Biomedical subjects

P B Reiner

Publications and source records attributed to P B Reiner.

At least 19 recordsLinked to original sources

PubMed1999

Vasoactive intestinal polypeptide excites medial pontine reticular formation neurons in the brainstem rapid eye movement sleep-induction zone.

Although it has long been known that microinjection of the cholinergic agonist carbachol into the medial pontine reticular formation (mPRF) induces a state that resembles rapid eye movement (REM) sleep, it is likely that other transmitters contribute to mPRF regulation of behavioral states. A key candidate is the peptide vasoactive intestinal polypeptide (VIP), which innervates the mPRF and induces REM sleep when injected into this region of the brainstem. To begin understanding the cellular mechanisms underlying this phenomenon, we examined the effects of VIP on mPRF cells using whole-cell patch-clamp recordings in the in vitro rat brainstem slice. VIP directly depolarized cells via activation of an inward current; these effects were attenuated and potentiated in low-sodium and low-calcium medium, respectively. The depolarization induced by VIP was slower in onset and longer-lived than that evoked by carbachol. The VIP-induced depolarization was reduced in a dose-dependent manner by a competitive antagonist of VIP receptors. Effects of VIP were attenuated in the presence of guanosine 5'-O-(2-thiodiphosphate, 2'5'dideoxyadenosine, and PKI15-24 and were nonadditive in the presence of 8-bromo-cAMP. We conclude that VIP excites mPRF neurons by activation of a sodium current. This effect is mediated at least in part by G-protein stimulation of adenylyl cyclase, cAMP, and protein kinase A. These data suggest that VIP may play a physiological role in REM induction by its actions on mPRF neurons.

Animals↗

PubMed1999

Dynamic properties of corticothalamic excitatory postsynaptic potentials and thalamic reticular inhibitory postsynaptic potentials in thalamocortical neurons of the guinea-pig dorsal lateral geniculate nucleus.

The properties of postsynaptic potentials evoked by stimulation of cortical, retinal and GABAergic thalamic afferents were examined in vitro in thalamocortical neurons of the guinea-pig dorsal lateral geniculate nucleus. Brief trains of stimulation (2-10 stimuli) delivered to corticothalamic fibers led to a frequency-dependent increase in excitatory postsynaptic potential amplitude associated with an increase in activation of both N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors. In addition, repetitive stimulation of corticothalamic fibers also gave rise to a slow excitatory postsynaptic potential that was blocked by local application of the glutamate metabotropic receptor antagonist alpha-methyl-4-carboxyphenylglycine. In contrast, repetitive stimulation of optic tract fibers resulted in monosynaptic excitatory postsynaptic potentials that did not potentiate and were not followed by the generation of a slow excitatory postsynaptic potential. Repetitive activation of the optic radiation also evoked both GABA(A) and GABA(B) receptor-mediated inhibitory postsynaptic potentials. These inhibitory postsynaptic potentials exhibited frequency-dependent depression during repetitive activation. The presence of frequency-dependent facilitation of corticothalamic excitatory postsynaptic potentials and frequency-dependent decrement of inhibitory postsynaptic potentials, as well as the ability of corticothalamic fibers to activate glutamate metabotropic receptors, suggests that sustained activation of corticothalamic afferents in vivo may result in postsynaptic responses in thalamocortical cells that are initially dominated by GABAergic inhibitory postsynaptic potentials followed by prominent monosynaptic excitatory postsynaptic potentials as well as a slow depolarization of the membrane potential.Therefore, the corticothalamic system may inhibit or enhance the excitability and responsiveness of thalamocortical neurons, based both on the spatial and temporal features of thalamocortical interactions.

Animals↗

PubMed1999

Noradrenaline excites non-cholinergic laterodorsal tegmental neurons via two distinct mechanisms.

Cholinergic neurons of the laterodorsal tegmental nucleus have been hypothesized to play a critical role in the-generation and maintenance of rapid eye movement sleep. Less is known about the function of non-cholinergic laterodorsal tegmental nucleus neurons. As part of our ongoing studies of the brainstem circuitry controlling behavioral state, we have begun to investigate the functional properties of these neurons. In the course of these experiments, we have observed a novel response to the neurotransmitter noradrenaline. Whole-cell patch-clamp recordings of laterodorsal tegmental nucleus neurons were carried out in 21- to 35-day-old rat brain slices. A subpopulation of laterodorsal tegmental nucleus cells responded to a 30-s application of 50 microM noradrenaline with depolarization and a decrease in input resistance which lasted several minutes. Following return to resting membrane potential, these cells invariably exhibited barrages of excitatory postsynaptic potentials which lasted at least 12 min. These excitatory postsynaptic potentials were reversibly abolished by bath application of tetrodotoxin, as well as by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, but were insensitive to application of the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid. To examine whether these neurons were cholinergic, the recorded cells were labeled with biocytin and tested for co-localization with reduced nicotinamide adenine dinucleotide phosphate-diaphorase, a marker for laterodorsal tegmental nucleus cholinergic neurons. In every instance, neurons with these properties were non-cholinergic. However, they were always located in close proximity to reduced nicotinamide adenine dinucleotide phosphate-diaphorase-positive laterodorsal tegmental nucleus cells. The present data indicate that noradrenaline, in addition to directly inhibiting cholinergic cells of the laterodorsal tegmental nucleus, also results in the direct and indirect excitation of non-cholinergic cells of the laterodorsal tegmental nucleus. The indirect excitation is long lasting and mediated by glutamatergic mechanisms. Our working hypothesis is that these non-cholinergic cells are local circuit inhibitory interneurons and that prolonged excitation of these neurons by noradrenaline may serve as a mechanism for inhibition of cholinergic laterodorsal tegmental nucleus cells during wakefulness, when noradrenaline tone is high.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1999

Regulation of amyloid precursor protein cleavage.

Multiple lines of evidence suggest that increased production and/or deposition of the beta-amyloid peptide, derived from the amyloid precursor protein, contributes to Alzheimer's disease. A growing list of neurotransmitters, growth factors, cytokines, and hormones have been shown to regulate amyloid precursor protein processing. Although traditionally thought to be mediated by activation of protein kinase C, recent data have implicated other signaling mechanisms in the regulation of this process. Moreover, novel mechanisms of regulation involving cholesterol-, apolipoprotein E-, and stress-activated pathways have been identified. As the phenotypic changes associated with Alzheimer's disease encompass many of these signaling systems, it is relevant to determine how altered cell signaling may be contributing to increasing brain amyloid burden. We review the myriad ways in which first messengers regulate amyloid precursor protein catabolism as well as the signal transduction cascades that give rise to these effects.

Alzheimer Disease↗

PubMed1999

Novel effects of FCCP [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone] on amyloid precursor protein processing.

Amyloidogenic processing of the beta-amyloid precursor protein (APP) has been implicated in the pathology of Alzheimer's disease. Because it has been suggested that catabolic processing of the APP holoprotein occurs in acidic intracellular compartments, we studied the effects of the protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) and the H+-ATPase inhibitor bafilomycin A1 on APP catabolism in human embryonic kidney 293 cells expressing either wild-type or "Swedish" mutant APP. Unlike bafilomycin A1, which inhibits beta-amyloid production in cells expressing mutant but not wild-type APP, FCCP inhibited beta-amyloid production in both cell types. Moreover, the effects of FCCP were independent of alterations in total cellular APP levels or APP maturation, and the concentrations used did not alter either cellular ATP levels or cell viability. Bafilomycin A1, which had no effect on beta-amyloid production in wild-type cells, inhibited endocytosis of fluorescent transferrin, whereas concentrations of FCCP that inhibited beta-amyloid production in these cells had no effect on endosomal function. Thus, in wild-type-expressing cells it appears that the beta-amyloid peptide is not produced in the classically defined endosome. Although bafilomycin A1 decreased beta-amyloid release from cells expressing mutant APP but not wild-type APP, it altered lysosomal function in both cell types, suggesting that in normal cells beta-amyloid is not produced in the lysosome. Although inhibition of beta-amyloid production by bafilomycin A1 in mutant cells may occur via changes in endosomal/lysosomal pH, our data suggest that FCCP inhibits wild-type beta-amyloid production by acting on a bafilomycin A1-insensitive acidic compartment that is distinct from either the endosome or the lysosome.

Adenosine Triphosphate↗

PubMed1998

Monitoring neuronal NO release in vivo in cerebellum, thalamus and hippocampus.

A variety of methods has been developed based on in vivo microdialysis which allow one to examine the NO/cGMP signal transduction system in action in behaving animals. The extracellular levels of cGMP, the NO oxidative products nitrate and nitrite, and NO itself can all be determined. Using these methods changes in NO and cGMP production in response to pharmacological manipulations can be examined in vivo. In addition, it has been discovered that the activity of this system varies with the behavioral state of the animal. NO and cGMP appear to act via distinct downstream effectors in different brain regions. This opens up the possibility of selectively manipulating NO and cGMP signaling in discrete neuronal populations.

Animals↗

PubMed1998

Nitric oxide regulates cyclic GMP-dependent protein kinase phosphorylation in rat brain.

Nitric oxide (NO) acts via soluble guanylyl cyclase to increase cyclic GMP (cGMP), which can regulate various targets including protein kinases. Western blotting showed that type II cGMP-dependent protein kinase (cGK II) is widely expressed in various brain regions, especially in the thalamus. In thalamic extracts, the phosphorylation of several proteins, including cGK II, was increased by exogenous NO or cGMP. In vivo pretreatment with a NO synthase inhibitor reduced the phosphorylation of cGK II, and this could be reversed by exogenous NO or cGMP. Conversely, brainstem electrical stimulation, which enhances thalamic NO release, caused a NO synthase-dependent increase in the phosphorylation of thalamic cGK II. These results indicate that endogenous NO regulates cGMP-dependent protein phosphorylation in the thalamus. The activation of cGKII by NO may play a role in thalamic mechanisms underlying arousal.

Animals↗

PubMed1997

Regulation of amyloid precursor protein catabolism involves the mitogen-activated protein kinase signal transduction pathway.

Catabolic processing of the amyloid precursor protein (APP) is subject to regulatory control by protein kinases. We hypothesized that this regulation involves sequential activation of the enzymes mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated protein kinase (ERK). In the present investigation, we provide evidence that MEK is critically involved in regulating APP processing by both nerve growth factor and phorbol esters. Western blot analysis of the soluble N-terminal APP derivative APPs demonstrated that the synthetic MEK inhibitor PD 98059 antagonized nerve growth factor stimulation of both APPs production and ERK activation in PC12 cells. Moreover, PD 98059 inhibited phorbol ester stimulation of APPs production and activation of ERK in both human embryonic kidney cells and cortical neurons. Furthermore, overexpression of a kinase-inactive MEK mutant inhibited phorbol ester stimulation of APP secretion and activation of ERK in human embryonic kidney cell lines. Most important, PD 98059 antagonized phorbol ester-mediated inhibition of Abeta secretion from cells overexpressing human APP695 carrying the "Swedish mutation." Taken together, these data indicate that MEK and ERK may be critically involved in protein kinase C and nerve growth factor regulation of APP processing. The mitogen-activated protein kinase cascade may provide a novel target for altering catabolic processing of APP.

Alzheimer Disease↗

PubMed1997

Nitric oxide production in rat thalamus changes with behavioral state, local depolarization, and brainstem stimulation.

Since its discovery as a putative neurotransmitter in the CNS, several functional roles have been suggested for nitric oxide (NO). However, few studies have investigated the role of NO in natural physiology. Because NO synthase (NOS) has been localized in regions believed to be important for attention and arousal, we hypothesized that NO production would be state-dependent. To test this hypothesis, we used in vivo microdialysis, coupled with the hemoglobin-trapping technique, to monitor extracellular NO concentrations in rat thalamus during wake, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. The thalamus is known to receive a massive innervation from the NOS/cholinergic neurons in the mesopontine brainstem, which have been suggested to play a key role in EEG desynchronized states. To test whether thalamic NO output was sensitive to neuronal-dependent changes in the mesopontine brainstem, we measured thalamic NO concentration in response to electrical stimulation in the laterodorsal tegmentum (LDT) of anesthetized rats. Finally, the calcium dependence of NO release was tested by local depolarization with a high potassium dialysate or by addition of a calcium chelator. The results showed that (1) extracellular NO concentrations in the thalamus were high during wake and REM sleep and significantly lower during SWS, (2) thalamic NO release increased in response to LDT stimulation in both a site-specific and tetrodotoxin (TTX)-dependent manner, and (3) NO production was calcium-dependent. These data suggest that thalamic NO production may play a role in arousal.

Animals↗

PubMed1996

Phorbol esters but not the cholinergic agonists oxotremorine-M and carbachol increase release of the amyloid precursor protein in cultured rat cortical neurons.

Conventional secretory processing of the amyloid precursor protein is nonamyloidogenic, releasing carboxyl-terminus-truncated amyloid precursor protein derivatives while cleaving the amyloid beta-peptide within its sequence. Alternative processing routes are potentially amyloidogenic, yielding the amyloid beta-peptide segment intact. In continuous cell lines, secretory processing of the amyloid precursor protein is regulated by both protein kinase C and muscarinic receptor stimulation. However, the first and second messenger systems that regulate amyloid precursor protein release in central neurons are still under investigation. In the present investigation, we examined whether or not first and second messengers of cholinergic neurotransmission increase production of soluble derivatives of the amyloid precursor protein in primary cultures of rat cortical neurons. Activation of protein kinase C by the phorbol esters phorbol 12,13-dibutyrate and phorbol 12-myristate 13-acetate increased production of the soluble form of the amyloid precursor protein dramatically. In contrast, activation of muscarinic receptors by oxotremorine-M or carbachol did not result in a significant increase in amyloid precursor protein release. Similarly, chemically induced depolarization using 35 mM KCl did not alter production of soluble amyloid precursor protein derivatives. Our data suggest that although protein kinase C stimulation plays an important role in regulating release of the amyloid precursor protein, cholinergic neurotransmission does not regulate its release in cultured rat cortical neurons.

Amyloid beta-Protein Precursor↗

PubMed1996

Role of the afterhyperpolarization in control of discharge properties of septal cholinergic neurons in vitro.

1. The properties of the cholinergic neurons of the rat medial septum and nucleus of the diagonal band of Broca (MS/DBB) were studied using whole cell patch-clamp recordings in an in vitro slice preparation. 2. Both the transmitter phenotype and the intrinsic membrane properties of 56 MS/DBB neurons were determined post hoc by visualizing intracellularly deposited biocytin with fluorescent avidin and endogenous choline acetyltransferase with immunofluorescence. Twenty seven of 28 MS/DBB neurons exhibiting both a prominent slow afterhyperpolarization (sAHP) following a single action potential and anomalous rectification were identified as cholinergic. The remaining 28 neurons exhibited other intrinsic membrane properties and none were choline acetyltransferase immunoreactive. 3. The sAHP in MS/DBB cholinergic neurons was blocked reversibly either by reducing extracellular calcium or addition of 100 microM cadmium and irreversibly blocked by 30 nM apamin, suggesting that the sAHP is produced by an apamin-sensitive calcium-activated potassium conductance. 4. MS/DBB cholinergic neurons also exhibited a postspike depolarizing afterpotential (DAP) preceeding the sAHP. Both the DAP and the sAHP were blocked when extracellular calcium was lowered as well as in the presence of 10-50 microM NiCl2. Application of 500 nM omega-conotoxin also reduced the sAHP, while leaving the DAP intact. These data suggest that both transient and high-threshold calcium conductances contribute to generation of the sAHP. 5. When depolarized, cholinergic neurons fired slowly (2-4 Hz) and regularly with little evidence of spike frequency adaptation. When the sAHP was blocked with apamin, the instantaneous frequency of firing increased and the neuron now exhibited prominent spike frequency adaptation. 6. Serotonin (5-HT) reversibly suppressed the sAHP in MS/DBB cholinergic neurons and altered the firing pattern from slow regular discharge to one which exhibited modest spike frequency adaptation. 7. It was concluded that the sAHP limits the firing rate of MS/DBB cholinergic neurons and that physiologically relevant supression of the sAHP by 5-HT may result in state-dependent changes in the discharge pattern of MS/DBB cholinergic neurons.

Acetylcholine↗

PubMed1996

Histamine depolarizes cholinergic septal neurons.

1. Bath application of 10 microM histamine (HA) resulted in a depolarization or inward current in 58/59 cholinergic neurons located in the medial septum and nucleus of the diagonal band of Broca (MS/DBB) in a slice preparation of rat brain. 2. In bridge mode, the histamine-induced depolarization consisted of both fast and slow phases; inward currents that followed the comparable time course were observed under voltage-clamp conditions. The fast depolarization was associated with variable changes in input resistance, while the slow depolarization always was associated with an increase in input resistance. 3. Both fast and slow responses persisted in the presence of tetrodotoxin (TTX), but only the fast response persisted when transmitter release was abolished by bathing the slice in either a low-Ca(2+)-, high-Mg(2+)-containing medium or one containing Cd2+. 4. When ramp voltage-clamp commands were applied during the fast depolarization, the resultant current-voltage (I-V) curves did not intersect over the range of membrane potentials from -130 to -30 mV. Ionic substitution experiments suggested that the bulk of the ionic current flowing during the fast depolarization was carried by sodium ions. 5. The I-V characteristics of the slow inward current identified it as a reduction in an inwardly rectifying potassium conductance. 6. The fast depolarization was significantly reduced by the H1 receptor antagonists pyrilamine and promethazine, but not by the H2 receptor antagonist cimetidine. Neither the H2 receptor agonist impromidine nor the H3 receptor agonist R-alpha-methylhistamine mimicked the response to HA. None of the agonists or antagonists had any observable effect upon the slow depolarization. 7. We conclude that HA directly depolarizes cholinergic MS/DBB neurons by acting as an H1 receptor, which primarily couples to an increase in a TTX-insensitive Na+ conductance. Additionally, HA evokes a slow depolarization mediated by a decrease in an inwardly rectifying potassium conductance but is not generated by activation of classically defined HA receptor subtypes.

Acetylcholine↗

PubMed1994

Isoflurane inhibits calcium currents in neocortical neurons.

We used voltage-clamp techniques to assess the effects of isoflurane anaesthesia in slices of sensorimotor cortex of guinea pigs and neonatal rats. Isoflurane (0.5-4%) depressed inward Ca(2+)-currents evoked by depolarizing commands from -50 mV. With additional blockade of K(+)-currents by internal Cs+, an early component of the sustained inward currents was a high voltage-activated current whereas the delayed component was an unclamped Ca(2+)-current; this was consistent with a simple compartmental model. Isoflurane decreased the magnitude of the high voltage-activated current.

Animals↗

PubMed1994

Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current.

Antihistamines, more formally termed H1 receptor antagonists, are well known to exert sedative effects in humans, yet their locus and mechanism of action in the human brain remains unknown. To better understand this phenomenon, the effects of histamine upon human cortical neurons were studied using intracellular recordings in brain slices maintained in vitro. Bath application of 50 microM histamine induced a depolarization which could be attributed to reduction of a background voltage-independent "leakage" potassium current: the depolarization was associated with an increase in apparent input resistance, under voltage clamp its reversal potential approximated the potassium reversal potential, and the histamine-induced current exhibited little voltage dependence. The pharmacology of the histamine-induced depolarization of human cortical neurons was studied by use of both agonists and antagonists. Depolarizing responses were blocked by the H1 antagonist mepyramine, but not by the H2 antagonist cimetidine nor the H3 antagonist thioperamide. The H3 receptor agonist R-alpha-methyl-histamine did not mimic the effects of histamine. Thus, histamine depolarizes human cortical neurons via action at an H1 receptor. These effects of neuronal histamine upon cortical neurons are likely to affect synaptic transmission in several ways. The depolarization per se should increase the likelihood that excitatory synaptic potentials will evoke an action potential. The increase in whole-cell input resistance evoked by H1 receptor activation should make the cell more electrotonically compact, thereby altering its integrative properties. We hypothesize that these mechanisms would allow histamine, acting at cortical H1 receptors, to enhance behavioral arousal. During waking when histamine release is highest, blockade of H1 receptors by systemically administered H1 receptor antagonists would be sedating.

Cerebral Cortex↗

PubMed1994

State-dependent release of acetylcholine in rat thalamus measured by in vivo microdialysis.

Mesopontine cholinergic neurons have long been thought to play a key role in behavioral state control. In particular, they have been implicated in the process of EEG desynchrony and in the generation of rapid eye movement (REM) sleep. However, the behavioral profile of identified mesopontine cholinergic neurons has not been unequivocally demonstrated. In an attempt to address this issue, in vivo microdialysis was used to monitor acetylcholine (ACh) release across behavioral state in the rat thalamus, a major projection site of mesopontine cholinergic neurons. Because REM periods in rats are of short duration, a method was developed to collect and accumulate sufficiently large samples from each of the individual states of wake, slow-wave sleep, and REM sleep to permit off-line analysis via (HPLC-ECD). Probe placement and the source of cholinergic innervation to the vicinity of the microdialysis probe were verified using retrograde tracing combined with ChAT immunohistochemistry. Finally, the sodium and calcium dependence of ACh measured in the thalamus were tested using TTX and calcium-free dialysates. The results showed that (1) extracellular ACh concentrations in the thalamus are high during both wake and REM sleep and significantly lower during slow-wave sleep, (2) the majority of cholinergic projections to the vicinity of the dialysis probes originate in the mesopontine tegmentum, and (3) ACh release in the thalamus is due to sodium- and calcium-dependent mechanisms. In contrast to predictions of some previous hypotheses, these results demonstrate that mesopontine cholinergic neurons are active during both wake and REM sleep.

Acetylcholine↗

PubMed1993

Reduced ionic conductance in turtle brain.

Whole cell recording techniques were employed to measure whole cell (Gw) and specific membrane (Gm) conductance in turtle and rat pyramidal neurons in slices. Results indicate that rat neurons are 4.2 times more conductive compared with turtle neurons at 25 degrees C, which is accentuated by temperature, so that rat neurons at 37 degrees C are 22 times more conductive than turtle neurons at 15 degrees C. A conductance Q10 of 1.9 was measured for both turtle (15-25 degrees C) and rat (25-35 degrees C) pyramidal neurons. Conductance measurements of turtle pyramidal neurons over 6-9 h of anoxia indicate no statistical difference between Gm or Gw from normoxic control measures. These results indirectly support the concept of low ATP-dependent ion pump activity in the turtle brain as one mechanism for reduced energy expenditure in the normoxic state.

Animals↗

PubMed1993

Noradrenaline hyperpolarizes identified rat mesopontine cholinergic neurons in vitro.

Inhibition of brainstem cholinergic neurons by noradrenergic neurons of the locus ceruleus has long been suggested as a key mechanism of behavioral state control. In particular, the commonly held view is that noradrenaline (NA) plays a permissive role in rapid eye movement (REM) sleep generation by disinhibiting brainstem cholinergic neurons. While this notion has been supported by numerous investigations, the inhibition of cholinergic neurons by NA has never been directly demonstrated. The purpose of this study was to investigate the effects of NA upon identified cholinergic neurons in the rat mesopontine tegmentum. Using whole-cell patch-clamp recordings in slices, 175 cells were studied during bath application of 50 microM NA. Cholinergic neurons were positively identified by intracellular labeling with biocytin and subsequent staining with NADPH-diaphorase, a reliable marker for brainstem cholinergic neurons (Vincent et al., 1983). Successful intracellular labeling was obtained in 96 cells. Ninety-two percent (36 of 39) of cholinergic neurons hyperpolarized in response to NA, while noncholinergic cells (n = 57) exhibited mixed responses. Application of NA in a low-Ca2+, high-Mg2+ solution elicited the same hyperpolarizing effect as in normal solution, which indicated that the effect of NA on cholinergic neurons was direct. The noradrenergic hyperpolarization was mimicked by the alpha 2-adrenoceptor agonist UK-14,304, and was blocked by the alpha 2-adrenoceptor antagonist idazoxan, which suggested an alpha 2-mediated response. Finally, voltage-clamp experiments revealed that NA activates the inwardly rectifying potassium current, IKG.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Serotonin hyperpolarizes cholinergic low-threshold burst neurons in the rat laterodorsal tegmental nucleus in vitro.

Serotonergic suppression of cholinergic neuronal activity implicated in the regulation of rapid eye movement sleep and its associated phenomenon, pontogeniculooccipital waves, has long been postulated, but no direct proof has been available. In this study, intracellular and whole-cell patch-clamp recording techniques were combined with enzyme histochemistry to examine the intrinsic electrophysiological properties and response to serotonin (5-HT) of identified cholinergic rat laterodorsal tegmental nucleus neurons in vitro. Sixty-five percent of the recorded neurons demonstrated a prominent low-threshold burst, and of these, 83% were cholinergic. In current-clamp recordings 64% of the bursting cholinergic neurons tested responded to the application of 5-HT with a membrane hyperpolarization and decrease in input resistance. This effect was mimicked by application of the selective 5-HT type 1 receptor agonist carboxamidotryptamine maleate. Whole-cell patch-clamp recordings revealed that the hyperpolarizing response was mediated by an inwardly rectifying K+ current. Application of 5-HT decreased excitability and markedly modulated the discharge pattern of cholinergic bursting neurons: during a 5-HT-induced hyperpolarization these neurons exhibited no rebound burst after hyperpolarizing current input and a burst in response to depolarizing current input. In the absence of 5-HT, the relatively depolarized cholinergic bursting neurons responded to an identical hyperpolarizing current input with a burst and did not produce a burst after depolarizing current input. These data provide a cellular and molecular basis for the hypothesis that 5-HT modulates rapid eye movement sleep phenomenology by altering the firing pattern of bursting cholinergic neurons.

Action Potentials↗