Conduction velocities and membrane properties of different classes of rat septohippocampal neurons recorded in vitro.

1. The membrane properties and conduction velocities of antidromically activated medial septum-diagonal band (MS-DB) neurons were examined using whole-cell recordings in a longitudinally cut rat brain slice preparation containing the MS-DB and the dorsal fornix. 2. MS-DB neurons were divided into three groups according to their action potential characteristics and firing properties. Slow firing neurons displayed a broad action potential followed by a prominent after-hyperpolarization. Burst firing neurons, when depolarized from hyperpolarized holding potentials, exhibited a high-frequency burst of spikes on the crest of a slow depolarizing potential. Fast firing neurons did not fire bursts of spikes when depolarized from hyperpolarized holding potentials. 3. Eighteen MS-DB neurons were identified as septohippocampal by antidromic activation. Of the septohippocampal neurons, four were slow firing neurons, five were burst firing neurons and nine were fast firing neurons. The mean axon conduction velocities of these neurons fell into two significant groups, termed slow conducting and fast conducting. Slow firing septohippocampal neurons had significantly slower conduction velocities than either fast firing or burst firing neurons (P < 0.05), being 0.7 +/- 0.5 ms-1 for slow firing neurons and 2.9 +/- 2.0 and 2.0 +/- 1.4 ms-1 for burst firing and fast firing neurons, respectively. 4. On the basis of previous evidence which has linked firing properties with the neurochemical identities of the neurons, we propose that the slow firing septohippocampal neurons are cholinergic whereas the burst firing and fast firing septohippocampal neurons are GABAergic.

Electrophysiological effects of the anticonvulsant remacemide hydrochloride and its metabolite ARL 12495AA on rat CA1 hippocampal neurons in vitro.

The electrophysiological actions of the putative anticonvulsants remacemide hydrochloride and its des-glycine metabolite ARL 12495AA were examined using whole-cell recordings from CA1 hippocampal neurons in adult rat brain in vitro. Remacemide hydrochloride (4-400 microM) and ARL 12495AA (4-400 microM) limited sustained high frequency repetitive firing (SRF) induced by application of long duration depolarizing current pulses (20-400 pA, 500 msec). This SRF limitation was concentration-dependent, and equipotent IC50 values of 66 and 60 microM were calculated for remacemide hydrochloride and ARL 12495AA, respectively. Examination of the spike configuration revealed that, over the same concentration range, each compound caused a concentration-related reduction of: (a) the action potential amplitude; and (b) the rate-of-rise. Remacemide hydrochloride or ARL 12495AA increased spike duration and decreased or eliminated the spike after-hyperpolarization. Possible mechanisms for these electrophysiological actions including modulation of sodium and/or potassium channel activity are considered. It is suggested that such multiple mechanisms, including inhibition of SRF may be relevant to the anticonvulsant properties of remacemide hydrochloride and its metabolite, ARL 12495AA. The activity of both compounds as modulators of neuronal excitability indicates that metabolic conversion of remacemide hydrochloride to ARL 12495AA could enhance the therapeutic efficacy of the former.

The stereo-isomers of the anticonvulsant ARL 12495AA limit sustained repetitive firing and modify action potential properties of rat hippocampal neurons in vitro.

The effects of the resolved enantiomers of the anticonvulsant ARL 12495AA ((S,R)-1-methyl-1,2-diphenylethylamine-monohydrochloride), (S)-ARL 12495 and (R)-ARL 12495, on (1) sustained repetitive firing and (2) action potential properties of rat hippocampal neurons were assessed. Whole-cell current-clamp recordings were made from CA1 neurons in slices of adult rat brain. Sustained repetitive firing was evoked by injection of long duration (500 msec) depolarizing (20-400 pA) current pulses. Sustained repetitive firing was inhibited by (S)-ARL 12495 and by (R)-ARL 12495; the threshold concentration was 5 microM reaching a near maximum at 400 microM. Comparing the potencies of the two isomers, IC50 values of 55 and 39 microM were calculated for (S)-ARL 12495 and (R)-ARL 12495, respectively. The actions of the two drugs on neuronal firing were not therefore markedly stereoselective. Examination of individual spike properties revealed a concentration-related (12-400 microM) and time-dependent increase in the spike duration by (S)-ARL 12495 and (R)-ARL 12495. The spike amplitude and rate-of-rise were attenuated significantly by these two drugs. Both isomers decreased the after-hyperpolarization after a single spike and after trains of spikes. No clear stereoselectivity was demonstrable for the effects of the two enantiomers on action potential properties. Possible mechanisms of action for (S)-ARL 12495 and (R)-ARL 12495 including partial blockade of voltage-sensitive sodium channels and modulation of potassium channels are considered. The possibility that multiple mechanisms of action contribute to the therapeutic efficacy of the anticonvulsant ARL 12495AA is discussed.

Agonists selective for tachykinin NK1 and NK3 receptors excite subpopulations of neurons in the rat medial habenula nucleus in vitro.

The purpose of the present study was to determine the tachykinin receptor types present on neurones of the rat medial habenula nucleus. Extracellular recordings were made from spontaneously active medial habenula neurones in tissue slices of rat brain. The tachykinin analogues [Sar9,Met(O2)11]substance P, [beta-Ala8]neurokinin A-(4-10) and senktide were chosen for their potency and selectivity at NK1, NK2 and NK3 receptors, respectively. No neurone was observed to respond to [beta-Ala8]neurokinin A-(4-10). Neurones did respond to [Sar9,Met(O2)11]substance P and to senktide with a rapid and concentration-dependent increase in firing rate. Of the neurones where recordings were made, responses were obtained to one, both or neither of the agonists. These data suggest that receptors similar to NK1 and NK3, but not NK2 receptors, are differentially expressed on subpopulations of neurones of this nucleus.

Posterior pituitary lobectomy chronically attenuates the nocturnal surge of prolactin in early pregnancy.

The posterior pituitary gland contains a potent PRL-releasing factor (PRF). The aim of this study was to determine whether this PRF was involved in the luteotropic PRL surges of early pregnancy. The posterior pituitary was removed from a group of rats at least 4 weeks before the experiment (LOBEX). LOBEX rats were tested for diabetes insipidus and checked postmortem for the absence of posterior lobes. Plasma samples were taken from these chronically LOBEX rats as well as from sham-operated and unoperated controls beginning at noon on day 3 of pregnancy and continuing for 3 days at times most likely to demonstrate the twice daily surges of PRL secretion. PRL in all groups was basal (less than 12 ng/ml) at noon and rose to a diurnal peak at 1800 h. While the unoperated and sham-operated controls then displayed a clear nocturnal surge of PRL, peaking at 300-400 ng/ml at 0300 h, LOBEX rats had a significantly attenuated peak of 102.7 +/- 17.7 ng/ml (P less than 0.001). On subsequent nights the nocturnal peaks were similarly attenuated in LOBEX rats, averaging 80.3 and 42.1 ng/ml on days 5 and 6, respectively. LOBEX rats all had normal sized litters, but lactation yields were depressed. These data support the hypothesis that the posterior pituitary secretes a potent PRL-releasing factor because its removal partially blocked the mating-induced nocturnal surge of PRL.