PubMed Health⌕ Search

Biomedical subjects

A E Watts

Publications and source records attributed to A E Watts.

8 recordsLinked to original sources
PubMed1996

Baclofen inhibition of the hyperpolarization-activated cation current, Ih, in rat substantia nigra zona compacta neurons may be secondary to potassium current activation.

1. The properties of the hyperpolarization-activated cation current (Ih), and its modulation by gamma-aminobuturic acid-B (GABAB) receptor activation and protein kinase A, were investigated using whole cell voltage clamp of substantia nigra zona compacta principal neurons in rat midbrain slices in vitro. 2. At 30 degrees C, Ih activated between -75 and -155 mV, with a V1/2 of -115 mV. At 35 degrees C, the activation curve shifted positive by 10 mV. Ih had an estimated reversal potential of -27 mV. Ion substitution experiments showed that the current was carried by Na+ and K+. 3. Application of the GABAB receptor agonist baclofen (30 microM) induced an outward potassium current (GIRK), increased neuronal membrane conductance and inhibited Ih. The inhibition of Ih was voltage independent. Baclofen induced an 11-mV positive shift in the reversal potential of Ih. 4. Extracellular barium (300 microM) markedly reduced the baclofen-evoked outward current and associated increase in membrane conductance due to GIRK activation. There was also very little inhibition of Ih by baclofen in the presence of barium. When cesium was the major intracellular cation, both the increase in membrane conductance due to GIRK activation and the inhibition of Ih evoked by baclofen were reduced by a similar extent. 5. Neither forskolin (10 microM) nor the protein kinase A inhibitor, H89 (10 microM), had any effect on Ih or its inhibition by baclofen. 6. These data suggest that the inhibition of Ih by baclofen is secondary to the activation of GIRK, i.e., due directly to alteration of membrane conductance, rather than a distinct effect, and is not mediated by inhibition of adenylyl cyclase.

Adenylyl Cyclases↗
PubMed1995

Putative pre- and postsynaptic ATP-sensitive potassium channels in the rat substantia nigra in vitro.

Pre- and postsynaptic adenosine 5'-triphosphate-sensitive potassium (ATP-K+) currents were studied using whole-cell recordings from substantia nigra zona compacta "principal" neurons in midbrain slices. The GABAA and GABAB receptor-mediated synaptic potentials were unaffected by the ATP-K+ channel inhibitor glibenclamide (30 microM) or by the opener diazoxide (500 microM), indicating that ATP-K+ channels on GABA-ergic terminals are not active, nor can they be activated pharmacologically, under control conditions. However, application of a glucose-free solution to reduce intracellular ATP levels caused a reduction of the GABAB IPSP in all neurons. This was substantially reversed by the sulfonylurea inhibitor tolbutamide (300 microM) in 50% of the neurons tested. The reduction of the GABAB IPSP was a presynaptic effect since postsynaptic hyperpolarizations induced by the GABAB receptor agonist baclofen (10 microM) were unaffected by glucose-free solutions. Diazoxide (500 microM) induced a slowly developing hyperpolarization or outward current in 64% of principal neurons, which was tolbutamide- (100-300 microM) or glibenclamide- (30 microM) sensitive. In contrast, the GABAB receptor agonist baclofen (30 microM) induced a rapid hyperpolarization or outward current in all neurons tested that was unaffected by tolbutamide (300 microM). Although both the diazoxide-induced current and the baclofen-induced current were inhibited by Ba2+ (300 microM), the currents elicited by diazoxide and baclofen summated. The reversal potential for the diazoxide-induced current was also less negative than that for baclofen, which was close to EK. In the presence of intracellular cesium, diazoxide induced a tolbutamide-sensitive inward current in a proportion of neurons, indicating that it has other actions in addition to activating a potassium current. Our results suggest that functional ATP-K+ channels exist both pre- and postsynaptically in the SN, where they modulate the activity of principal neurons. They are different to the potassium channels activated by the GABAB receptor agonist baclofen.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Epileptic focus induced in rat by intrahippocampal cholera toxin: neuronal properties in vitro.

Injecting 0.5-1.0 microgram of cholera toxin into rat hippocampus induces a chronic epileptic focus which generates interictal discharges and brief epileptic seizures intermittently over the following seven to 10 days. Here we examined the electrophysiological properties of hippocampal slices prepared from these rats three to four days after injection, at the height of the epileptic syndrome. These slices generated epileptic discharges in response to electrical stimulation of afferent pathways. In many cases epileptic discharges occurred spontaneously in the CA3 subregion; these usually lasted < 200 ms, but they could last < 0.6 s. Intracellular recordings from pyramidal layer cells revealed depolarization shifts synchronous with the epileptic field potentials. These depolarization shifts had slow onsets compared with those induced by blocking inhibition with bicuculline (depolarizations started a mean of 57 ms before, and reached 5.2 mV by, the onset of the cholera toxin epileptic field potential, compared with 12 ms and 3.6 mV respectively for 70 microM bicuculline methiodide). Extracellular unit recordings showed that the slow predepolarization seen in the cholera toxin focus was associated with an acceleration of the firing of other pyramidal layer neurons. The epileptic activity in this model cannot be attributed to the loss of synaptic inhibition, because inhibitory postsynaptic potentials could be evoked when the synchronous bursts were blocked by increasing [Ca2+]o from 2 to 8 mM. Observations of monosynaptic inhibitory postsynaptic currents isolated by application of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione, 50 microM DL-2-amino-5-phosphonovaleric acid and 100-200 microM 3-amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic acid showed a small effect of the toxin only on the time course of the inhibitory postsynaptic current. On the other hand, there were significant changes in the intrinsic properties of individual neurons. The membrane potentials of cells in the cholera toxin focus did not differ from those in slices from rats injected with vehicle solution, but their input resistances were significantly increased. Unlike the other cellular changes in this model, the increase in input resistance was not seen in slices exposed acutely to 1 micrograms/ml cholera toxin for 30 min, suggesting there may be morphological changes in the chronic focus. Action potential accommodation and the slow afterhyperpolarization were depressed in both acute and chronic epileptic tissue, indicating impairments of Ca(2+)- and/or voltage-dependent K+ currents, and we conclude that these provide the most likely basis for cholera toxin epileptogenesis.

2-Amino-5-phosphonovalerate↗
PubMed1993

Effects of carbamazepine and baclofen on 4-aminopyridine-induced epileptic activity in rat hippocampal slices.

1. Rat transverse hippocampal slices exposed to 100 microM 4-aminopyridine (4-AP) generate spontaneous epileptic discharges ranging in duration from short 50 ms 'interictal' bursts to long 0.5-2 s 'polyspike' activity. 2. Here we compared the effects of the commonly used anticonvulsant, carbamazepine (40 microM) and the antispastic drug, baclofen (2 microM) on the various types of burst. 3. Carbamazepine completely abolished long bursts whilst leaving shorter bursts intact. This is consistent with its known anticonvulsant properties. 4. Baclofen greatly reduced the frequency of short bursts but did not block the long bursts. Rather, they became significantly more prolonged, indicating that baclofen does not have an anticonvulsant action, and may be proconvulsant. 5. These results conflict with conclusions based on studies using models that exhibited only interictal bursts, and emphasize the need to use experimental epilepsies which generate several types of epileptic discharge to evaluate the effects of putative anticonvulsant drugs. 6. The present findings suggest that GABAB receptors play a role in the transition of benign interictal bursts to longer polyspike activity which could develop into seizures in the whole animal.

4-Aminopyridine↗
PubMed1989

A model for managing epilepsy in a rural community in Africa.

As most Malawians with epilepsy consider treatment of seizures to be the domain of traditional healers and attend hospital only when they require treatment for burns which they suffer during fits, steps were taken to encourage people with epilepsy to attend hospital for regular treatment with anticonvulsant drugs. At first only a few patients attended, but within two years 461 had registered at the hospital and two mobile clinics. Publicity was spread through the area action committee, which was organised by the area chief. The main drug used was phenobarbitone. After treatment was given for six months seizures were fully controlled in 40 (56%) out of 71 patients. A further 20 (28%) had greatly improved. As news of the clinics spread other health units adopted the model, and eventually over 3000 patients with epilepsy were receiving regular treatment at 45 units throughout Malawi.

Epilepsy↗
PubMedDate not supplied

The natural history of untreated epilepsy in a rural community in Africa.

The duration of epilepsy was evaluated in over 460 previously untreated patients who attended newly established epilepsy clinics in a rural area of Malawi. The mean duration at first attendance was 6.5 years. It was found that as the duration of active epilepsy increased, the number of patients having epilepsy of a given duration decreased. Possible explanations for this result, such as an increasing incidence of epilepsy or a high mortality rate, are considered, but thought to be unlikely. Since the distribution of patients with epilepsy of differing durations is similar to that described in a study carried out in Tonbridge, Kent, England, where the number of patients in remission was found to increase over time, it is postulated that the observed distribution also reflects remission, and that spontaneous remission of epilepsy is a frequent occurrence, independent of antiepileptic drug treatment.

Adolescent↗