P.E. Vos

Neurohypophyseal hormone receptors in the septum are implicated in social recognition in the rat.

The effects on social recognition memory of (Arg(8))-vasopressin (AVP-(1-9), [pGlu(4), Cyt(6)]AVP-(4-8) and oxytocin locally administered into the rats septum were investigated. In the behavioural paradigm used, a juvenile intruder was presented to an adult resident male rat twice for 5 min, with an inter-exposure interval of 120 min. Peptide-free residents investigated the juvenile during the second encounter as long as during the first encounter. Intraseptal injection just after the first encounter with graded doses of (Arg(8))-vasopressin, [pGlu(4),Cyt(6)]AVP-(4-8) or oxytocin caused a decrease of social investigation, as compared to placebo treatment, indicating facilitation of social recognition. The least effective dose was 100pg, 200pg and 300pg respectively. The action of vasopressin was blocked by both d(CH(2))(5)[Tyr(Me)(2)]AVP and d(CH(2))(5)[D-Ile(2)Ile(4)]AVP, V(1) and V(2) vasopressinergic receptor antagonists, but not by desGly(NH(2))(9)-d(CH(2))(5)[Tyr(Me)(2)Thr(4)]-OVT, an oxytocinergic receptor antagonist. None of the antagonists blocked the oxytocin-facilitating action on social recognition. They also did not affect social recognition when injected alone. The effects of vasopressin seem to be mediated by vasopressinergic receptors dissimilar to those found in the periphery, while the receptors involved in the action of oxytocin remain to be elucidated.

Subtle involvement of the sympathetic nervous system in amyotrophic lateral sclerosis

The literature on the involvement of the autonomic nervous system (ANS) in amyotrophic lateral sclerosis (ALS) is conflicting. We therefore investigated several aspects of autonomic function, namely muscle sympathetic nerve activity (MSNA), blood pressure, cardiac function (electrocardiogram; ECG), and respiration in 16 patients with sporadic ALS and in 12 age‐matched healthy volunteers, both at rest and during sympathoexcitatory stimulation. We measured MSNA by provoking venous pooling during short‐lasting lower body negative pressure (LBNP) and during the cold pressor test (CPT). To assess the vagal (baroreflex) control of heart rate (HR), we measured spontaneous baroreflex sensitivity (BRS). To assess the involvement of the ANS beyond the cardiovascular system, we measured the sympathetic skin response (SSR). The stand‐up test showed that none of the subjects had orthostatic intolerance. In comparison with the control group, the ALS patients had an increased HR and a decreased BRS at rest, and a reduced MSNA response to LBNP. The CPT response was normal and the total MSNA at rest did not differ significantly from that of controls. The latencies of the palmar and plantar SSR were prolonged, and in 3 ALS patients there was no plantar SSR. The results indicate that the sympathetic nervous system shows subtle abnormalities in ALS, predominantly sympathetic overactivity. They also point to the involvement of the preganglionic sympathetic column as the cause of the higher sympathetic activity and the absence of SSR. The higher sympathetic activity is postulated to be due to changes in modulation of the sympathetic system, whereas the absence of the SSR is probably caused by disruption of the reflex pathway.

Microbiological quality and quality control of purified water and ultrapure dialysis fluids for online hemodiafiltration in routine clinical practice

During online hemodiafiltration, patients are directly infused with sterile substitution solutions to maintain fluid balance. Adequate water treatment and a well-organized quality control process are essential to provide non-pyrogenic fluids with consistent optimal quality. We sought to assess water quality, the water treatment system, and the methods for surveillance of microbiological water quality in 10 Dutch dialysis centers that routinely treat patients with hemodiafiltration. Microbiological monitoring results (micro-organisms and endotoxins) were collected over a 1-year period representing 11,258 hemodiafiltration sessions covering 97 patients. In all centers, water purification was based on a reverse osmosis module in combination with a second reverse osmosis and/or an electrodeionizer. All centers regularly and routinely monitored the microbiological purity of the dialysis water with adequate analytical methods but with variable monitoring frequency. Microbiological assessments were compliant with reference quality levels in 3923 of 3961 samples. Our study suggests that non-pyrogenic substitution fluids can be produced online for a prolonged period of time. It is likely that the current Dutch Quality of Care Guideline has contributed to high-quality water treatment and a well-organized control process.

Modifications in glutamatergic transmission after dopamine depletion of the nucleus accumbens. A combinedin vivo/in vitro electrophysiological study in the rat

The interaction between the glutamatergic and dopaminergic input in the nucleus accumbens was examined by studying the effects of dopamine depletion of the nucleus accumbens on the local field potentials, and the L-glutamate elicited responses of the nucleus accumbens in anaesthetized rats in vivo. A characteristic field potential in the nucleus accumbens is evoked by electrical stimulation of the fornix/fimbria fibres, with a monosynaptic positive peak at 10 ms (P10). Rats were unilaterally injected with 6-hydroxydopamine in the nucleus accumbens. The contralateral accumbens was sham lesioned. The rats were divided into short-term and long-term survival groups of one to two weeks and 24 weeks, respectively. In the short-term group, a striking increase (up to three times) of the amplitude of the P10 components, at the site of the lesion, compared with the sham lesioned contralateral accumbens and untreated rats, was found. The long-term group could still display a slight increase although on average this was not significantly different from controls. In the short-term group, at the centre of the lesion, the paired-pulse facilitation ratio was significantly smaller than at the more ventral, less denervated, border of the accumbens. These differences were no longer visible in the long-term group. Single-unit activity of the accumbens, elicited by the iontophoretical application of L-glutamate showed, in controls, a maximal firing frequency ranging from 5 to 40 Hz (mean 25 Hz), whereas in the short-term group more than 50% of the accumbens neurons fired with higher frequencies, reaching up to 90 Hz (mean 55 Hz). In the long-term group the firing frequency varied from 5 to 60 Hz (mean 41 Hz). No changes in threshold ejection glutamate current were found for both lesioned groups. In control rats the L-glutamate elicited responses of six cells tested could be suppressed by dopamine whereas in lesioned rats three of the six cells tested were unresponsive to dopamine. Intracellular recordings of accumbens cells in slices in 6-hydroxydopamine and sham lesioned rats, showed no significant changes in the intrinsic membrane properties, e.g. resting membrane potential, input resistance, spike threshold, action potential amplitude or duration. We conclude that dopamine denervation leads to an increase of excitability of the principal accumbens neurons. This is reflected by the increase of the firing frequency of these cells and of the amplitude of the evoked field potentials. The former is more likely of postsynaptic origin whereas the latter may also have a presynaptic contribution. These effects cannot be attributed to changes in intrinsic membrane properties of the cells.

The behavioral effects of habituation and challenge with apomorphine after 6-OHDA lesioning of the nucleus accumbens in rats

In rats the function of the dopamine system in the nucleus accumbens was tested after 6-OHDA lesioning of this brain area and after ORG 2766 induced facilitation of recovery in 6-OHDA lesioned animals. A low dose of systemically administered apomorphine (50 micrograms/kg) decreased motility when sham operated rats were placed in a novel environment. A similar decrease was found in saline treated rats tested for the second time 1 day later. In thus habituated animals, the low dose of apomorphine did not induce hypomotility. Thus habituation and hypomotility after a low dose of apomorphine may be due to a similar mechanism, viz. diminished dopamine release. A higher dose of apomorphine (125 micrograms/kg) increased motility, but only when the rats were habituated to the test environment. Animals with a bilateral 6-OHDA lesion of the nucleus accumbens showed hypomotility when tested for the first time 1 week after the lesion. The low and the higher dose of apomorphine elicited hypermotility in both nonhabituated and habituated lesioned rats. Their activity was higher than in sham operated animals, suggesting supersensitivity of postsynaptically located dopamine receptor systems in lesioned rats. Treatment with the ACTH(4-9) analog ORG 2766 during the first week after induction of the lesion counteracted the hypomotility of the lesioned rats. Furthermore ORG 2766 enhanced the supersensitivity as revealed by challenge with the low dose of apomorphine.

Short and long term plasticity after lesioning of the cell body or terminal field area of the dopaminergic mesocorticolimbic system in the rat.

To investigate within one study regenerative capacities of dopaminergic axons and cell bodies, short and long term recovery of behavioral and biochemical impairments following a bilateral 6-hydroxydopamine (6-OHDA) lesion of the ventral tegmental area (VTA)-nucleus accumbens (NAc) pathway was investigated in rats. Novelty-induced motility, presynaptic functions and the levels of dopamine (DA) and its metabolites were reduced when cell bodies in the VTA or axons in the NAc were lesioned. Spontaneous recovery of the behavioral deficit was observed 4 weeks after a lesion of the NAc. Subsequently presynaptic functions recovered as shown by the reappearance of low dose apomorphine (50 mg/kg)-induced hypomotility, normalization of [(3)H]dopamine uptake, reinnervation of the NAc and normalization of levels of DA and its metabolites within 24 weeks. In contrast, after a VTA lesion no recovery was observed during 48 weeks, neither from hypomotility and loss of the low dose apomorphine response nor from decreased [(3)H]dopamine uptake and levels of DA in the NAc. Short term postsynaptic supersensitivity (hypermotility upon a higher dose of apomorphine (125 mg/kg)) was present 1 and 4 weeks after the lesion but not thereafter. A near total absence of dopaminergic neurons in the VTA and axons in the NAc were found 24 weeks postlesion. Treatment with the ACTH-(4-9) analog ORG 2766 (10 mg/kg s.c., 6 days once daily) facilitated recurrence of presynaptic functions after a lesion of axons but had no short or long term effect when cell bodies were lesioned. These findings substantiate the postulate that the peptide facilitates recovery processes.

Reinnervation after destruction of the dopaminergic system in the rat nucleus accumbens : a quantitative immunohistochemical analysis

The recurrence of dopamine-immunoreactive (DAi) fibers and the effect of the adrenocorticotrophic hormone (ACTH)-(4-9) analog ORG 2766 on this process were investigated 1, 4, 12 and 24 weeks after a unilateral 6-hydroxydopamine (6-OHDA) lesion in the nucleus accumbens (NAc). DAi fibers were almost completely absent 1 week after the lesion. A gradual increase in DAi fibers throughout the NAc was observed, with subnormal values at 24 weeks. Treatment with ORG 2766 during the first week after the lesion resulted in more DAi fibers 4 weeks after the lesion as compared to placebo treatment, but not 12 and 24 weeks after the lesion. After 6-OHDA lesioning reinnervation of the NAc takes place and this process is transiently facilitated by ORG 2766.

The ACTH-(4-9) Analogue ORG 2766 Facilitates Denervation Supersensitivity After a Unilateral 6-OHDA Lesion of the Corpus Striatum in Rats

UNLABELLED Direct bilateral 6-OHDA lesioning of the nucleus accumbens causes a temporary reduction in motility, followed by a spontaneous recovery in 3-4 weeks. The ACTH-(4-9) analogue ORG 2766 shortens this period to 1 week. The functional and the peptide-induced facilitation of recovery are accompanied by enhanced motility upon administration of the dopamine agonist apomorphine which may be related to denervation supersensitivity. The present experiments were performed to investigate the interaction between ORG 2766 and denervation supersensitivity in another dopaminergic terminal area i.e. the corpus striatum. After a unilateral 6-OHDA lesion of the right corpus striatum, contralateral rotation was observed upon administration of a high dose of apomorphine 2, 3 and 4 weeks after the lesion, indicating supersensitivity of postsynaptic dopaminergic receptor systems. Contralateral rotation upon administration of this dose of apomorphine was observed in ORG 2766 treated animals, already at 1 week after the lesion. Peptide treatment resulted in an enhanced sensitivity for apomorphine, since contralateral rotation was observed in peptide but not in placebo treated, 6-OHDA lesioned animals after a low dose of apomorphine. IN CONCLUSION treatment with ORG 2766 facilitates the development of denervation supersensitivity and enhances sensitivity for apomorphine probably through an increased affinity of dopaminergic receptors for dopamine agonists.

ACTH neuropeptides and recovery after brain damage

Abstract The time course of behavioral, biochemical and histological changes that follow a 6-hydroxydopamine (6-OHDA) lesion in the nucleus accumbens of rats has been studied up to 6 months after the lesion. At all investigated levels recovery was demonstrated, albeit at different periods in time. Both compensatory and reorganizational processes were observed. The functional and morphological recovery appears to be accelerated by treatment with the ACTH-(4-9) analogue ORG 2766 during the first week after the lesion.