Assessment of dopamine (DA) synthesis rate in selected parts of the rat brain with central noradrenergic lesion after administration of 5-HT3 receptor ligands.

INTRODUCTION: The study objective was to determine the effect of central noradrenergic system lesions performed in the early extrafetal life period on dopamine synthesis in the rat brain. The content of L-dihydroxyphenylalanine (L-DOPA) was assessed in the frontal lobe, thalamus, hypothalamus and brain stem of rats by high-pressure chromatography with electrochemical detection (HPLC/ED) after administration of 5-HT3 receptor ligands. MATERIAL AND METHODS: Adult male Wistar rats which underwent central noradrenergic lesions by DSP-4 administration (50 mg/kg m.c. i.p.) on day 1 and 3 of life received i.p. injections of the aromatic amino acid decarboxylase inhibitor (NSD-1050) in a dose of 100 mg/kg b.w. Next, 30 min after NSD-1050 injection, the animals were decapitated by guillotine. Selected brain structures were dissected and L-DOPA content was determined by HPLC/ED. RESULTS AND CONCLUSIONS: A statistically significant reduction was found in DA synthesis in the group of animals with DSP-4 lesions induced by PBG (1-phenylbiguanide, 7.5 mg/kg b.w. i.p.) and ondansetron (1.0 mg/kg b.w. i.p.). Morphine and PBG had no major effect on DA synthesis in the cerebral cortex of both control animals and in rats with noradrenergic lesions. The assessment of the effect of DSP-4 lesions on L-DOPA content in the brain stem after administration of morphine (7.5 mg/kg b.w. s.c.), PBG (7.5 mg/kg b.w. i.p.) or ondansetron (1.0 mg/kg b.w. i.p.) separately or jointly showed a statistically significant increase in the synthesis of DA in animals with DSP-4 lesions, as compared to the control group exposed to 0.9% NaCl and morphine. The analysis of the effect of DSP-4 lesions on L-DOPA content in the thalamus and hypothalamus revealed no statistically significant differences between the control groups of rats and those with DSP-4 lesions. As shown by this model, permanent noradrenergic lesions in animals in the early extra-fetal period result in increased reactivity of the central dopamine system.

Post-tetanic increase in the fast-releasing synaptic vesicle pool at the expense of the slowly releasing pool.

Post-tetanic potentiation (PTP) at the calyx of Held synapse is caused by increases not only in release probability (P(r)) but also in the readily releasable pool size estimated from a cumulative plot of excitatory post-synaptic current amplitudes (RRP(cum)), which contribute to the augmentation phase and the late phase of PTP, respectively. The vesicle pool dynamics underlying the latter has not been investigated, because PTP is abolished by presynaptic whole-cell patch clamp. We found that supplement of recombinant calmodulin to the presynaptic pipette solution rescued the increase in the RRP(cum) after high-frequency stimulation (100 Hz for 4-s duration, HFS), but not the increase in P(r). Release-competent synaptic vesicles (SVs) are heterogeneous in their releasing kinetics. To investigate post-tetanic changes of fast and slowly releasing SV pool (FRP and SRP) sizes, we estimated quantal release rates before and 40 s after HFS using the deconvolution method. After HFS, the FRP size increased by 19.1% and the SRP size decreased by 25.4%, whereas the sum of FRP and SRP sizes did not increase. Similar changes in the RRP were induced by a single long depolarizing pulse (100 ms). The post-tetanic complementary changes of FRP and SRP sizes were abolished by inhibitors of myosin II or myosin light chain kinase. The post-tetanic increase in the FRP size coupled to a decrease in the SRP size provides the first line of evidence for the idea that a slowly releasing SV can be converted to a fast releasing one.

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake.

For humans and animal models alike there is general agreement that the central nervous system processing of gastrointestinal (GI) signals arising from ingested food provides the principal determinant of the size of meals and their frequency. Despite this, relatively few studies are aimed at delineating the brain circuits, neurochemical pathways and intracellular signals that mediate GI-stimulation-induced intake inhibition. Two additional motivations to pursue these circuits and signals have recently arisen. First, the success of gastric-bypass surgery in obesity treatment is highlighting roles for GI signals such as glucagon-like peptide-1 (GLP-1) in intake and energy balance control. Second, accumulating data suggest that the intake-reducing effects of leptin may be mediated through an amplification of the intake-inhibitory effects of GI signals. Experiments reviewed show that: (1) the intake-suppressive effects of a peripherally administered GLP-1 receptor agonist is mediated by caudal brainstem neurons and that forebrain-hypothalamic neural processing is not necessary for this effect; (2) a population of medial nucleus tractus solitarius (NTS) neurons that are responsive to gastric distention is also driven by leptin; (3) caudal brainstem-targeted leptin amplifies the food-intake-inhibitory effects of gastric distention and intestinal nutrient stimulation; (4) adenosine monophosphate-activated protein kinase (AMPK) activity in NTS-enriched brain lysates is elevated by food deprivation and reduced by refeeding and (5) the intake-suppressive effect of hindbrain-directed leptin is reversed by elevating hindbrain AMPK activity. Overall, data support the view that the NTS and circuits within the hindbrain mediate the intake inhibition of GI signals, and that the effects of leptin on food intake result from the amplification of GI signal processing.

Objective assessment of neurotoxicity while shifting from carbamazepine to oxcarbazepine.

OBJECTIVES: Objective assessment of non-overt neurotoxicity of carbamazepine (CBZ) vs oxcarbazepine (OXC) in patients with difficult-to-treat partial epilepsy, who were resistant to CBZ treatment and were converted from CBZ monotherapy to OXC monotherapy. MATERIAL AND METHODS: Therapeutically equivalent doses (150 mg OXC for every 100 mg CBZ) were compared in 20 adult patients. Neurological investigation, conventional and spectral EEG analysis, brainstem auditory evoked responses (BAER) were carried out in both treatment conditions. EEG and BAER data of 20 age-matched healthy controls helped interpretation. Primary target variables (electrophysiological parameters) were evaluated blindly. RESULTS: There were no significant differences between treatment conditions concerning the neurological condition, lack of clinically evident neurotoxicity, seizure frequency and EEG spike frequency. OXC treatment was characterized by less delta, theta, and alpha power, more beta power, and significantly greater mean alpha frequency (P = 0.03 and 0.05 for the left and right occipital leads, respectively), than CBZ treatment. Interpeak latencies were prolonged in the CBZ condition as compared with normals (P = 0.01) and OXC (P = 0.02). CONCLUSION: In this cohort of patients substitution of OXC for CBZ was associated with significant normalization of electrophysiological parameters, indicating decreasing neurotoxicity while shifting from CBZ to OXC monotherapy.

Neuropathological assessment of artemether-treated severe malaria.

In animals, high doses of intramuscular artemether and artemotil have been shown to cause an unusual pattern of selective damage to certain brainstem nuclei, especially those implicated in hearing and balance. We aimed to investigate whether a similar pattern arises in human adults. We examined the brainstems of adults who died after treatment with high dose artemether or quinine for severe falciparum malaria for evidence of a pattern of selective neuronal damage. Neuropathological findings were similar in recipients of quinine (n=15) and artemether (n=6; total artemether doses received 4-44 mg/kg). No evidence was recorded for artemether-induced neurotoxic effects.

Assessment of the neurotoxicity of parenteral artemisinin derivatives in mice.

In all experimental mammals tested (rats, dogs, primates), intramuscular injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stem centers predominantly involved in auditory processing and vestibular reflexes. Artesunate, the most widely used of these compounds, is a water soluble hemisuccinate derivative given parenterally either by intravenous or intramuscular injection. The neurotoxic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-day regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detected with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. These were reversible in all but one (artemether) mouse. At 100 mg/kg/day, eight of 36 artemether recipients, two of 36 artesunate recipients, and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnormalities of balance and equilibrium, whereas only four artesunate recipients (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence interval) for death or disability was 5.3 (2.6-11.2) for artemether recipients. Intramuscular artemether is significantly more neurotoxic than intramuscular artesunate in this murine model.

Ototoxicity assessment of a gentamicin sulfate otic preparation in dogs.

Vestibulotoxic and ototoxic effects often are seen after long-term, high-dose systemic treatment with gentamicin, but toxic effects after topical use have not been reported in animals, to the authors' knowledge. Vestibular and auditory effects of twice daily otic gentamicin treatment for 21 days were evaluated in 10 dogs with intact tympanic membranes and in the same 10 dogs after experimental bilateral myringotomy. Each dog served as its own control; 7 drops of gentamicin sulfate (3 mg/ml in a buffered aqueous vehicle) were placed in 1 ear, and 7 drops of vehicle were placed in the opposite ear. Treatment and control ears were reversed after myringotomy. Vestibular function was evaluated daily by neurologic examination and behavioral assessment. Auditory function was evaluated twice weekly by determination of brain stem auditory evoked potentials. Gentamicin sulfate placed in the ear of clinically normal dogs with intact or ruptured tympanic membranes, in the quantities used in this study, did not induce detectable alteration of cochlear or vestibular function. Serum gentamicin concentration after 21 days of treatment was detectable in only 2 dogs and was an order of magnitude below documented toxic concentrations.

[Autoradiography of protein synthesis as a method of assessment of morphofunctional changes in brain structures]. / Avtoradiografiia sinteza belka kak metod otsenki morfofuntsional'nykh izmenenii v strukturakh mozga.

A combination of two groups of autoradiography technique (for a hole brain and individual cells) was applied with using 3H-leucine to evaluate the changes of brain functional activity on the level as anatomical structures and as different type neurons. It was found that Wistar rats with lowered motor activity induced by 3-4 weeks treatment with L-DOPA 100 mg/kg displayed the motor nuclei of the brain stem the cerebellum as highly labelled structures and the motor cortex and n. caudatus as feebly ones in comparison with control. However, a quantitative assessment of silver grains over the neurons of layers III and V of motor cortex and n. caudatus showed not only a significant increase of labelling, especially in neurons of layer V on 174%, in comparison with control but revealed unequal labelling of different type neurons. It was concluded that the applied two groups of autoradiography technique can be a useful approach to assess the brain functional activity.

Electrophysiologic assessment of low-frequency hearing: sedation effects.

Sixteen normal-hearing adults were tested in both awake and sedated states for several evoked responses to low-frequency stimuli. Responses obtained by cross-correlation function, middle latency responses, and the 40-Hz response proved most sensitive; all had mean thresholds of less than 20 dB normal hearing level for the awake-alert state, but 40-Hz and middle latency response mean thresholds were shifted about 10 dB under sedation. The cross-correlation method seems to offer promise for pediatric auditory assessment.