Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling rem sleep: An in vitro electrophysiological study

Leonard, Christopher; Llinás, R.

doi:10.1016/0306-4522(94)90599-1

Cited by 252 publications

(173 citation statements)

References 92 publications

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“…Under voltage-clamp both transient outward (A) and inward (T) currents could be observed. As expected, carbachol strongly hyperpolarized these cells in current-clamp recordings or caused a large outward current in voltage-clamp which reversed at the potassium equilibrium potential, consistent with the activation of somatodendritic muscarinic autoreceptors (Leonard and Llinas, 1994). As shown previously for cholinergic LDT neurons (Luebke et al, 1992;Rainnie et al, 1994;Leonard and Llinas, 1994;Burlet et al, 2002), these neurons were inhibited by adenosine and serotonin and excited by orexin A.…”

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confidence: 59%

Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins

et al. 2006

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Pharmacological, lesion and single-unit recording techniques in several animal species have identified a region of the pontine reticular formation (Subcoeruleus, SubC) just ventral to the locus coeruleus as critically involved in the generation of rapid-eye-movement (REM) sleep. However, the intrinsic membrane properties and responses of SubC neurons to neurotransmitters important in REM sleep control, such as acetylcholine and orexins/hypocretins, have not previously been examined in any animal species and thus were targeted in this study.We obtained whole-cell patch-clamp recordings from visually identified SubC neurons in rat brain slices in vitro. Two groups of large neurons (mean diameter 30 and 27μm) were tentatively identified as cholinergic (rostral SubC) and noradrenergic (caudal SubC) neurons. SubC reticular neurons (noncholinergic, non-noradrenergic) showed a medium-sized depolarizing sag during hyperpolarizing current pulses and often had a rebound depolarization (low-threshold spike, LTS). During depolarizing current pulses they exhibited little adaptation and fired maximally at 30-90 Hz. Those SubC reticular neurons excited by carbachol (n=27) fired spontaneously at 6 Hz, often exhibited a moderately sized LTS, and varied widely in size (17-42 μm). Carbachol-inhibited SubC reticular neurons were medium-sized (15-25 μm) and constituted two groups. The larger group (n=22) was silent at rest and possessed a prominent LTS and associated 1-4 action potentials. The second, smaller group (n=8) had a delayed return to baseline at the offset of hyperpolarizing pulses. Orexins excited both carbachol excited and carbachol inhibited SubC reticular neurons.SubC reticular neurons had intrinsic membrane properties and responses to carbachol similar to those described for other reticular neurons but a larger number of carbachol inhibited neurons were found (> 50 %), the majority of which demonstrated a prominent LTS and may correspond to PGO-on neurons. Some or all carbachol-excited neurons are presumably REM-on neurons.Keywords rapid-eye-movement; whole-cell; in vitro; sublaterodorsal; hypocretin; narcolepsy NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAbbreviations ACSF Artificial cerebrospinal fluid; AHP Afterhyperpolarization; AP Action potential; CARB Carbachol; CARB-E Carbachol excited; CARB-I Carbachol inhibited; CCD Charge coupled device; ChAT Choline acetyltransferase; DAB Diaminobenzidine; DC Direct current; GABA Gammaamino-butyric acid; GAD67 glutamic acid decarboxylase 67 kDa isoform; HCN Hyperpolarization activated and cyclic nucleotide gated cation channels; IACUC Institutional Animal Care and Use committee; IR-DIC Infra-red differential interference contrast; LC locus coeruleus; LDT laterodorsal tegmental nucleus; LTS low-threshold spike; mPRF medial pontine reticular formation; nNOS neuronal nitric oxide synthase; Ox A Orexin A; PGO pontine-geniculate-occipital waves; PnC pontine nucleus caudalis; PnO pontine nucleus oralis; P waves Pontine component of PGO wave...

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confidence: 59%

Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins

et al. 2006

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“…In vitro (Gillet et al, 1985;Maura et al, 1989) and in vivo (Leonard and Llinas, 1994;Robinson, 1983) studies suggest that a general increase in serotonergic activity leads to an inhibition in cholinergic activity. Accordingly, it would be expected that TRP depletion would result in an increase in cholinergic activity and a subsequent improvement in object recognition (cf.…”

Section: -Ht/ach and Memorymentioning

confidence: 99%

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Lieben

Blokland

Şık

et al. 2005

Neuropsychopharmacol

134

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Antagonists at serotonin type 6 (5-HT 6 ) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT 6 antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic-(tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT 6 receptor antagonists.

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“…The functional involvement of the PMT in this cholinergicallyinduced long-term behavioral response adds a novel finding to the known behavioral and autonomic responses of this pontine region [5,26,[43][44][45]50,69,73].…”

Section: Introductionmentioning

confidence: 80%

“…Neurons within this region have been extensively studied for their executive role in sleep-wake behavioral state control [1,78] and have been shown to be a source of net excitatory drive with reciprocal connections to cholinergic cell groups of the PMT [44,80]. Our recent anatomical studies of LDT/PPT neurons during LTPE reveal the presence of cholinergic, gamma-amino-butyric acid (GABA)-ergic, and glutamatergic transmitter phenotypes [29] and reciprocity between Fos-IR projection neurons and injection sites in the caudolateral PMT [30].…”

Section: Molecular and Network Implications Of Regional C-fos Expressionmentioning

confidence: 99%

From synapse to gene product: prolonged expression of c-fos induced by a single microinjection of carbachol in the pontomesencephalic tegmentum

Quattrochi

Bazalakova

Hobson

2005

Molecular Brain Research

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It is not known how the brain modifies its regulatory systems in response to the application of a drug, especially over the long term of weeks and months. We have developed a model system approach to this question by manipulating cholinergic cell groups of the laterodorsal and pedunculopontine tegmental (LDT/PPT) nuclei in the pontomesencephalic tegmentum (PMT), which are known to be actively involved in the timing and quantity of rapid eye movement (REM) sleep. In a freely moving feline model, a single microinjection of the cholinergic agonist carbachol conjugated to a latex nanosphere delivery system into the caudolateral PMT elicits a long-term enhancement of one distinguishing phasic event of REM sleep, ponto-geniculo-occipital (PGO) waves, lasting 5 days but without any significant change in REM sleep or other behavioral state. Here, we test the hypothesis that cholinergic activation within the caudolateral PMT alters the postsynaptic excitability of the PGO network, stimulating the prolonged expression of c-fos that underlies this long-term PGO enhancement (LTPE) effect. Using quantitative Fos immunohistochemistry, we found that the number of Fos-immunoreactive (Fos-IR) neurons surrounding the caudolateral PMT injection site decreased sharply by postcarbachol day 03, while the number of Fos-IR neurons in the more rostral LDT/PPT increased >30-fold and remained at a high level following the course of LTPE. These results demonstrate a sustained c-fos expression in response to pharmacological stimulation of the brain and suggest that carbachol's acute effects induce LTPE via cholinergic receptors, with subsequent transsynaptic activation of the LDT/PPT maintaining the LTPE effect.

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Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling rem sleep: An in vitro electrophysiological study

Cited by 252 publications

References 92 publications

Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins

Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

From synapse to gene product: prolonged expression of c-fos induced by a single microinjection of carbachol in the pontomesencephalic tegmentum

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