Preoperative word-finding difficulties in children with posterior fossa tumours: a European cross-sectional study.

PURPOSE: Posterior fossa tumour surgery in children entails a high risk for severe speech and language impairments, but few studies have investigated the effect of the tumour on language prior to surgery. The current crosslinguistic study addresses this gap. We investigated the prevalence of preoperative word-finding difficulties, examined associations with medical and demographic characteristics, and analysed lexical errors. METHODS: We included 148 children aged 5-17 years with a posterior fossa tumour. Word-finding ability was assessed by means of a picture-naming test, Wordrace, and difficulties in accuracy and speed were identified by cut-off values. A norm-based subanalysis evaluated performance in a Swedish subsample. We compared the demographic and medical characteristics of children with slow, inaccurate, or combined slow and inaccurate word finding to the characteristics of children without word-finding difficulties and conducted a lexical error analysis. RESULTS: Thirty-seven percent (n = 55) presented with slow word finding, 24% (n = 35) with inaccurate word finding, and 16% (n = 23) with both slow and inaccurate word finding. Children with posterior fossa tumours were twice as slow as children in the norming sample. Right-hemisphere and brainstem location posed a higher risk for preoperative word-finding difficulties, relative to left-hemisphere location, and difficulties were more prevalent in boys than in girls. The most frequent errors were lack of response and semantically related sideordinated words. CONCLUSION: Word-finding difficulties are frequent in children with posterior fossa tumours, especially in boys and in children with right-hemisphere and brainstem tumours. Errors resemble those observed in typical development and children with word-finding difficulties.

Nitric oxide is involved in nicotine-induced burst firing of rat ventral tegmental area dopamine neurons.

In the present study, using single cell recordings in vivo and intracellular recordings in vitro from midbrain slices, the role of N-methyl-d-aspartate (NMDA) receptor signaling on firing activity in ventral tegmental area dopamine neurons elicited by nicotine was investigated in the rat. In accordance with previous studies, systemic nicotine (0.5 mg/kg s.c.) increased both firing rate and burst firing of dopamine neurons in vivo, and bath-applied nicotine (10 microM) increased firing rate in vitro. The competitive NMDA receptor antagonist CGP39551 (2.5 mg/kg i.p.) inhibited nicotine's effects on burst firing and also attenuated the nicotine-induced increase in firing rate. Moreover, although the nitric oxide (NO)-synthase inhibitor N-nitro-l-arginine-methyl-ester (l-NAME; 5.0 mg/kg i.p.) had no effect on cell firing by itself, it prevented the response to nicotine in vivo. In contrast, l-NAME (100 microM) did not influence nicotine's effect on dopamine cell firing in vitro, suggesting that the effect of l-NAME seen in vivo is dependent on presynaptic afferent input. The present study confirms previous results suggesting that the effect of systemically administered nicotine is in part presynaptic and mediated via NMDA receptors. The data also indicate that NO plays an important role in the previously demonstrated, indirect, glutamate-mediated excitation of these neurons by nicotine. By inference, our results provide additional support for the involvement of NO in nicotine dependence.

Nicotine-induced excitation of midbrain dopamine neurons in vitro involves ionotropic glutamate receptor activation.

Presynaptic nicotinic acetylcholine receptors (nAChR) on glutamatergic as well as GABAergic synaptic terminals are considered to play a major role in mediating nicotinic effects on neurons in many parts of the brain. However, to what extent the excitatory effect of nicotine on the dopamine (DA) neurons in the ventral tegmental area (VTA) is mediated via their glutamatergic input remains unclear. The excitatory effect of nicotine on these cells was therefore studied by means of intracellular recordings from a midbrain slice preparation in the presence of antagonists to NMDA and non-NMDA receptors and compared to the effect of nicotine alone. Our results show that the excitatory effect of nicotine is markedly reduced both in the presence of 2-amino-5-phosphonopentanoic acid (AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), i.e., from 115 +/- 14.3% to 63.4 +/- 11.0% and 63.2 +/- 13.6%, respectively. The coapplication of both antagonists did not have an additional effect in reducing the nicotine-induced increase in firing frequency. These findings clearly indicate that ionotropic glutamate receptor activation partly, but not entirely, mediates the excitatory effect of nicotine on DA neurons in VTA. In addition, we have pharmacologically characterized the nicotinic effect by the use of different nAChR antagonists, i.e., dihydro-beta-erythroidine (DHBE), mecamylamine, and methyllycaconitine (MLA). DHBE and mecamylamine but not MLA completely blocked the effect of nicotine, indicating that nAChRs other than alpha(7)-subtype are involved in the nicotine-induced excitation of the dopamine neurons in the brain slice preparation.

Muscarinic receptors depress GABAergic synaptic transmission in rat midbrain dopamine neurons.

The effects of muscarine and nicotine on evoked and spontaneous release of GABA were studied using intracellular and whole-cell patch-clamp recordings from rat midbrain dopamine neurons in an in vitro slice preparation. Muscarine (30 microM) reversibly depressed the pharmacologically isolated inhibitory postsynaptic potential evoked by local electrical stimulation. The maximal inhibition of the inhibitory postsynaptic potential amplitude was 39.6+/-5%. This depressant effect of muscarine was blocked by the M3/M1 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (100 nM), but was slightly affected by the M1/M3 receptor antagonist pirenzepine (1 microM). In addition, muscarine decreased the frequency of the miniature synaptic currents without any effect on their amplitude. Moreover, muscarine did not change the GABA-induced hyperpolarization, indicating that its effect on the inhibitory postsynaptic potential is mediated by presynaptic receptors. On the contrary, the cholinergic agonist nicotine did not change the frequency or the amplitude of the spontaneous glutamatergic and GABAergic synaptic currents. Our data indicate that a prevalent activation of presynaptic M3 muscarinic receptors inhibits the GABA-mediated synaptic events, while the activation of nicotinic receptors does not affect the release of glutamate and GABA on midbrain dopamine neurons.

Presynaptic muscarinic (M3) receptors reduce excitatory transmission in dopamine neurons of the rat mesencephalon.

The effects of carbachol (0.01-30 microM) and muscarine (10-30 microM) on the excitatory synaptic potentials were studied using conventional intracellular recordings from dopaminergic neurons in rat mesencephalic slices. Both muscarinic agonists reversibly reduced the excitatory synaptic potentials, evoked by local electrical stimulation. The EC50 for carbachol was determined to be 4.5 microM. The maximal degree of the excitatory synaptic potentials suppression caused by carbachol and muscarine was around 40% of control. This suppression was completely blocked by the non-specific muscarinic antagonist atropine (1 microM) and the selective M3 antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (1 microM). Other antagonists, preferentially acting at M1, M2 and M4 receptors, were not effective. Furthermore, the acetylcholinesterase inhibitor, physostigmine (50 microM), decreased the amplitude of the excitatory synaptic potentials, indicating that ambient acetylcholine can depress this potential. Direct depolarizing responses to glutamate were not changed by muscarine. In addition, muscarine facilitated the second excitatory synaptic potentials during a paired-pulse protocol. Thus, the effect of the muscarinic agonists is attributable to a presynaptic locus of action. The action of muscarine was not mediated by an N-ethylmaleimide-sensitive G-protein since it was not modified by a treatment of the slices with this agent. The calcium channels blockers, omega-conotoxin GIVA, omega-agatoxin IVA and omega-conotoxin MVIIC did not affect the action of muscarine on the excitatory synaptic potentials. When the potassium currents were reduced by extracellular barium and 4-aminopyridine, the muscarinic agonists still depressed the excitatory synaptic potentials. Our data indicate that presynaptically located M3 receptors modulate the excitatory transmission to midbrain dopaminergic neurons via a N-ethylmaleimide-insensitive G-protein which activates mechanisms neither linked to N-, P-, Q-type calcium channels nor to barium- and 4-aminopyridine-sensitive potassium channels.

L-Type calcium channels mediate a slow excitatory synaptic transmission in rat midbrain dopaminergic neurons.

Patch pipettes were used to record whole-cell synaptic currents under voltage-clamp in dopaminergic neurons in slices of rat substantia nigra pars compacta and ventral tegmental area. We report that dihydropyridines (DHPs), L-type Ca2+ channel antagonists, depressed a slow EPSC (EPSCslow) evoked by a train of focally delivered electrical stimuli. In fact, the amplitude of the EPSCslow was reduced by the DHP antagonists nifedipine (1-100 microM), nimodipine (1-100 microM), and isradipine (30 nM-100 microM) in a concentration-dependent and reversible manner. On the other hand, Bay-K 8644 (1 microM), an L-type Ca2+ channel agonist, increased the EPSCslow. The DHPs depressed the EPSCslow only when the high-frequency stimulation that was used to evoke this synaptic current lasted >70 msec. On the other hand, Bay-K 8644 increased the amplitude of the EPSCslow only when it was evoked by a train <70 msec. Moreover, the DHPs did not affect the EPSCfast, the IPSCfast, and the IPSCslow. The inhibition of the EPSCslow caused by the DHPs is attributed to presynaptic mechanisms because (1) the inward current generated by exogenously administered glutamate was not affected and (2) the EPSCslow was reduced to a similar degree even when the activation state of postsynaptic L-type Ca2+ channels was changed by holding the neurons at -100, -60, and +30 mV. Finally, a DHP-sensitive component of the EPSCslow could even be detected after the blockade of N-, Q-, and P-type Ca2+ channels by the combination of omega-conotoxin GVIA, omega-agatoxin IVA, and omega-conotoxin MVIIC. Taken together, these results indicate that under certain patterns of synaptic activity, L-type Ca2+ channels regulate the synaptic release of excitatory amino acids on the dopaminergic neurons of the ventral mesencephalon.

Altered neuronal activity rhythm and glutamate receptor expression in the suprachiasmatic nuclei of Trypanosoma brucei-infected rats.

The parasites Trypanosoma brucei cause African trypanosomiasis (sleeping sickness), a severe neuropsychiatric disease with marked disturbances of sleep-wake alternation. The sites of brain lesions are not well characterized. The present experimental investigation is focused on the hypothalamic suprachiasmatic nuclei, which play a role of a biological clock entraining endogenous rhythms in the mammalian brain. The electrophysiological properties of these neurons were analyzed in slice preparations from trypanosome-infected rats. The neuronal spontaneous activity, which shows a circadian oscillation, was markedly altered in the infected animals, displaying a reduced firing rate and phase advance of its circadian peak. The direct retinal fibers, which play a pivotal role in entrainment of the circadian pacemaker, displayed a normal density and distribution in the suprachiasmatic nuclei of infected animals after intraocular tracer injections in vivo. At the postsynaptic level, immunohistochemistry and Western blotting revealed in the suprachiasmatic nuclei of infected rats a selective decrease of the expression of glutamate AMPA GluR2/3 and NMDAR1 receptor subunits that gate retinal afferents. These data disclose an impairment of the neuronal functions in the biological clock in African trypanosomiasis, and may serve to unravel functional and molecular mechanisms behind endogenous rhythm disturbances.

Chronic nicotine enhances basal and nicotine-induced Fos immunoreactivity preferentially in the medial prefrontal cortex of the rat.

In the present study, expression of the immediate early gene protein products Fos and Jun-B within the dorsolateral striatum, the core and shell of the nucleus accumbens (NAC), the medial prefrontal cortex (mPFC), and the ventrolateral orbital cortex was examined. Rats were injected s.c. with either saline or nicotine (0.5 mg/kg) once daily for 12 days. On day 13, animals received a challenge injection of either saline or nicotine (0.5 or 1.0 mg/kg, s.c.) and 2 h later their brains were examined for Fos-like (FLI) and Jun-B-like (JLI) immunoreactivity. Chronic nicotine significantly increased basal expression of FLI selectively in the mPFC. Nicotine challenge significantly increased FLI in the mPFC of saline-treated animals and even further increased FLI in the mPFC of nicotine-treated animals. In the shell of the NAC, nicotine challenge also increased FLI in nicotine-treated animals, whereas it increased JLI only in saline-treated animals. After chronic nicotine treatment, injection of D1 receptor antagonist SCH 23390 (0.1 mg/kg, i.p.) 10 min before a nicotine challenge (0.5 mg/kg, s.c.), significantly attenuated the nicotine-induced FLI in the mPFC and the shell of the NAC. These results suggest that the regionally selective effect of nicotine challenge on FLI is due to enhanced dopaminergic transmission, mediated via stimulation of D1 receptors.

Glutamate metabotropic receptor agonists depress excitatory and inhibitory transmission on rat mesencephalic principal neurons.

Intracellular and whole-cell patch-clamp recordings were used to evaluate the actions of different metabotropic glutamate receptor (mGluR) agonists on the synaptic inputs evoked on principal cells of the rat mesencephalon. Bath application of the group III mGluR agonists L-2-amino-4-phosphonobutyric acid (L-AP4) and L-serine-O-phosphonobutanoate (L-SOP) did not change the holding current of the cells held at resting potential (-60 mV) but produced a dose-dependent inhibition of the amplitude of the excitatory and inhibitory events. L-AP4 and L-SOP were more effective at inhibiting the excitatory postsynaptic currents (EPSCs) than the GABA(A) and GABA(B) inhibitory postsynaptic currents (IPSCs). The suppressing effects of L-AP4 and L-SOP were antagonized by (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP-4) but not by +/- -alpha-methyl-4-carboxyphenylglycine (MCPG). Moreover, the group II agonist (2S,1'S,2'S)-(carboxycyclopropyl)glycine (L-CCG1) and the group I agonist (RS)-3,5-dihydrophenylglycine (3,5-DHPG) depressed in a dose-related manner the EPSC, the GABA(A) IPSC and the GABA(B) IPSC. The suppressing effect of the two mGluRs agonists was partially antagonized by MCPG but not by MAP-4. In addition, both L-CCG1 and 3,5-DHPG caused an inward shift of the holding current. To characterize the site of action of the metabotropic receptor agonists, experiments were performed to examine the amplitude and ratio of EPSC and GABA(A) IPSC pairs. The increase of the s2/s1 ratio caused by the agonists suggests that the location of the inhibitory mGluRs was presynaptic. These results indicate that the activation of presynaptic mGluRs controls the release of excitatory and inhibitory transmitters on presumed dopaminergic cells within the ventral mesencephalon.

N-methyl-D-aspartate receptors mediate a slow excitatory postsynaptic potential in the rat midbrain dopaminergic neurons.

Repetitive local application of a short train of stimuli to the rat substantia nigra and ventral tegmental area elicited a predominant depolarizing, slow, long-lasting synaptic response in the dopaminergic cells intracellularly recorded in vitro. This slow excitatory postsynaptic potential ranged between 13 and 27 mV at holding potentials of about-75 mV and lasted for 0.2-6 s. It was not greatly affected by the perfusion of 6-cyano-7-nitroquinoxaline-2,3-dione (10-20 microM), while it was potentiated in the presence of bicuculline methiodide (30 microM) or picrotoxin (50-100 microM) and 2-hydroxysaclofen (100-300 microM). In contrast, a substantial component of the slow excitatory postsynaptic potential was reversibly depressed, in a concentration-dependent manner, by the application of the N-methyl-D-aspartate receptor antagonists D,1-2-amino-5-phosphonovalerate (10-100 microM). Furthermore, the slow excitatory postsynaptic potential was reversibly increased by the superfusion of nominally magnesium-free solution. It was graded, increasing in amplitude with increased stimulus intensity, and was blocked by tetrodotoxin (0.5 microM). We suggest that a sustained activation of synaptic terminals containing excitatory amino acids mediates a slow excitatory postsynaptic potential in the dopaminergic cells of the midbrain. N-Methyl-D-aspartate receptors participate in the generation of this slow potential, while the alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate/kainate receptors do not seem to contribute substantially to this potential. This N-methyl-D-aspartate-mediated synaptic event could be implicated in the release of dopamine as well as in the excitotoxic injury of the dopaminergic neurons.

The 5-HT1A receptor antagonist (S)-UH-301 augments the increase in extracellular concentrations of 5-HT in the frontal cortex produced by both acute and chronic treatment with citalopram.

In a recent study, utilizing single cell recording techniques, we have shown that administration of 5-HT1A receptor antagonists, e.g. (S)-UH-301, to rats concomitantly treated, acute or chronically, with the selective serotonin reuptake inhibitor (SSRI) citalopram significantly increases the activity of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN). Here we report correlative experiments using microdialysis in freely moving animals to measure extracellular levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex, a major projection area for DRN-5-HT neurons. Acute administration of (S)-UH-301 (2.5 mg/kg s.c.) or citalopram (2.0 mg/kg s.c.) increased 5-HT concentrations with a maximum of about 70% and 185%, respectively, above baseline. However, when (S)-UH-301 was administered 30 min before citalopram the maximal increase in 5-HT levels was approximately 400%. In rats chronically treated with citalopram (20 mg/kg/day i.p. for 14 days) basal 5-HT concentrations in the frontal cortex were significantly increased and 5-HIAA concentrations were decreased when measured 10-12 h, but not 18-20 h, after the last injection of citalopram, as compared to basal 5-HT and 5-HIAA concentrations in chronic saline-treated rats. When (S)-UH-301 (2.5 mg/kg s.c.) was administered 12 h, but not 20 h, after the last dose of citalopram it produced a significantly larger increase in extracellular concentrations of 5-HT than in control rats. However, in rats pretreated with a single, very high dose of citalopram, 20 mg/kg i.p., administration of (S)-UH-301 at 12 h after citalopram did not increase 5-HT levels. The augmentation by (S)-UH-301 of the increase in brain 5-HT output produced by acute administration of citalopram is probably due to antagonism of the citalopram induced feedback inhibition of 5-HT cells in the DRN, as previously suggested. However, the capacity of (S)-UH-301 to further increase the already elevated extracellular concentrations of 5-HT in brain in animals maintained on a chronic citalopram regimen, in which significant tolerance to the initial feedback inhibition of DRN-5-HT cells and developed, represents a novel finding. Generally, the reduced feedback inhibition of 5-HT neurons obtained with chronic citalopram treatment, and the associated elevation of brain 5-HT concentrations, may be related to functional desensitization of somatodendritic 5-HT1A autoreceptors in the DRN. This phenomenon may also largely explain the larger increase in 5-HT output produced by (S)-UH-301 in chronic citalopram treated animals as compared to its effect in control animals. Yet, a contributory factor may be a slight, remaining feedback inhibition of the 5-HT cells caused by residual citalopram at 12, but not 20 h after its last administration. Previous clinical studies suggest that addition of a 5-HT1A receptor antagonist to an SSRI in the treatment of depression may accelerate the onset of clinical effects. Moreover, in therapy-resistant cases maintained on SSRI treatment, addition of a 5-HT1A receptor antagonist may improve clinical efficacy. Since the therapeutic effect of SSRIs in depression has been found to be critically linked to the availability of 5-HT in brain, our experiments results support, in principle, both of the above clinically based notions.

5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram.

In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT1A receptor antagonists, [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl-propionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)-WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.). We have also studied the effects of (S)-UH-301 (0.03-0.50 mg/kg i.v.) on the firing rate of single DRN-5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. x 14 days). Administration of (S)-UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 ml/kg/day i.p. x 14 days), control rats. Our results thus suggest that 5-HT1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Two types of motor rhythm induced by NMDA and amines in an in vitro spinal cord preparation of neonatal rat.

Rhythmic motor activities were studied in two rat spinal cord preparations; in the first one, the spinal cord was completely isolated and the ventral roots activity was recorded; in the other, spinal cord and hindlimbs were kept in order to record muscle activities. Motor patterns were therefore recorded in ventral roots and/or hindlimb muscles. Two kinds of specific patterns were elicited by neurochemicals. The first which was induced by N-methyl-D,L-aspartate (NMDA) and serotonin (5-HT) was a slow rhythm (0.5-0.2 Hz) of left and right alternating bursts of spikes. The second one which was induced by NMDA, 5-HT and norepinephrine (NE), was a high frequency rhythm (5-10 Hz). One particularity observed was that these two rhythms could occur simultaneously. The relationship between the two in vitro rhythms is discussed and they are compared with those reported in other rhythmic systems.