Altered profile and D2-dopamine receptor modulation of high voltage-activated calcium current in striatal medium spiny neurons from animal models of Parkinson's disease.

In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca2+) currents in freshly isolated striatal medium spiny neurons (MSNs) from rodent models of both idiopathic and familial forms of Parkinson's disease (PD). MSNs were recorded from reserpine-treated and 6-hydroxydopamine (6-OHDA)-lesioned rats, and from DJ-1 and PINK1 (PTEN induced kinase 1) knockout (-/-) mice. Our analysis showed no significant changes in total HVA Ca2+ current. However, we recorded a net increase in the L-type fraction of HVA Ca2+ current in dopamine-depleted rats, and of both N- and P-type components in DJ-1-/- mice, whereas no significant change in Ca2+ current profile was observed in PINK1-/- mice. Dopamine modulates HVA Ca2+ channels in MSNs, thus we also analyzed the effect of D1 and D2 receptor activation. The effect of the D1 receptor agonist SKF 83822 on Ca2+ current was not significantly different among MSNs from control animals or PD models. However, in both dopamine-depleted rats and DJ-1-/- mice the D2 receptor agonist quinpirole inhibited a greater fraction of HVA Ca2+ current than in the respective controls. Conversely, in MSNs from PINK1-/- mice we did not observe alterations in the effect of D2 receptor activation. Additionally, in both reserpine-treated and 6-OHDA-lesioned rats, the effect of quinpirole was occluded by the selective L-type Ca2+ channel blocker nifedipine, while in DJ-1-/- mice it was mostly occluded by ω-conotoxin GVIA, blocker of N-type channels. These results demonstrate that both dopamine depletion and DJ-1 deletion induce a rearrangement in the HVA Ca2+ channel profile, specifically involving those channels that are selectively modulated by D2 receptors.

Age-related functional changes of high-voltage-activated calcium channels in different neuronal subtypes of mouse striatum.

By means of whole-cell patch-clamp recordings, we characterized the developmental profile of high-voltage-activated (HVA) calcium (Ca(2+)) channel subtypes in distinct neuronal populations of mouse striatum. Acutely dissociated medium spiny neurons (MSNs) and cholinergic interneurons (ChIs) were recorded from mice at five developmental stages: postnatal-days (PD) 14, 23, 40, 150 and 270. During ageing, total HVA Ca(2+) current recorded from both MSNs and ChIs was unchanged. However, the pharmacological analysis of the differential contribution of HVA Ca(2+) channel subtypes showed a significant rearrangement of each component. In both neuronal subtypes, a large fraction of the total HVA current recorded from PD14 mice was inhibited by the L-type HVA channel blocker nifedipine. This dihydropyridine-sensitive component accounted for nearly 50%, in MSNs, and 35%, in ChIs, of total current at PD14, but its contribution was down-regulated up to 20-25% at 9 months. Likewise, the N-type, omega-conotoxin GVIA-sensitive component decreased from 35% to 40% to about 25% in MSNs and 15% in ChIs. The P-type, omega-agatoxin-sensitive fraction did not show significant changes in both neuronal subtypes, whereas the Q-type, omega-conotoxin MVIIC-sensitive channels did show a significant up-regulation at 9 months. As compared with striatal neurons, we recorded pyramidal neurons dissociated from cortical layers IV-V and found no significant developmental change in the different components of HVA Ca(2+) currents. In conclusion, our data demonstrate a functional reconfiguration of HVA Ca(2+) channels in striatal but not cortical pyramidal neurons during mouse development. Such changes might have profound implications for physiological and pathophysiological processes of the striatum.

Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92.

202W92 (R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine) is a novel compound in the same chemical series as the antiepileptic drug lamotrigine and the neuroprotective sipatrigine. Here 202W92 was quantitatively assessed as a neuroprotective agent in focal cerebral ischaemia, and as an inhibitor of sodium and calcium channels and of synaptic transmission. In the rat permanent middle cerebral artery occlusion (MCAO) model of acute focal ischaemia, 202W92 reduced infarct volume by 75% in cortex and by 80% in basal ganglia, with ED(50) approximately 2 mg/kg (single i.v. dose, 10 min post-occlusion). In whole-cell current recordings from single cells, 202W92 completely and reversibly inhibited voltage gated sodium channels (IC(50) 3 x 10(-6) M) in rat freshly-isolated cortical neurons and in the GH(3) pituitary cell line. 202W92 also inhibited a nifedipine-sensitive fraction (approximately 35%) of native high-voltage-activated (HVA) calcium current in rat cortical neurons (IC(50) 15 x 10(-6) M) and weakly inhibited low-voltage-activated (LVA) calcium currents of the recombinant alpha1I-mediated T-type (IC(50)>100 x 10(-6) M). The drug inhibited the amplitude and frequency of 4-aminopyridine-evoked glutamatergic excitatory post-synaptic currents (EPSCs). In conclusion, 202W92 is an effective neuroprotective agent when administered post-ischaemia and a potent sodium channel inhibitor in vitro.

Effects of extracellular pH on the interaction of sipatrigine and lamotrigine with high-voltage-activated (HVA) calcium channels in dissociated neurones of rat cortex.

Acidic extracellular pH reduced high-voltage-activated (HVA) currents in freshly isolated cortical pyramidal neurones of adult rats, shifting activation to more positive voltages (V(1/2)=-18 mV at pH 7.4, -11 mV at pH 6.4). Sipatrigine inhibited HVA currents, with decreasing potency at acidic pH (IC(50) 8 microM at pH 7.4, 19 microM at pH 6.4) but the degree of maximal inhibition was >80% in all cases (pH 6.4-8.0). Sipatrigine has two basic groups (pK(A) values 4.2, 7.7) and at pH 7.4 is 68% in monovalent cationic form and 32% uncharged. From simple binding theory, the pH dependence of sipatrigine inhibition indicates a protonated group with pK(A) 6.6. Sipatrigine (50 microM) shifted the voltage dependence of channel activation at pH 7.4 (-7.6 mV shift) but not at pH 6.4. Lamotrigine has one basic site (pK(A) 5.5) and inhibited 34% of the HVA current, with similar potency over the pH range 6.4--7.4 (IC(50) 7.5--9 microM). These data suggest that the sipatrigine binding site on HVA calcium channels binds both cationic and neutral forms of sipatrigine, interacts with a group with pK(A)=6.6 and with the channel activation process, and differs from that for lamotrigine.

The activation of mu opioid receptors promotes a small modulation of calcium currents in rat pallidal neurons.

Globus pallidus receives, from dorsal neostriatum, a dense enkephalinergic innervation whose role is still uncertain. We examined the possibility that the activation of mu, delta or k opioid receptors modulate high-voltage-activated calcium currents in isolated GP neurons. Neither dynorphin nor DPEPE inhibited calcium current, whilst DAMGO produced a small (-16%) but consistent response, selectively antagonized by CTOP. The mu-mediated modulation required the activation of G-proteins but was voltage-independent. The pre-incubation in omega-conotoxinVIA abolished the response, implying the involvement of N-type calcium channels. These findings suggest that enkephalin may exert a direct influence on GP excitability also through post-synaptic effects. In degenerative conditions as Parkinsonism, an excessive stimulation of mu binding sites might induce a pathological inhibition of calcium signals, thus contributing to modify the GP firing pattern and transmitter release.

The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons.

A clear picture of the mechanisms of action of the anti-epileptic agent gabapentin is far from being accomplished. We have analyzed the effects of gabapentin on ligand- and voltage-gated currents in isolated adult rat cortical neurons. Gabapentin failed to modify glutamate currents and produced a slight reduction of GABA responses. Negligible inhibition of sodium, but consistent inhibition of high-voltage-activated calcium conductance was promoted by gabapentin. In addition, gabapentin reduced calcium current sensitivity to dihydropyridine agonist and antagonists. Interestingly, gabapentin also decreased a not-inactivating, cadmium-sensitive, potassium current. These unconventional effects might underlie its efficacy in a variety of diseases which involve periodic discharge patterns as neuropathic pain or essential tremor.

Electrophysiology of sipatrigine: a lamotrigine derivative exhibiting neuroprotective effects.

Sipatrigine (BW619C89), a derivative of the antiepileptic agent lamotrigine, has potent neuroprotective properties in animal models of cerebral ischemia and head injury. In the present study we investigated the electrophysiological effects of sipatrigine utilizing intracellular current-clamp recordings obtained from striatal spiny neurons in rat corticostriatal slices and whole-cell patch-clamp recordings in isolated striatal neurons. The number of action potentials produced in response to a depolarizing current pulse in the recorded neurons was reduced by sipatrigine (EC(50) 4.5 microM). Although this drug preferentially blocked action potentials in the last part of the depolarizing current pulse, it also decreased the frequency of the first action potentials. Sipatrigine also inhibited tetrodotoxin-sensitive sodium (Na(+)) current recorded from isolated striatal neurons. The EC(50) for this inhibitory action was 7 microM at the holding potential (V(h)) of -65 mV, but 16 microM at V(h) = -105, suggesting a dependence of this pharmacological effect on the membrane potential. Moreover, although the inhibitory action of sipatrigine on Na(+) currents was maximal during high-frequency activation (20 Hz), it could also be detected at low frequencies. The amplitude of excitatory postsynaptic potentials (EPSPs), recorded following stimulation of the corticostriatal pathway, was depressed by sipatrigine (EC(50) 2 microM). This inhibitory action, however, was incomplete; in fact maximal concentrations of this drug reduced EPSP amplitude by only 45%. Sipatrigine produced no increase in paired-pulse facilitation, suggesting that the modulation of a postsynaptic site was the main pharmacological effect of this agent. The inhibition of voltage-dependent Na(+) channels exerted by sipatrigine might account for its depressant effects on both repetitive firing discharge and corticostriatal excitatory transmission. The modulation of Na(+) channels described here, as well as the previously observed inhibition of high-voltage-activated calcium currents, might contribute to the neuroprotective efficacy exerted by this compound in experimental models of in vitro and in vivo ischemia.

Selective vulnerability of pallidal neurons in the early phases of manganese intoxication.

Prolonged exposure to manganese in mammals may cause an extrapyramidal disorder characterized by dystonia and rigidity. Gliosis in the pallidal segments underlies the well-established phase of the intoxication. The early phase of the intoxication may be characterized by psychic, nonmotor signs, and its morphological and electrophysiological correlates are less defined. In a rat model of manganese intoxication (20 mg/ml in drinking water for 3 months), neither neuronal loss nor gliosis was detected in globus pallidus (GP). However, a striking vulnerability of manganese-treated GP neurons emerged. The majority of GP neurons isolated from manganese-treated rats died following brief incubation in standard dissociation media. In addition, patch-clamp recordings in the whole-cell configuration were not tolerated by surviving GP neurons. Neither coeval but untreated GP neurons nor striatal ones manifested analogous susceptibility. Using the perforated-patch mode of recording we attempted at identifying the functional hallmarks of GP vulnerability: in particular, voltage-gated calcium currents and glutamate-induced currents were examined. Manganese-treated GP neurons exhibited calcium currents similar to control cells aside from a slight reduction in the dihydropyridine-sensitive current facilitation. Strikingly, manganese-treated GP cells--but not striatal ones--manifested peculiar responses to glutamate, since repeated applications of the excitatory amino acid, at concentrations which commonly promote desensitizing responses, produced instead an irreversible cell damage. Possible mechanisms are discussed.

The modulation of calcium current by GABA metabotropic receptors in a sub-population of pallidal neurons.

Globus pallidus (GP) receives an abundant GABAergic (gamma-aminobutyric acid) pathway from the corpus striatum. Several evidences suggested that alterations of this pathway might underlie the development of movement disorders. Classical models on Parkinsonism are centred on the increased excitability of GABAergic striatofugal neurons impinging GP and, therefore, on the presumed hypoactivity of GP neurons, but very few electrophysiological studies have addressed the activation of GABA receptors in mammalian GP. We have isolated calcium currents in GP neurons dissociated from the adult rat brain and analysed GABA-mediated responses. In the presence of bicuculline, the fast, chloride-mediated, ionotropic responses were obscured and GABA produced a large (>/= 35%) inhibition of calcium currents. The GABA-induced inhibition of calcium currents strongly desensitized was mimicked by baclofen and prevented by hydroxy-saclofen, supporting the involvement of GABAB receptors. The baclofen-mediated modulation was: (i) associated with slowing of activation kinetics; (ii) relieved by prepulse facilitation; and (iii) G-protein-mediated. The response was slow in onset, requiring the mobilization of intracellular cAMP, and was abolished by the combination of N-type and P-type calcium channel blockers. The GABAB-mediated effect, however, was confined to a particular subtype of GP neurons, identified by relatively small to medium soma. Differently, in cells characterized by larger somata and capacitance, the baclofen response was negligible. Intriguingly, these baclofen-resistant, larger neurons manifested a consistent low-voltage-activated (LVA) calcium current, not detected in baclofen-sensitive cells, at least when recorded in whole-cell mode. This study demonstrates that GP neurons express functional GABAA and GABAB receptors. In a subset of GP neurons, the activation of GABAB receptors induces a large modulation of high-voltage-activated (HVA) calcium currents, which may strongly influence basal ganglia circuitry and partially explain some discrepancies of classical models of extrapyramidal disorders.

On the inhibition of voltage activated calcium currents in rat cortical neurones by the neuroprotective agent 619C89.

1. The lamotrigine analogue 619C89, utilised to reduce postischaemic and posttraumatic neuronal injury, has been shown to inhibit sodium channels and cloned N-type calcium channels. To verify whether this neuroprotective agent also blocked native calcium channels, we have tested its action in cortical pyramidal neurones, acutely isolated from the adult rat brain. 2. 619C89 inhibited more than 90% of the high voltage-activated calcium currents recorded in the whole-cell configuration. The response was relatively slow in onset (30-60 s), recovered incompletely (96%), but showed no consistent desensitization. 3. This inhibitory effect was not selective for any calcium channel subtype, being largely unaffected by omega-conotoxin-GVIA, omega-agatoxin-IVA, omega-conotoxin-MVIIC and dihydropyridine antagonists. 4. Saturating responses to 619C89 were detected for concentrations > or = 50 microM. Dose-response curves revealed that 619C89 have an approximately 8 microM binding site. 5. The effect of 619C89 was dependent on the divalent concentrations in that its potency was reduced on increase of the charge carrier up to 20 mM barium. Since the lamotrigine analogue shifted to the right the dose-dependence of the cadmium block, the 619C89-mediated inhibition of calcium currents seemed to rely on a direct interaction with the channel pore. Functional implications are discussed.

Group I mGluRs modulate calcium currents in rat GP: functional implications.

The modulation of voltage-dependent calcium currents strongly affects the firing pattern of central neurons. Changes in the intrinsic firing properties of mammalian globus pallidus cells (external pallidus in humans) are indicated as underlying the development of movement disorders. Pallidal neurons receive an excitatory input from the subthalamus, supposed to activate both ionotropic and metabotropic glutamate receptors. Since the activation of glutamate metabotropic receptors in rodent basal ganglia affects dopamine-mediated motor behaviors, we examined whether agonists at metabotropic sites modulate high-threshold calcium currents in pallidus. The broad agonist 1S,3R-ACPD produced a 22% reduction of calcium currents, which was mimicked by the group I agonist DHPG. These two responses were not additive; furthermore, the ACPD- and DHPG-mediated inhibition of high-threshold calcium currents were prevented by the cycloglycine MCPG, suggesting the involvement of a group I mGluR. The modulation was fast, saturating in less than 3 sec, partially voltage-dependent, in that about one-third was relieved by facilitation, and G-protein-mediated, since it was largely suppressed by NEM. Finally, the response was antagonized by omega-conotoxin-GVIA and omega-agatoxin-IVA, supporting the involvement of N- and P-type channels. The observed reduction of calcium signals might shape pallidal excitability, influencing the physiological balancing between globus pallidus and subthalamus. In pathological conditions such as parkinsonism, characterized by the putative increase of the endogenous release of glutamate from subthalamic neurons, the inhibition of high-threshold calcium currents in pallidus might modify the firing pattern of pallidal neurons and partially counteract the excitatory drive from STN. Nevertheless, the putative mGluR-induced reduction of intrinsic excitability might turn out to decrease the transmitter release from pallidal axon terminals, leading to further disinhibition of the output stations of the basal ganglia.

Gabapentin inhibits calcium currents in isolated rat brain neurons.

Gabapentin (1(aminomethyl) cyclohexane acetic acid; GBP) is a recently developed anticonvulsant, for which the mechanism of action remains quite elusive. Besides its possible interaction with glutamate synthesis and/or GABA release, in cerebral membranes gabapentin has been shown to bind directly to the alpha2delta subunit of the calcium channel. Therefore, we have tested the possibility that gabapentin affects high threshold calcium currents in central neurons. Calcium currents were recorded in whole-cell patch-clamp mode in neurons isolated from neocortex, striatum and external globus pallidus of the adult rat brain. A large inhibition of calcium currents by gabapentin was observed in pyramidal neocortical cells (up to 34%). Significantly, the gabapentin-mediated inhibition of calcium currents saturated at particularly low concentrations (around 10 microM), at least in neocortical neurons (IC50 about 4 microM). A less significant inhibition was seen in medium spiny neurons isolated from striatum (-12.4%) and in large globus pallidus cells (-10.4%). In all these areas, however, the GBP-induced block was fast and largely voltage-independent. Dihydropyridines (nimodipine, nifedipine) prevented the gabapentin response. Omega-conotoxin GVIA and omega-conotoxin MVIIC, known to interfere with the currents driven by alpha1b and alpha1a calcium channels, did not prevent but partially reduced the response. These findings imply that voltage-gated calcium channels, predominately the L-type channel, are a direct target of gabapentin and may support its use in different clinical conditions, in which intracellular calcium accumulation plays a central role in neuronal excitability and the development of cellular damage.

Group III metabotropic glutamate receptor agonists modulate high voltage-activated Ca2+ currents in pyramidal neurons of the adult rat.

In pyramidal neurons of the rat sensorimotor cortex, we have investigated the modulation of high voltage-activated calcium currents by agonists at group III metabotropic glutamate receptors (mGluRs). l-2-Amino-4-phosphonobutyrate (l-AP4) and l-serine-O-phosphate (l-SOP) reduced calcium currents in the vast majority of cells isolated from the adult animal. Interestingly, this modulation was negligible in the young animals (2-14 postnatal days), becoming prominent only after full development (more than 21 days). The efficacy of l-SOP mimicked l-AP4 in reducing calcium currents. Yet, l-SOP produced saturating responses at about 3 microM and significant modulation at nanomolar concentrations (EC50=923 nM). The voltage-dependence of the group III mGluR-mediated responses was evaluated by comparing the inhibition of "standard" and "facilitated" conductances. On the calcium currents facilitated by depolarizing prepulse, 3 microM l-SOP produced a mean 13.4% inhibition compared with 19.6% in control condition, supporting the proposition that part of the inodulation was voltage-dependent. The calcium current inhibition caused by the activation of group III metabotropic glutamate receptors was only partially sensitive to omega-conotoxin GVIA, but largely inhibited by omega-agatoxin IVA, at concentrations (100 nM) known to block P- and Q-type channels. Conversely, the dihydropyridine antagonists nifedipine and nimodipine (50-500 nM) failed to prevent the group III mGluR-mediated response in the majority of tested cells (more than 65%). Furthermore, the long-lasting tail promoted by the inclusion of the dihydropyridine agonist Bay K 8644 was not consistently affected by l-SOP and l-AP4. These findings imply that the observed modulation involves different channel subtypes, namely N- and P- or Q-type channels, and suggests that group III mGluRs play an important role in the intrinsic and synaptic functions of adult cortical pyramidal neurons.

Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies.

Among the several classes of drugs currently studied as neuroprotective agents, glutamate release blockers have been indicated as being rather effective. In particular, lamotrigine and riluzole have shown promise in the treatment of either acutely developing cellular damages (stroke, posttraumatic lesions) or slowly progressing neurodegenerative diseases as amyotrophic lateral sclerosis. These drugs are supposed to interfere with the release of endogenous glutamate in situ, yet the mechanisms underlying this effect are not fully defined. One possibility is that lamotrigine and riluzole act by inhibiting voltage-dependent inward conductances active in the soma and/or in the axon terminal region. Therefore, we have investigated the effects of lamotrigine and riluzole on the voltage-gated sodium and calcium currents of acutely isolated neurons from the adult rat neocortex. In addition, since phenytoin is a well-known blocker of the sodium channel, we have compared lamotrigine and riluzole responses with the peak current inhibition produced by phenytoin in the same cells. Lamotrigine produced a large reduction of the high-voltage-activated calcium currents and a smaller; use-dependent inhibition of the sodium conductance. Riluzole inhibited significantly the sodium current at surprisingly low concentrations (nanomolar range) and by up to 80% at saturating doses (1-10 microM). Furthermore, riluzole inhibited both high- and low-voltage-activated calcium currents in neocortical neurons isolated from adult and young animals. By contrast, phenytoin caused only a slight reduction of high-voltage-activated calcium currents even at supratherapeutic doses (by < 12% at 10 microM). Taken together, the different pharmacological profiles of the tested agents might indicate that glutamate release blockers do not represent a homogenous class of drugs. Conversely, our findings could support their selective utilization in different disease status.

Voltage-activated calcium channels: targets of antiepileptic drug therapy?

Voltage-gated calcium currents play important roles in controlling neuronal excitability. They also contribute to the epileptogenic discharge, including seizure maintenance and propagation. In the past decade, selective calcium channel blockers have been synthesized, aiding in the analysis of calcium channel subtypes by patch-clamp recordings. It is still a matter of debate whether whether any of the currently available antiepileptic drugs (AEDs) inhibit these conductances as part of their mechanism of action. We tested oxcarbazepine, lamotrigine, and felbamate and found that they consistently inhibited voltage-activated calcium currents in cortical and striatal neurons at clinically relevant concentrations. Low micromolar concentrations of GP 47779 (the active metabolite of oxcarbazepine) and lamotrigine reduced calcium conductances involved in the regulation of transmitter release. In contrast, felbamate blocked nifedipine-sensitive conductances at concentrations significantly lower than those required to modify N-methyl-D-aspartate (NMDA) responses or sodium currents. Aside from contributing to AED efficacy, this mechanism of action may have profound implications for preventing fast-developing cellular damage related to ischemic and traumatic brain injuries. Moreover, the effects of AEDs on voltage-gated calcium signals may lead to new therapeutic strategies for the treatment of neurodegenerative disorders.

Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications.

In pyramidal cortical cells, high-voltage-activated Ca2+ currents affect seizure propagation and the release of excitatory amino acids at the corticostriatal axon terminals. The new antiepileptic drug lamotrigine (Lamictal) produced a large and dose-dependent inhibition of high-voltage-activated Ca2+ currents (IC50 = 12.3 microM) in rat cortical neurons. This action was not blocked by the dihydropyridine receptor antagonist nifedipine; instead, the response was blocked by the concomitant application of the N-type Ca2+ channel blocker, omega-conotoxin GVIA (1-3 microM) and the P-type Ca2+ channel blocker, omega-agatoxin-IVA (20-100 nM). These findings demonstrate that lamotrigine, at therapeutic doses, is capable of modulating the Ca2+ conductances involved in excitatory amino acid release in the corticostriatal pathway, partially explaining lamotrigine usefulness in the therapy of epilepsy as well as in the treatment of excitatory amino acid-induced neurotoxicity.

L-AP4 inhibits high voltage-activated Ca2+ currents in pyramidal cortical neurones.

We tested the ability of L-AP4 to modulate high voltage-activated (HVA) calcium (Ca2+) currents in pyramidal neurones acutely isolated from the adult rat (4-8 weeks). Whole cell recordings, with barium (Ba2+) ions as the charge carrier, were performed. L-AP4 reduced HVA Ca2+ conductances in 86% of the recorded cells. Saturating concentrations of L-AP4 inhibited about 21% of the current (+/- 8.3%, n = 8), although great variability was observed. Interestingly, low micromolar concentrations of (1S,3R)-1-aminocyclo-pentane-1,3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4R)-alpha-(carboxy-cyclopropyl)-glycine (1-CCGI) had weaker effects than L-AP4. MAP4 fully antagonized the L-AP4-mediated reduction of HVA Ca2+ currents. These findings suggest the involvement of the AP4-sensitive receptor in the control of both cellular excitability and transmitter release in rat neocortical neurones.

Centred radio-frequency hyperthermia in solid tumours.

After some notions on the mechanisms of action of radio-waves on solid tumours, the treatise illustrates the results achieved in the first 125 cases of malignant tumours treated with this method, its results are definitely encouraging, even in cases apparently with no hope. It also describes briefly the histologic modifications induced by this therapeutic method on neoplastic masses and discusses the criteria of the directions of thermotherapy, alone or combined, which is obviously the fifth weapon against tumours.