[The new Parkinson's disease pain classification system (PD-PCS)]. / Die neue Parkinson-Schmerzklassifikation (PSK).

BACKGROUND: Chronic pain is a common non-motor symptom in patients with Parkinson's disease (PD). AIM: To facilitate the diagnosis of pain in PD, we developed a new classification system the Parkinson's disease pain classification system (PD-PCS) and translated the corresponding validated questionnaire into German. METHODS: A causal relationship of the respective pain syndrome with PD can be determined by four questions before assigning it hierarchically into one of three pain categories (neuropathic, nociceptive and nociplastic). RESULTS: In the initial validation study 77% of the patients (122/159) had PD-associated pain comprising 87 (55%) with nociceptive, 36 (22%) with nociplastic and 24 (16%) with neuropathic pain. The study revealed a high validity of the questionnaire and a moderate intrarater and interrater reliability. The questionnaire has been adapted into German and employed in 30 patients. DISCUSSION: The PD-PCS questionnaire is a valid and reliable tool to determine the relationship of a pain syndrome with PD before classifying it according to the underlying category, facilitating further diagnostics and treatment.

Impaired eye blink classical conditioning distinguishes dystonic patients with and without tremor.

INTRODUCTION: Tremor is frequently associated with dystonia, but its pathophysiology is still unclear. Dysfunctions of cerebellar circuits are known to play a role in the pathophysiology of action-induced tremors, and cerebellar impairment has frequently been associated to dystonia. However, a link between dystonic tremor and cerebellar abnormalities has not been demonstrated so far. METHODS: Twenty-five patients with idiopathic isolated cervical dystonia, with and without tremor, were enrolled. We studied the excitability of inhibitory circuits in the brainstem by measuring the R2 blink reflex recovery cycle (BRC) and implicit learning mediated by the cerebellum by means of eyeblink classical conditioning (EBCC). Results were compared with those obtained in a group of age-matched healthy subjects (HS). RESULTS: Statistical analysis did not disclose any significant clinical differences among dystonic patients with and without tremor. Patients with dystonia (regardless of the presence of tremor) showed decreased inhibition of R2 blink reflex by conditioning pulses compared with HS. Patients with dystonic tremor showed a decreased number of conditioned responses in the EBCC paradigm compared to HS and dystonic patients without tremor. CONCLUSION: The present data show that cerebellar impairment segregates with the presence of tremor in patients with dystonia, suggesting that the cerebellum might have a role in the occurrence of dystonic tremor.

Neuroanatomical correlates of tube dependency and impaired oral intake after hemispheric stroke.

BACKGROUND AND PURPOSE: Acute stroke patients with severely impaired oral intake are at risk of malnutrition and dehydration. Rapid identification of these patients is necessary to establish early enteral tube feeding. Whether specific lesion location predicts early tube dependency was analysed, and the neural correlates of impaired oral intake after hemispheric ischaemic stroke were assessed. METHODS: Tube dependency and functional oral intake were evaluated with a standardized comprehensive swallowing assessment within the first 48 h after magnetic resonance imaging proven first-time acute supratentorial ischaemic stroke. Voxel-based lesion symptom mapping (VLSM) was performed to compare lesion location between tube-dependent patients versus patients without tube feeding and impaired versus unimpaired oral intake. RESULTS: Out of 119 included patients 43 (36%) had impaired oral intake and 12 (10%) were tube dependent. Both tube dependency and impaired oral intake were significantly associated with a higher National Institutes of Health Stroke Scale score and larger infarct volume and these patients had worse clinical outcome at discharge. Clinical characteristics did not differ between left and right hemispheric strokes. In the VLSM analysis, mildly impaired oral intake correlated with lesions of the Rolandic operculum, the insular cortex, the superior corona radiata and to a lesser extent of the putamen, the external capsule and the superior longitudinal fascicle. Tube dependency was significantly associated with affection of the anterior insular cortex. CONCLUSIONS: Mild impairment of oral intake correlates with damage to a widespread operculo-insular swallowing network. However, specific lesions of the anterior insula lead to severe impairment and tube dependency and clinicians might consider early enteral tube feeding in these patients.

The role of cerebellum in patients with late onset cervical/segmental dystonia?--evidence from the clinic.

BACKGROUND: There is evidence from animal studies, post-mortem pathology, functional imaging and neurophysiological studies to suggest that the cerebellum may be involved in the pathophysiology of dystonia. We sought to explore further the association of clinical and radiological abnormalities of the cerebellum in patients with dystonia. METHODS: We retrospectively reviewed patients from our movement disorders research database, with predominant cervical dystonia who have been seen within last 6 months and had available routine magnetic resonance imaging (MRI). The clinical details including presence of cerebellar signs, imaging findings and results of investigations were recorded on a proforma. The results were analysed using percentages and means with standard deviation. RESULTS: Out of 188 patients included 26 had evidence of cerebellar abnormality on neuroimaging. 17 patients showed cerebellar atrophy and 10 of these had cerebellar signs on examination. These patients were tested negative for common inherited ataxias. 9 patients had cerebellar lesions on MRI, reported as low grade tumour (n = 2), cerebellar infarct (n = 3), cyst (n = 2), white matter hyperintensity (n = 1) and ectopia (n = 1) out of these 4 had cerebellar signs. CONCLUSION: The findings from our study suggest that there may be overt clinical or radiological cerebellar involvement in 14% of cases with cervical/segmental dystonia. However, larger prospective studies are needed in this context.

[Predictors of mental and physical quality of life in Huntington's disease]. / Prädiktoren der psychischen und physischen Lebensqualität beim Morbus Huntington.

BACKGROUND: The assessment of health-related quality of life (hrQoL) is an important tool in therapy studies and in the treatment of patients with Huntington's disease (HD). In the absence of causal interventions, HD therapy targets the alleviation of symptoms aiming to improve impaired hrQoL. The aim of this study was to determine the impact of disease characteristics on hrQoL in HD. METHODS: A total of 80 genetically confirmed HD patients underwent an assessment using the Unified Huntington's Disease Rating Scale, the Beck Depression Inventory, the Hamilton Rating Scale and the SF-36, a scale for the assessment of physical and mental QoL. RESULTS: Multiple regression analysis revealed that health-related physical and mental QoL was considerably influenced by the functional capacity. The mental QoL also correlated with the degree of depressive symptoms, age and the number of CAG repeats. However, there was no statistical relation between QoL and motor and cognitive abilities. DISCUSSION: This study underlines the relationship between function capacity and depressive symptoms with mental and physical QoL. This is the first time that hrQoL has been investigated in a German speaking cohort. The results are in accordance with previous studies of hrQoL in HD.

Policy principles and implementation guidelines for private sector participation in the water sector--a step towards better results.

To achieve the Millennium Development Goals, all partners (public, private, NGOs) must be engaged for improving and expanding the water supply and sanitation services. Yet, high transaction costs, unclear role allocation and lack of trust and commitment put Private Sector Participation (PSP) at risk. The initiative "Policy Principles and Implementation Guidelines for Private Sector Participation in Sustainable Water Supply and Sanitation" contributes to equitable, effective, ecological and efficient PSP projects. Based on a multi stakeholder process, the Policy Principles are offering an open and transparent framework for the negotiation of valid, widely accepted and action-oriented solutions, while the Implementation Guidelines focus on success factors for building partnerships on the operational level.

NKP608: a selective NK-1 receptor antagonist with anxiolytic-like effects in the social interaction and social exploration test in rats.

NKP608 is a non-peptidic derivative of 4-aminopiperidine which acts as a selective, specific and potent antagonist at the neurokinin-1 (NK-1) receptor both in vitro and in vivo. In vitro, the binding of NKP608 to bovine retina was characterized by an IC50 of 2.6+/-0.4 nM, whereas the compound's affinity to other receptor binding sites, including NK-2 and NK-3, was much lower. Species differences in IC(50) values with NKP608 were less pronounced than with previously described NK-1 receptor antagonists, being 13+/-2 and 27+/-2 nM in gerbil midbrain and rat striatum, respectively. In vivo, using the hind foot thumping model in gerbils, NKP608 exhibited a potent NK-1 antagonistic activity following oral administration (ID(50)=0.23 mg/kg; 2 h pretreatment), supporting a central activity of NKP608. The compound had a long duration of action with an ID(50) value of 0. 15 mg/kg p.o. and 0.38 mg/kg p.o. following a pretreatment of 5 and 24 h, respectively. Following a subchronic administration for 7 consecutive days (once daily) there was no evidence for the development of tolerance or accumulation. In the social interaction test performed in a highly illuminated, unfamiliar test arena, NKP608 specifically increased the time the two rats spent in social contact, and there was no concomitant increase in parameters reflecting general activity, i.e. ambulation (number of square entries) or the number of rearings. Active social time was maximally increased at a dose range of 0.01-1 mg/kg p.o. NKP608, the effect being weaker or absent at both lower (0.001 mg/kg p.o.) and higher (10 mg/kg p.o.) doses. A comparable bell-shaped dose-response relation was seen in the social exploration test in rats. In this modified resident/intruder paradigm, maximal increase in social contact of the intruder rat directed towards the resident rat was seen at a similar dose range (0.03-3 mg/kg p.o.) The effects observed following an acute oral administration of NKP608 were comparable to those seen following a treatment with the well-known benzodiazepine, chlordiazepoxide, in both these tests. These findings indicate that NKP608 exhibits an anxiolytic-like effect and that this effect, as concluded from the observed antagonism of the hind foot thumping induced by i.c.v. administration of the NK-1 receptor agonist SPOMe, is centrally mediated. This makes this compound a potentially promising candidate for treating anxiety-related disorders in humans.

Guanosine 3',5'-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-amyloid: protective effects of propentofylline.

Apoptotic cell death has been implicated in Alzheimer's disease pathology and amyloid peptide induced neurotoxicity. We investigated the survival promoting effects of Propentofylline in two models of apoptotic cell death, nerve growth factor withdrawal and beta-amyloid mediated cell death in nerve growth factor differentiated rat pheochromocytoma cell lines. The increase in cell death as measured by lactate dehydrogenase release in response to nerve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso-N-acetylpenicillamine (12.5 to 200 microM) and by 8-bromoguanosine-3',5'-cyclic monophosphate (1.25 to 10mM). Both agents decreased cell death mediated by 25 microM beta-amyloid, suggesting that the protective mechanism involves guanosine -3', 5'-cyclic monophosphate. In support of this hypothesis we can show that S-nitroso-N-acetylpenicillamine increases intracellular levels of guanosine -3',5'-cyclic monophosphate in pheochromocytoma cell lines 3 to 8 fold.Propentofylline, a phosphodiesterase inhibitor, has previously demonstrated neuroprotective activity in stroke models and is a potential candidate for therapeutic treatment in neurodegenerative diseases. The present findings support this claim by providing evidence that Propentofylline has protective effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and caspase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guanosine-3',5'-cyclic monophosphate levels over the same dose range that provided protection. We hypothesized that guanosine-3',5'-cyclic monophosphate is a key mediator of neuroprotection under these conditions.

Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F x DP, in B-amyloid-induced neuronal death.

Previous evidence by others has indicated that a variety of cell cycle-related molecules are up-regulated in brains of Alzheimer's disease patients. The significance of this increase, however, is unclear. Accordingly, we examined the obligate nature of cyclin-dependent kinases and select downstream targets of these kinases in death of neurons evoked by B-amyloid (AB) protein. We present pharmacological and molecular biological evidence that cyclin-dependent kinases, in particular Cdk4/6, are required for such neuronal death. In addition, we demonstrate that the substrate of Cdk4/6, pRb/p107, is phosphorylated during AB treatment and that one target of pRb/p107, the E2F x DP complex, is required for AB-evoked neuronal death. These results provide evidence that cell cycle elements play a required role in death of neurons evoked by AB and suggest that these elements play an integral role in Alzheimer's disease-related neuronal death.

Amyloid beta-peptides inhibit Na+/K+-ATPase: tissue slices versus primary cultures.

Abeta1-40 (20 microM) has been reported to selectively inhibit Na+/K+-ATPase activity in rat primary hippocampal cultures after 2-6 days of exposure. We expanded these studies to include Abeta's effects on Na+/K+-ATPase activity in rat primary cortical cultures and hippocampal slices, and we correlated these effects with estimates of cell survival in rat brain primary cultures. Using optimized assay conditions, a 5-day exposure to 50 microM Abeta 25-35, 20 microM Abeta 1-40, and 20 microM Abeta 1-42 decreased Na+/K+-ATPase activity in rat primary cortical cultures 66%, 60%, and 22%, respectively. Abeta 25-35 (50 microM) at 24 h was the only condition that caused inhibition of Na+/K+-ATPase activity in the absence of cell death, defined as an extracellular shift in the localization of the cytoplasmic enzyme lactate dehydrogenase (LDH). We also found that hippocampal slices were sensitive to Abeta, exhibiting a 40-60% reduction in membrane Na+/K+-ATPase activity when exposed to 1-30 nM of Abeta 1-40 for 60 min. This inhibition was not readily reversible, as it withstood homogenization and repeated dilution and centrifugation. Additionally, this inhibition occurred only after amyloid incubation with intact hippocampal slices, not with disrupted membranes. The inhibition of Na+/K+-ATPase in brain slices by physiological, low nM concentrations of Abeta 1-40 is consistent with effects on neurotransmitter release and intrasynaptosomal calcium responses.

Depression of A and C fibre-evoked segmental reflexes by morphine and clonidine in the in vitro spinal cord of the neonatal rat.

1. Population synaptic responses of motoneurones were recorded from a ventral root following electrical stimulation of the corresponding lumbar dorsal root in neonatal rat hemisected spinal cord preparations in vitro. Two levels of electrical stimulation were used to elicit dorsal root compound action potentials that contained either an A fibre component alone or both A and C fibre components. The effects of centrally acting analgesics and an N-methyl-D-aspartate (NMDA) receptor antagonist were tested on synaptic responses produced by these two levels of stimulation. 2. At stimulus intensities below four times threshold (T) there was no C fibre component in the dorsal root compound action potential. Responses to a single pulse at 3T (the low intensity excitatory postsynaptic potential (e.p.s.p.)), a train of five pulses at 2T (the train e.p.s.p.) and a single supramaximal pulse (the high intensity e.p.s.p.) were used to compare the depressant actions of morphine, clonidine and the competitive NMDA antagonist CGP40116 (D-(E)-2- amino-4-methyl-5-phosphono-pentenoic acid). The train e.p.s.p. (mean half-time to decay 5 +/- 0.6 s, n = 6) had a similar profile to the high intensity e.p.s.p. (mean half-time to decay 6.8 +/- 0.7, n = 8). 3. The monosynaptic compound action potential of motoneurones (MSR) was resistant to all three drugs irrespective of the intensity of dorsal root stimulation. The low intensity e.p.s.p., the train e.p.s.p. and the high intensity e.p.s.p. were depressed by all three drugs. The EC50 values for depression by morphine were 79 +/- 1 nM (n = 8) for the high intensity e.p.s.p. and 99 +/- 1 nM (n = 4) for the low intensity e.p.s.p. The corresponding values for clonidine were 25 +/- 1 nM (n = 8) and 9 +/- 1 nM (n = 4) and those for CGP40116 were 860 +/- 1.3 nM (n = 4) and 76 +/- 1.1 nM (n = 4). 4. The depressant profile of the NMDA antagonist, having the least depressant activity on the C fibre-mediated response, was different from that of the two analgesics. CGP40116 (3 microM) depressed the high intensity e.p.s.p. to 62 +/- 8%, the low intensity e.p.s.p. to 22 +/- 4% and the train e.p.s.p. to 16 +/- 2% of control values. 5. The depressant actions of morphine were fully reversed by naloxone (1 microM) and those of clonidine were fully reversed by atipamezole (1 microM). 6. These results show that, in contrast to previous findings, activation of primary afferent C fibres in dorsal roots is not required for generation of morphine- or clonidine-sensitive synaptic responses in ventral roots of this in vitro preparation.

The effects of neurokinin-1 receptor agonists on spinal motoneurones of the neonatal rat.

The effects of substance P (SP) and the selective NK1 receptor agonist [Sar9Met(O2)11] substance P on neonate rat spinal motoneurones were examined using intracellular recordings. Bath-administration of SP (0.1-3 microM) or [Sar9Met(O2)11] substance P (0.01-3 microM) induced a tetrodotoxin (TTX)-insensitive (10 microM) depolarization and a tetraethylammoniumchloride (TEA)-sensitive (3 mM) decrease in membrane conductance. The duration of the slow afterhyperpolarizations (AHPs) following the action potentials were significantly reduced (p = 0.003) by both NK1 receptor agonists. The mean duration of the sAHPs (+/- SEM) in control was 67.8 +/- 6.3 ms whereas in the presence of SP and [Sar9Met(O2)11] substance P their duration was reduced to 41.7 +/- 4.6 ms. Low Ca2+ (0.2 mM)-containing artificial cerebrospinal fluid (ACSF) or addition of BaCl2 or CdCl2 (2 mM) reduced the durations of the slow AHPs by 55%. In the presence of these agents SP and [Sar9Met(O2)11] substance P practically abolished the remaining slow AHPs, suggesting that the agonists also reduce a calcium-independent current. None of the effects induced by the NK1 receptor agonists were antagonized by the NK1 receptor antagonists (+/-)-CP-96,345 (10 microM), RP 67580 (1 microM) or GR 82334 (3-5 microM). In conclusion this study demonstrates that SP and [Sar9Met(O2)11] substance P elicit their effects on NK1 receptors by modulating at least two potassium currents, namely IK and ICa(K).

Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.

The antispastic agent and muscle relaxant baclofen 1 is a potent and selective agonist for bicuculline-insensitive GABAB receptors. For many years efforts to obtain superior GABAB agonists were unsuccessful. We describe the syntheses and biological properties of two new series of GABAB agonists, the best compounds of which are more potent than baclofen in vitro and in vivo. They were obtained by replacing the carboxylic acid group of GABA or baclofen derivatives with either the phosphinic acid or the methylphosphinic acid residue. Surprisingly, ethyl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABAB antagonists, which are described in part 2 of this series. Structure-activity relationships of the novel GABAB agonists are discussed with respect to their affinities to GABAB receptors as well as to their effects in many functional tests in vitro and in vivo providing new muscle relaxant drugs with significantly improved side effect profiles.

Physiological and pharmacological characterization of the spinal tachykinin NK2 receptor.

The goal of these investigations was to study the role of tachykinin NK2 receptors in neonatal spinal cords using the selective NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10) and the new NK2 receptor antagonist GR 94800. Experiments were performed with superfused hemisected rat and gerbil spinal cords. Dorsal roots were electrically stimulated and the synaptically elicited responses and the DC-potentials were recorded extracellularly from the corresponding ventral roots. [beta-Ala8]neurokinin A-(4-10) depolarized ventral roots (0.01-10 microM) and increased their spontaneous activity in a concentration-dependent manner. These effects of [beta-Ala8]neurokinin A-(4-10) were reduced by GR 94800. The action of GR 94800 was selective because the depolarizing effects of similar magnitude evoked by the NK1 receptor agonist [Sar9,Met(O2)11]substance P were not affected by GR 94800. The pA2 values of GR 94800 amounted to 6.0 +/- 0.4 in the rat and 5.4 +/- 0.3 in the gerbil. The NK2 receptor agonist was more potent in the rat than in the gerbil. The estimated EC50 (mean +/- S.E.M.) was found to be 3.9 + 6.0/-1.3 microM in the rat and 2.4 + 2.9/-1.3 microM in the gerbil spinal cord. The NK2 receptor agonist [beta-Ala8]neurokinin A-(4-10) potentiated the monosynaptic reflex evoked by dorsal root stimulation. The potentiation manifested itself as an increase in the amplitude of the early component of the response. The receptor type mediating this effect could not be elucidated. The potentiation ranged between 30 +/- 27 and 110 +/- 36% (0.3 and 10 microM), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action.

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and > 6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 x 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 x 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 x 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of baclofen-induced depression of whole-cell synaptic currents in spinal dorsal horn neurones by the potent GABAB antagonist CGP55845.

The potencies of two GABAB receptor antagonists P-[3-aminopropyl]- P-diethoxymethyl-phosphinic acid (CGP35348) and the novel compound 3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P- benzyl-phosphinic acid (CGP55845) have been compared in an in vitro spinal cord preparation. They have been tested as antagonists of baclofen-induced depression of EPSCs of patch-clamped dorsal horn neurons following electrical stimulation of dorsal roots. Mean EC50 values for the depressant action of baclofen were increased by 50- and 140-fold respectively in the presence of CGP35348 (200 microM) (n = 5) and CGP55845 (100 nM) (n = 4). This potency of CGP55845 is > 1000-fold higher than that reported previously for other GABAB receptor antagonists.

The modulation of the monosynaptic reflex by substance P in the hemisected spinal cord preparation of the rat and gerbil.

The effects of substance P and the selective neurokinin-1 receptor antagonist (+/-)-CP-96,345 have been compared on in vitro spinal cord preparations from the rat and the gerbil. Substance P produced a concentration-dependent depolarization of motoneurons recorded from ventral roots of both species. The EC50 values (microM mean +/- S.E.M.) obtained in rat (0.95 + 1.0/-0.49) and gerbil (0.47 + 0.26/-0.17) preparations were comparable. The mean maximal depolarization (mV mean +/- S.E.M.) evoked in rat (2.07 + 0.26/-0.25) was approximately two-fold greater than that evoked in gerbil (1.21 + 0.15/-0.14) preparations. In the rat substance P had a biphasic effect (depression followed by potentiation) on the short latency probably monosynaptic reflex evoked by electrical stimulation of a dorsal root. In gerbil preparations substance P produced only potentiation of the monosynaptic reflex. The EC50 values (microM) mean +/- S.E.M.) for this potentiating action in rat (0.97 + 0.75/-0.43) and gerbil (0.46 + 3.6/-0.4) preparations were similar. This potentiation demonstrates a positive modulation of an endogenous excitatory probably glutamatergic transmission by substance P in the ventral horn of the spinal cord. The depressant phase observed in rat preparations may be related to the relative immaturity of myelination in rat ventral root fibres compared to the gerbil. The selective neurokinin-1 antagonist (+/-)-CP-96,345 was one hundred-fold less potent as an antagonist of substance P-induced depolarizations in the rat (pA2 4.69 +/- 0.18, n = 7) than in the gerbil (pA2 6.79 +/- 0.16, n = 5) spinal cord. This finding suggests that (+/-)-CP-96,345 may not act solely at the neurokinin-1 recognition site. In conclusion this study demonstrates that substance P modulates the monosynaptic reflex in the spinal cord presumably via activation of neurokinin-1 receptors.

The action of new potent GABAB receptor antagonists in the hemisected spinal cord preparation of the rat.

CGP 52432 (3-N-(3,4-dichlorobenzyl)aminopropyl-P-diethoxymethylphosphinic acid), CGP 54062 (3-N[1-(R,S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P-benzy l- phosphinic acid), CGP 54626 (3-N[[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)- hydroxypropyl-P-cyclohexylmethylphosphinic acid) and CGP 55845 (3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)- hydroxypropyl-P-benzyl-phosphinic acid) are novel selective GABAB receptor antagonist. The apparent Kd values for the complex formed between the GABAB receptor and these compounds were determined using the monosynaptic reflex in the hemisected rat spinal cord preparation in vitro. CGP 55845 was found to be the most potent GABAB receptor antagonist tested (apparent Kd = 30 nM). On the same preparation 0.3 microM CGP 55845 was equipotent with 100 microM of CGP 35348 (P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid) for reversal of the depressant action of (R)-(-)-baclofen.

The actions of orally active GABAB receptor antagonists on GABAergic transmission in vivo and in vitro.

The goal of this report is to present the results obtained with three new GABAB receptor antagonists. CGP 54062 has an IC50 in a GABAB binding test of 0.013 microM which is roughly 2500-fold lower than one of the most potent blockers known so far, CGP 35348 (IC50 = 34 microM). CGP 46381 and CGP 36742 have IC50s of 4.9 and 36 microM respectively. The latter two compounds are the first orally active GABAB receptor antagonists. All three compounds bind to the GABAB receptor selectively, and are inactive in a number of binding tests assessing the compounds' affinity to various other receptor sites. The effect of these blockers on GABAergic transmission was investigated in the CA1 area of hippocampal slices. The Schaffer collateral/commissural fibers were stimulated and the evoked postsynaptic potentials were recorded intracellularly in pyramidal neurons. The three antagonists blocked the late inhibitory postsynaptic potential with the following rank order of potency CGP 54062 > 46381 > 36742 approximately 35348. These findings support the hypothesis that these potentials are mediated by GABAB receptors. Orally administered CGP 36742 and CGP 46381 block the neuronal depression induced by iontophoretically applied baclofen in anaesthetised rats. Up to a dose of 10 mg/kg i.v. CGP 54062 was inactive and thus does not appear to cross the blood-brain barrier at this dose. In anaesthetised rats the effects of the three new GABAB antagonists and of CGP 35348 were investigated on the paired-pulse inhibition of the population spikes evoked in the CA1 area of the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)