Biomedical subjects

Pia Weikop

Publications and source records attributed to Pia Weikop.

5 recordsLinked to original sources

PubMed2006

The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat.

Homo- and heteromeric complexes of KCNQ channel subunits are the molecular correlate of the M-current, a neuron-specific voltage-dependent K(+) current with a well established role in control of neural excitability. We investigated the effect of KCNQ channel modulators on the activity of dopaminergic neurons in vitro and in vivo in the rat ventral mesencephalon. The firing of dopaminergic neurons recorded in mesencephalic slices was robustly inhibited in a concentration-dependent manner by the KCNQ channel opener N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester (retigabine). The effect of retigabine persisted in the presence of tetrodotoxin and simultaneous blockade of GABA(A) receptors, small-conductance calcium-activated K(+) (SK) channels, and hyperpolarization-activated (I(h)) channels, and it was potently reversed by the KCNQ channel blocker 4-pyridinylmethyl-9(10H)-anthracenone (XE991), indicating a direct effect on KCNQ channels. Likewise, in vivo single unit recordings from dopaminergic neurons revealed a prominent reduction in spike activity after systemic administration of retigabine. Furthermore, retigabine inhibited dopamine synthesis and c-Fos expression in the striatum under basal conditions. Retigabine completely blocked the excitatory effect of dopamine D(2) autoreceptor antagonists. Again, the in vitro and in vivo effects of retigabine were completely reversed by preadministration of XE991. Dual immunocytochemistry revealed that KCNQ4 is the major KCNQ channel subunit expressed in all dopaminergic neurons in the mesolimbic and nigrostriatal pathways. Collectively, these observations indicate that retigabine negatively modulates dopaminergic neurotransmission, likely originating from stimulation of mesencephalic KCNQ4 channels.

Animals↗

PubMed2006

Serotonin depletion results in a decrease of the neuronal activation caused by rivastigmine in the rat hippocampus.

Interactions between the serotonergic and cholinergic systems are known to occur and are believed to play a role in the mechanism underlying both major depression and Alzheimer's disease. On a molecular level, studies suggest that acetylcholine (ACh) increases serotonin (5-HT) release through nicotinic receptors located at nerve terminals. The aim of the present study was to determine in which areas and to what extent 5-HT mediates the neuronal response to ACh release. For this purpose, neuronal activity was measured in rats with rivastigmine-induced elevated ACh levels after a 95% 5-HT depletion obtained by dosing p-chlorophenylalanine followed by D,L-fenfluramine. Neuronal activation was quantified by stereological measurements of c-Fos immunoreactivity. The brain areas examined were medial prefrontal cortex, septum, dorsal hippocampus, and dorsal raphe nucleus. Rivastigmine significantly increased c-Fos immunoreactivity in medial prefrontal cortex and the hippocampus, but not in the septum and dorsal raphe nucleus. 5-HT depletion decreased ACh-induced c-Fos immunoreactivity in the dentate gyrus. By contrast, 5-HT depletion had no effect on the ACh-induced activity in the other brain areas examined. It is concluded that 5-HT mediates part of the ACh-induced hippocampal neuronal activation, possibly mediated via locally released 5-HT.

Acetylcholine↗

PubMed2005

Central serotonin depletion affects rat brain areas differently: a qualitative and quantitative comparison between different treatment schemes.

Depletion of rat brain serotonin (5-hydroxytryptamin, 5-HT) has been widely used to study effects of serotonin and its interaction with other transmitter systems. Various treatment regimes for serotonin depletion have been applied, but the efficacy of these seems to vary considerably. So far, no studies have systematically examined and compared different approaches. The present work combines quantitative and qualitative measurements and compares six different treatment schemes for 5-HT depletion. Treatment outcome was evaluated by HPLC measurements of 5-HT and 5-HIAA concentrations, and by 5-HT and tyrosine hydroxylase immunocytochemistry. The schemes included repeated administration of fenfluramine (FEN) and/or p-chlorophenylalanine (pCPA). The most efficient treatment for rat brain 5-HT depletion was the combined treatment with one daily pCPA (200 mg/kg) injection for 3 days followed by one injection of d,l-FEN (20 mg/kg) on the fourth day, causing a 94.9% brain 5-HT depletion. Immunostaining revealed a distinct brain distribution of the remaining 5-HT, with an almost complete depletion of 5-HT in the cerebral cortex, hippocampus and thalamus, while a substantial amount of 5-HT still was left in the raphe nuclei, the medial forebrain bundle, and the medial eminence. FEN or pCPA treatment alone caused from 68.2 to 94.0% decrease in 5-HT levels. While the pattern of 5-HT depletion using pCPA alone was comparable to the one seen with the combined treatment, the 5-HT depletion using FEN alone showed a different pattern with 5-HT distributed in several brain regions.

Animals↗

PubMed2004

Application of triple-probe microdialysis for fast pharmacokinetic/pharmacodynamic evaluation of dopamimetic activity of drug candidates in the rat brain.

The technique of microdialysis utilizing three simultaneously implanted probes in the anaesthetized rat enables monitoring of pharmacokinetic (PK) profiles of a tested drug both in blood (1st probe) and brain (2nd probe) compartments and the pharmacodynamic (PD) response of neurotransmitters (3rd probe) released into, or accumulating within the brain extracellular fluid (ECF). In the present study, the PK/PD characteristics of cocaine (psychostimulant, strong abuse potential) and methylphenidate (dopamimetic drug without reinforcing properties) and two novel NeuroSearch (NS) drug candidates, NS-A and NS-B, were examined in blood and brain microdialysates from the anaesthetized rats. The extracellular levels of dopamine (DA) were monitored in the striatum or prefrontal cortex. The NS-A compound entered the brain ECF at a slightly slower rate then methylphenidate; however, both compounds showed about the same effect on the speed of accumulation of extracellular DA concentrations, which gradually increased to about 450% of the basal, predrug levels at the end of the sampling period (180 min). The NS-B compound showed more rapid PK profiles than those observed after methylphenidate and NS-A. The concentrations of NS-B reached the maximal values already 40 min after its administration, while at that time, the corresponding DA values were still unchanged. In fact, the increase in DA concentrations was about two times slower when compared to that of methylphenidate or NS-A-drugs. Faster kinetics of NS-B and its delayed effect on extracellular DA suggests that this compound is metabolized to an active intermediate product, which itself exerts stronger dopamimetic activity in the rat prefrontal cortex that the original NS-B substance. The present study illustrates the feasibility of triple-probe microdialysis to monitor the rate of extracellular accumulation of a drug candidate and DA levels in vivo and compare the resulting PK/PD profiles to those obtained for cocaine and methylphenidate. These measures may serve as initial neurochemical indicators of potential psychomimetic or reinforcing properties of the tested substances.

Animals↗

PubMed2004

Hypericum perforatum L (St John's wort) preferentially increases extracellular dopamine levels in the rat prefrontal cortex.

The effects of hydro-alcoholic extracts of Hypericum perforatum L on extracellular serotonin (5-HT), noradrenaline (NA) and dopamine (DA) levels and the acidic metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-3-indoleacetic acid (5-HIAA)) were examined by in vivo microdialysis in the prefrontal cortex of awake rats. Thus, a single dose (60 mg kg(-1) i.p. or 300 mg kg(-1) p.o.) of H. perforatum increased DA concentrations to 165 and 140% of control values, respectively, and increased locomotor activity in nonhabituated rats. DOPAC and HVA levels were markedly reduced. 5-HT concentrations were elevated only moderately, while the NA levels were not affected by any treatment. The whole-tissue analysis revealed that hypericum increased, whereas the monoamine oxidase (MAO) A/B inhibitor phenelzine decreased DA and 5-HT turnover. The present data indicate that the mechanism of action of hypericum extract in vivo is more complex than the inhibition of monoamine reuptake or metabolism observed in vitro. The finding of preferential enhancement of DA transmission is in agreement with human studies measuring DA-mediated neuroendocrine responses.

Animals↗