.

We investigated whether the neuropeptide galanin affects the nitric oxide synthase/cyclic GMP pathway in rat hippocampus by measuring in vivo the extracellular cyclic GMP levels during microdialysis. Galanin (2.5 and 3.5 nmol; i.c.v.) dose-dependently raised the extracellular levels of cyclic GMP in the ventral but not the dorsal hippocampus. The effect of 3.5 nmol galanin was blocked by local application of tetrodotoxin and inhibited by the high-affinity galanin antagonist M40 (galanin-[1-12]-Pro3-[Ala-Leu]2-Ala amide). The non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine maleate (30 microM infused into the ventral hippocampus or 0.2 mg/kg, i.p.) and the competitive one, 3-([R]-carboxypiperazin-4-yl)-propyl-phosphonic acid (50 microM infused), but not local perfusion of the AMPA antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (15 microM) abolished the galanin-evoked cyclic GMP response in the hippocampus. Inhibitors of nitric oxide synthase, L-Arg(NO2)-OMe.HCl and 7-nitroindazole monosodium salt, applied locally, blocked the galanin-induced increase in hippocampal extracellular cyclic GMP. This increase was also prevented by local application of 1H-(1,2,4)oxadiazolo(4,3a) quinoxalin-1-one, a selective inhibitor of soluble guanylyl cyclase. The galanin receptors mediating the rise in cyclic GMP reside outside the hippocampus, as galanin (0.35-3 nmol) locally applied had no effect. The results provide in vivo evidence that galanin stimulates the N-methyl-D-aspartate receptor/nitric oxide synthase/cyclic GMP pathway in the ventral hippocampus, which may be of importance in memory processes.

Post-ventricular tachycardia P wave change simulating atrial enlargement.

An abnormal P wave was observed in a child affected by prolonged idiopathic ventricular tachycardia (fascicular tachycardia). After sinus rhythm restoration, the P wave was very tall and peaked (0.5 mV in lead II), suggesting a diagnosis of atrial enlargement. No cardiac abnormality, however, was detected by clinical and echocardiographic examination. The P wave abnormality lasted for about 1 month, with progressive voltage and shape normalization. These P wave changes were probably dependent on tachycardia; since the arrhythmia was long-lasting and characterized by atrioventricular dissociation, repetitive atrial contraction against closed atrioventricular valves caused stretching of atrial fibers, resulting in P wave abnormality. This observation suggests that very prolonged ventricular tachycardia may be associated with an electrocardiographic pattern of pseudoatrial enlargement.

Novel and highly potent 5-HT3 receptor agonists based on a pyrroloquinoxaline structure.

The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT3 receptor and were able to functionally discriminate the central and peripheral 5-HT3 receptor, being agonists and antagonists, respectively. In functional studies ([14C]-guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT3 agonists identified to date that are able to cross the blood-brain barrier.

The parafascicular thalamic nucleus modulates messenger RNA encoding glutamate decarboxylase 67 in rat striatum.

We investigated whether the parafascicular thalamostriatal pathway, one of the major excitatory inputs to the striatum, regulates the expression in rat striatum of messenger RNA encoding two isoforms of glutamate decarboxylase (mol. wt 67,000: glutamate decarboxylase 67 and mol. wt 65,000: glutamate decarboxylase 65). Acute (one day) and chronic (14 days) electrolytic lesions of the parafascicular nucleus resulted in 58% and 23% decreases in glutamate decarboxylase 67 messenger RNA expression, respectively, as determined by northern blot analysis. Glutamate decarboxylase 65 messenger RNA was not modified by either lesion. Sections of sham- and acute-lesioned striata were processed for in situ hybridization histochemistry at the single cell level with an RNA probe for glutamate decarboxylase 67. Labelling of glutamate decarboxylase 67 messenger RNA was decreased in both types of cells known to be present in the striatum, i.e. the lightly and the very densely-labelled neurons. The frequency distribution of glutamate decarboxylase 67 labelling per neuron in the lesioned striata, in fact, was shifted to the left and its median was lower than in the sham-lesioned striata. In view of the excitatory nature of the thalamostriatal pathway, we examined the subtype of glutamate receptors modulating the glutamate decarboxylase 67 gene expression. The N-methyl-D-aspartate-type receptor antagonist, dizocilpine, at 0.1-0.5 mg/kg i.p., produced a marked and persistent reduction in striatal glutamate decarboxylase 67 messenger RNA. The non-N-methyl-D-aspartate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (12 nmol/side, i.c.v.) had no such effect. The results provide evidence that excitatory thalamostriatal afferents selectively modulate the gene expression of glutamate decarboxylase 67, probably through the N-methyl-D-aspartate subtype of glutamate receptors.

Galparan induces in vivo acetylcholine release in the frontal cortex.

The chimeric peptide galparan (galanin(1-13)-mastoparan) induced the in vivo release of acetylcholine in the frontal cortex of rats when injected intracerebroventricularly, i.c.v. The ACh-releasing effects of galparan are reversible, dose-dependent, and not exerted at galanin receptors or at sites where mastoparan acts. Pertussis toxin pretreatment (i.c.v.) of the rats for 96 h prior to injection of galparan or of mastoparan completely prevented the ACh-releasing effects of both galparan and mastoparan. It appears that galparan acts at a novel site in the release of ACh in the cerebral cortex in vivo.

The cerebral cortex and parafascicular thalamic nucleus facilitate in vivo acetylcholine release in the rat striatum through distinct glutamate receptor subtypes.

Electrical stimulation (ten pulses of 0.5 ms, 10 V applied over 10 s at 10 Hz, 140 microA) delivered bilaterally to the prefrontal cortex or the parafascicular thalamic nucleus of freely moving rats facilitated acetylcholine release in dorsal striata, assessed by trans-striatal microdialysis. The facilitatory effects were blocked by coperfusion with 5 microM tetrodotoxin, suggesting that the release was of neuronal origin. The response of the striatal cholinergic neurons to prefrontal cortical stimulation was short-lived and required a longer period of stimulation (20 min) that the response to thalamic stimulation (4 min) to reach maximal effect. The alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate glutamatergic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione [DNQX; 12 nmol per side, intracerebroventricularly (i.c.v.)] and the AMPA antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX; 12 nmol per side, i.c.v. or 12.8 microM infused into the striatum), but not the NMDA-type receptor antagonist MK-801 (0.2 mg/kg, i.p.), abolished the facilitatory effect on striatal acetylcholine release evoked by stimulation of the prefrontal cortex. By contrast, DNQX or NBQX did not prevent the increase in striatal acetylcholine release evoked by parafascicular nucleus stimulation, but MK-801, in accordance with previous results, did so. MK-801 by itself lowered striatal acetylcholine output while DNQX and NBQX did not. The results provide in vivo evidence that the cerebral cortex facilitates cholinergic activity in the dorsal striatum apparently through the non-tonic activation of AMPA-type glutamatergic receptors while the parafascicular nucleus does this through tonic activation of NMDA receptors. Both glutamate receptor types are probably located in the striatum. The overall results suggest that the two pathways operate independently to regulate striatal cholinergic activity through distinct mechanisms.

Surgical anaesthesia with pentobarbital prevents the effect of local SCH 23390 on rat striatal acetylcholine release in a strain-dependent manner.

This study was performed in order to clarify existing discrepancies about the ability of the D1 antagonist SCH 23390 to reduce striatal acetyicholine (ACh) release after intrastriatal application by reverse dialysis. The possibility that negative findings were related to the use of pentobarbital rather than Equithesin as surgical anaesthesia for implanting microdialysis probes, and of Wistar rather than Sprague-Dawley rats, was tested. SCH 23390, applied by reverse dialysis at the concentration of 24µM, although able to reduce dialysate ACh in male Wistar rats implanted under Equithesin anaesthesia, failed to do so in rats of the same strain implanted 24h or 3 days earlier under pentobarbital anaesthesia. In male Sprague-Dawley rats, local SCH 23390 (24µM) reduced striatal dialysate ACh, both in rats implanted under Equithesin as well as in rats implanted under pentobarbital anaesthesia. Systemic SCH 23390 (0.3mg/kg s.c.) reduced dialysate A Ch both in Wistar and in Sprague-Dawley rats implanted under pentobarbital anaesthesia, but was more effective in the Sprague-Dawley strain. These observations, although consistent with a striatal localization of D1-receptors controlling ACh release, can be explained as being the result of a strain-dependent barbiturate-induced inactivation of D1-mediated control of ACh transmission, which is potentiated by the local changes induced by microdialysis probe implant.

Endogenous serotonin facilitates in vivo acetylcholine release in rat frontal cortex through 5-HT 1B receptors.

We characterized the role of endogenous serotonin (5-HT) in regulating in vivo acetylcholine (ACh) output in frontal cortex of freely moving rats using the microdialysis technique. Systemic (0.63, 1.25 and 2.5 mg/kg, i.p.) or local (20 and 40 microM, reverse dialysis) administration of the 5-HT releaser and uptake inhibitor, d-norfenfluramine, dose-dependently enhanced frontal cortex ACh output. The d-norfenfluramine-induced increase in cortical ACh release was tetrodotoxin sensitive and completely prevented by a 7-day chemical degeneration of the serotonergic afferents to the frontal cortex. Investigating the 5-HT receptors that might mediate the d-norfenfluramine cholinergic effect, we found that the 5-HT4 (GR 125487) and 5-HT2A/2C (ritanserin) receptor antagonists, at doses effective in other in vivo tests, did not prevent the increase in cortical ACh output induced by the maximal effective does of d-norfenfluramine. However, the 5-HT1A/1B receptor antagonists (-)-pindolol (8 mg/kg, s.c.) or (-)-propanolol (8.8 mg/kg, i.p.) antagonized the increasing effect of d-norfenfluramine although the selective 5-HT1A receptor antagonist WAY-100635 (1 and 2 mg/kg, s.c.) did not. In accordance with an involvement of the 5-HT1B receptor in the ACh facilitation induced by d-norfenfluramine is the finding that the selective 5-HT1B agonist, CP-93,129, given locally (2, 4 and 8 micrograms/side) does-dependently raised cortical ACh release. In conclusion, the overall regulatory control exerted by endogenous 5-HT in vivo is to facilitate frontal cortex ACh release through 5-HT1B receptors located in the frontal cortex. The 5-HT1B receptors may act indirectly to facilitate ACh release probably by inhibiting cortical inhibitory inputs onto the cholinergic neurons.

Role of the parafascicular thalamic nucleus and N-methyl-D-aspartate transmission in the D1-dependent control of in vivo acetylcholine release in rat striatum.

We investigated the involvement of glutamatergic neurotransmission in the modulation of D1 receptor-mediated stimulation of acetylcholine outflow in dorsal striatum in freely moving rats, and the relative roles of the thalamostriatal and corticostriatal pathways in this regulation using in vivo microdialysis. The selective N-methyl-D-aspartate non-competitive antagonist dizocilpine maleate (0.1 mg/kg i.p.), but not the kainate/quisqualate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (3 micrograms per side i.c.v.), completely prevented the rise in striatal extracellular acetylcholine elicited by maximal effective doses of the full D1 agonist SKF 82958 (3 mg/kg s.c.) and of the dopamine releaser d-amphetamine (2 mg/kg s.c.). Acute bilateral electrolytic lesions of the parafascicular nucleus of the thalamus prevented the stimulation of striatal acetylcholine output by SKF 82958 and d-amphetamine but only slightly reduced basal acetylcholine release. In contrast acute interruption of the corticostriatal pathway did not alter the effect of the two dopaminergic drugs although it markedly reduced basal striatal acetylcholine release. Lesions of the parafascicular thalamic nucleus, or a low dose of dizocilpine maleate (0.1 mg/kg i.p.), also prevented the acetylcholine-increasing effect of the neuroleptic remoxipride (10 mg/kg s.c.), an effect known to be D1 receptor dependent. The results suggest that striatal projections arising from the parafascicular thalamic nucleus and utilizing N-methyl-D-aspartate receptors play a critical role in the D1-mediated stimulation of acetylcholine release in dorsal striata.