Activation of the GABAA Receptor Inhibits the Proliferative Effects of bFGF in Cortical Progenitor Cells

Recent studies have localized γ-aminobutyric acid (GABA)-containing neurons and identified cells that express subunits of the GABA_A receptor in the proliferative zone of the developing cerebral cortex and have demonstrated a role for GABA in cortical neurogenesis. We examined here the interactions between a number of neurotrophic factors, known to be involved in cortical cell proliferation and differentiation, and the GABAergic system (GABA and GABA_A receptors) in the regulation of cell production in dissociated cortical cell cultures. We found that basic fibroblast growth factor (bFGF) increased the number of cells labelled for the α₁ subunit of the GABA_A receptor but not for the α₂, α₃ or α₅ subunits. The α₁ subunit was expressed by the majority of proliferating neuroepithelial cells as well as by differentiated neurons. We also found that activation of the GABA_A receptor by GABA or muscimol inhibited the proliferative effects of bFGF on cortical progenitors, leading to an increased number of differentiated neurons. These results suggest that bFGF stimulates cell proliferation and GABA_A receptor expression in cultured progenitor cells of the developing neocortex, and that GABA regulates cell production by providing a feedback signal that terminates cell division.     

Functional Heterogeneity of Hippocampal GABAA Receptors

γ-Aminobutyric acid type A (GABA_A) receptors were studied in cultured neurons taken from rat hippocampus at early postnatal stages. GABA-induced whole-cell currents showed a broad range of peak amplitudes and time-courses of desensitization. Dose – response curves of rapidly and slowly desensitizing cells revealed EC₅₀ values of 8.5 and 37.3 μM GABA, respectively, with the Hill coefficient being greater than unity. The main-state conductance of GABA_A receptor channels was 28 – 31 pS in all cells. GABA responses of low-affinity cells were more strongly affected by benzodiazepine receptor agonists (e.g. flunitrazepam, clonazepam) and inverse agonists (e.g. methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate), as compared to cells exhibiting high-affinity GABA responses. Currents were also potentiated by zolpidem, but were little affected by Ro 15-4513 and Zn²⁺. These data suggest the presence of physiologically and pharmacologically distinct GABA_A receptor isoforms in neurons of the early postnatal hippocampus, which may subserve different inhibitory control mechanisms in this brain region.     

GABA receptor proteins within lipid rafts in the AY-9944 model of atypical absence seizures

Purpose:   The inhibition of cholesterol synthesis with AY-9944 (AY) results in chronic recurrent atypical absence seizures in rodents. We hypothesized that cholesterol inhibition during the course of creating the AY model of atypical absence seizures results in an alteration of the entry of γ-aminobutyric acid (GABA)_A and GABA_B receptors into lipid rafts that contributes to epileptogenesis in this model.
Methods:   The cholesterol synthesis inhibitor AY (7.5 mg/kg) was administered on postnatal day (P) 2, P8, P14, and P20 in Long-Evans hooded rats. The incorporation of GABA_A and GABA_B receptor proteins into lipid rafts of the brain was then determined.
Results:   AY produced a shift of both GABA_A and GABA_B receptors in the examined detergent-resistant membranes (DRMs) and the soluble fractions. The percentage of the GABA_A and GABA_B receptors that shifted out of the DRMs varied between 17% and 50%, but the proportion of receptors in DRMs were decreased to levels around that of P5 animals or even lower. The shift observed in the AY-treated versus control animals was statistically significant (p < 0.01) for both GABA_A and GABA_B receptors.
Conclusion:   Cholesterol synthesis inhibition during rat brain development that is induced by AY leads to chronic atypical absence seizures and is associated with an alteration of GABA_A and GABA_B receptor proteins within lipid rafts. These data suggest a novel avenue of investigation into the epileptogenesis of experimental chronic atypical absence seizures.     

GABAA Receptor Internalization during Seizures

Summary:  A rapid modification in the postsynaptic γ-aminobutyric acid (GABA_A) receptor population occurs during the prolonged seizures of status epilepticus (SE). This rapid modification contributes to a reduction in GABA-mediated inhibition and the development of benzodiazepine pharmacoresistance. Previous hypotheses to explain the modification have included an alteration in the structural composition or posttranslational modification of the receptors. In a cultured hippocampal neuron model, we found that there was differential subcellular distribution of GABA_A receptor subunits and that the constitutive internalization of GABA_A receptors containing a β2/3 subunit was rapid and activity-dependent. Based on this finding, we posit that an activity-dependent increase in the rate of internalization of synaptic GABA_A receptors during SE contributes to the reduction in inhibitory transmission and the development of benzodiazepine pharmacoresistance.     

Regulation of cardiac sympathetic afferent reflex by GABA(A) and GABA(B) receptors in paraventricular nucleus in rats

The aim of the present study was to determine the role of GABA_A and GABA_B receptors in paraventricular nucleus (PVN) in regulating cardiac sympathetic afferent reflex (CSAR). Under urethane (800 mg/kg) and α-chloralose (40 mg/kg) anesthesia, renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were recorded in sinoaortic-denervated and cervical-vagotomized rats. CSAR was evaluated based in the response of RSNA to epicardial application of capsaicin (0.3 nmol) or bradykinin (1 nmol). Bilateral PVN microinjection of the GABA_A receptor agonist isoguvacine (10 nmol) attenuated CSAR, while the GABA_B receptor agonist baclofen (1 nmol) abolished CSAR. Both isoguvacine and baclofen greatly decreased baseline RSNA and MAP. The GABA_A receptor antagonist gabazine (0.1 nmol) had no significant effect on CSAR, but the GABA_B receptor antagonist CGP-35348 (10 nmol) enhanced CSAR. Gabazine caused greater increases in baseline RSNA and MAP than CGP-35348. Vigabatrin (10 nmol), a selective GABA-transaminase inhibitor which increases endogenous GABA level, abolished CSAR, and decreased baseline RSNA, MAP and HR. The effects of vigabatrin were antagonized by combined gabazine (0.1 nmol) and CGP-35348 (10 nmol). The results indicate that activation of either GABA_A or GABA_B receptors in the PVN inhibits CSAR, while blockage of GABA_B receptors in the PVN enhances CSAR. Endogenous GABA in the PVN could have an important role in regulating CSAR.     

Glycine- and GABA-activated Currents in Identified Glial Cells of the Developing Rat Spinal Cord Slice

In the neonatal rat spinal cord, four types of glial cells, namely astrocytes, oligodendrocytes and two types of precursor cells, can be distinguished based on their membrane current patterns and distinct morphological features. In the present study, we demonstrate that these cells respond to the inhibitory neurotransmitters glycine and GABA, as revealed with the whole-cell recording configuration of the patch-clamp technique. All astrocytes and glial precursor cells and a subpopulation of oligodendrocytes responded to glycine. The involvement of glycine receptors was inferred from the observation that the response was blocked by strychnine and that the induced current reversed close to the Cl^- equilibrium potential. GABA induced large membrane currents in astrocytes and precursor cells while oligodendrocytes showed only small responses. The GABA-activated current was due to the activation of GABA_A receptors since muscimol mimicked and bicuculline blocked the response; moreover, the reversal potential was close to the Cl^- equilibrium potential. Besides the increase in a Cl^- conductance, GABA^A receptor activation also induced a block of the resting K⁺ conductance, as observed previously in Bergmann glial cells. Our experiments show that while glial GABA_A receptors are found in many brain regions and the spinal cord, glial glycine receptors have so far been detected only in the spinal cord. The restricted coexpression of glial and neuronal glycine receptors in a defined central nervous system grey matter area implies that such glial receptors may be involved in synaptic transmission.     

Hippocampal Neurons Express GABAA Receptor Insensitive to Diazepam in Hyperexcitable Conditions

Summary: Purpose : To define the properties of γ-aminobutyric acid-type A (GABA_A) receptors expressed on dentate granule cells in neonatal rats and to define the impact of prolonged seizures on GABA_A receptors in 28- to 35-day-old rats.
Methods : Whole GABA_A receptor currents were recorded from acutely isolated dentate granule cells. Cells were isolated from 7- to 14-day-old rats for the first experiment. For the second experiment, cells were isolated from 28- to 35-day-old naive rats and rats that had undergone 45 minutes of status epilepticus. Modulation of GABA_A receptor currents by diazepam (DZP), zinc, and zolpidem was studied.
Results : In 7- to 14-day-old rats, dentate granule cells express DZP- and zolpidem-insensitive, zinc-sensitive GABA_A receptors. In 28- to 35-day-old rats, dentate granule cells express DZP-sensitive GABA_A receptors. At the latter age, prolonged seizures render GABA_A receptors DZP-insensitive.
Conclusion : Hippocampal dentate granule cells express DZP-insensitive receptors in hyperexcitable states. These receptors are likely to contain α4 subunit.     

Multiple functions of GABA A and GABA B receptors during pattern processing in the zebrafish olfactory bulb

γ-Aminobutyric acid (GABA)ergic synapses are thought to play pivotal roles in the processing of activity patterns in the olfactory bulb (OB), but their functions have been difficult to study during odor responses in the intact system. We pharmacologically manipulated GABA_A and GABA_B receptors in the OB of zebrafish and analysed the effects on odor responses of the output neurons, the mitral cells (MCs), by electrophysiological recordings and temporally deconvolved two-photon Ca²⁺ imaging. The blockade of GABA_B receptors enhanced presynaptic Ca²⁺ influx into afferent axon terminals, and changed the amplitude and time course of a subset of MC responses, indicating that GABA_B receptors have a modulatory influence on OB output activity. The blockade of GABA_A receptors induced epileptiform firing, enhanced excitatory responses and abolished fast oscillations in the local field potential. Moreover, the topological reorganization and decorrelation of MC activity patterns during the initial phase of the response was perturbed. These results indicate that GABA_A receptor-containing circuits participate in the balance of excitation and inhibition, the regulation of total OB output activity, the synchronization of odor-dependent neuronal ensembles, and the reorganization of odor-encoding activity patterns. GABA_A and GABA_B receptors are therefore differentially involved in multiple functions of neuronal circuits in the OB.     

Inhibition of the bradycardic component of the von Bezold–Jarisch reflex and carotid chemoreceptor reflex by periaqueductal gray stimulation: involvement of medullary receptors

Stimulation of the dorsolateral periaqueductal gray matter (dlPAG) and the B3 cell group inhibits the cardiovagal component of the baroreflex in rats. Our aim was to determine whether the defence reaction induces similar modulatory effects on the cardiac response of the von Bezold–Jarisch reflex and the carotid chemoreceptor reflex. We examined the effects of dlPAG stimulation on the reflex bradycardia triggered by systemic administration of phenylbiguanide or potassium cyanide. Electrical and chemical stimulation of the dlPAG produced marked inhibition of the cardiovagal components of the von Bezold–Jarisch and the carotid chemoreceptor reflexes. In addition, as 5-HT₃, NK₁ and GABA_A receptor activation blocks cardiac reflex responses, we studied whether these receptors were involved in the dlPAG-induced inhibitory effects. We found that, after microinjection of granisetron (a 5-HT₃ receptor antagonist), bicuculline (a GABA_A receptor antagonist) and GR-205171 (an NK₁ receptor antagonist) into the nucleus of the solitary tract (NTS), reflex bradycardic responses were preserved during dlPAG stimulation. Finally, activation of the B3 region also inhibited both reflex bradycardic responses, and these effects were prevented by prior blockade of 5-HT₃ receptors in the NTS. The inhibitory effect of dlPAG stimulation on the cardiac reflex responses was prevented by inhibition of neurons in the medullary B3 region. In conclusion, 5-HT₃, GABA_A and NK₁ receptors in the NTS appear to be involved in the inhibition of the von Bezold–Jarisch reflex and the carotid chemoreceptor reflex bradycardia evoked by activation of neurons in the dlPAG and the raphé magnus.     

Giant GABAB-mediated Synaptic Potentials Induced by Zinc in the Rat Hippocampus: Paradoxical Effects of Zinc on the GABAB Receptor

The interaction of zinc with pre- and postsynaptic GABA_B receptors was studied in adult rat hippocampal slices using intracellular recording in CA1 and CA3 pyramidal neurons. Zinc (50 – 300 μM) antagonized baclofen responses with a variable potency, whereas CGP-35348 (100 μM) or barium (300 μM) produced a more substantial and consistent inhibition. Zinc also induced giant GABA_A-mediated depolarizing potentials (GDP) in these neurons. After blocking GABA_A and excitatory synaptic transmission, monosynaptic hyperpolarizing inhibitory postsynaptic potentials (IPSP) mediated by GABA_B receptors (IPSP_B) were inhibited by CGP-35348 or barium; however, zinc increased the latency and prolonged the duration of the IPSP_B and also induced the appearance of spontaneous giant GABA_B-mediated hyperpolarizing potentials (GHP). In some cells, IPSP_Bs in zinc exhibited a multiphasic appearance. The early component was partially inhibited by 300 μM zinc and was followed by a late GHP. CGP-35348 at 100 μM inhibited the early monosynaptic IPSP_B but not the GHP; however, at 300 μM both components were blocked. Paired-pulse inhibition of the IPSP_B was used to assess the effect of zinc on presynaptic GABA_B receptors. Neither the zinc-chelating agent CP94 (400 μM) nor zinc affected this phenomenon. CGP-35348, barium and polyvalent cations, such as cadmium, copper, cobalt, manganese, iron and aluminium, failed to induce giant potentials in hippocampal neurons. It is concluded that zinc is apparently unique in synchronizing the release of GABA to produce GDPs and GHPs.     

Timing of the Developmental Switch in GABAA Mediated Signaling from Excitation to Inhibition in CA3 Rat Hippocampus Using Gramicidin Perforated Patch and Extracellular Recordings

Summary:  The timing of the developmental switch in the GABA_A mediated responses from excitatory to inhibitory was studied in Wistar rat CA3 hippocampal pyramidal cells using gramicidin perforated patch-clamp and extracellular recordings. Gramicidin perforated patch recordings revealed a gradual developmental shift in the reversal potential of synaptic and isoguvacine-induced GABA_A mediated responses from –55 ± 4 mV at postnatal days P0–2 to −74 ± 3 mV at P13–15 with a midpoint of disappearance of the excitatory effects of GABA at around P8. Extracellular recordings in CA3 pyramidal cell layer revealed that the effect of isoguvacine on multiple unit activity (MUA) switched from an increase to a decrease at around P10. The effect of synaptic GABA_A mediated responses on MUA switched from an increase to a decrease at around P8. It is concluded that the developmental switch in the action of GABA via GABA_A receptors from excitatory to inhibitory occurs in Wistar rat CA3 pyramidal cells at around P8–10, an age that coincides with the transition from immature to mature hippocampal rhythms. We propose that excitatory GABA contributes to enhanced excitability and ictogenesis in the neonatal rat hippocampus.     

Role of GABAA receptors in rat hindbrain nuclei controlling gastric motor function

It has been shown in cats that gastric motor control by the dorsal vagal complex and nucleus ambiguus is under a tonic GABAergic influence. Since much more work has been performed in rats to define vago-vagal reflexes controlling gastrointestinal function, an understanding of the potential inhibition by candidate neurotransmitters such as GABA (gamma aminobutyric acid) in the rat dorsal vagal complex (DVC) is essential to assess. Multiple-barrelled micropipettes were used to apply to the dorsal vagal complex the GABA_A antagonist, bicuculline methiodide (0.1–1 nmol), and a GABA_A agonist, muscimol (10 nmol) prior to micro-injection of the GABA_A antagonist. Micro-injections of bicuculline (353 pmol and 1 nmol), which were localized primarily in the dorsal motor nucleus of the vagus, produced significant increases in intragastric pressure and pyloric motility. These responses were abolished by vagotomy and by a prior micro-injection of muscimol. To determine whether GABAergic blockade in the dorsal vagal complex results in gastric motor excitation through excitatory amino acid receptors, kynurenic acid (5 nmol), a kainate/NMDA (N-methyl D -aspartic acid) receptor antagonist, was micro-injected prior to bicuculline. This abolished the increase in gastric motor function normally evoked by bicuculline. In the other two important hindbrain nuclei controlling gastric function, the nucleus raphe obscurus and nucleus ambiguus, bicuculline (353 pmol) significantly increased intragastric pressure via vagally mediated pathways. These data demonstrate that all three rat hindbrain nuclei known to influence gastric function via the vagus nerve are under tonic GABAergic control. In addition, in the dorsal vagal complex, relief from GABAergic inhibition results in increases in gastric motor function through kainate/NMDA receptor-mediated excitation.     

GABAergic signaling induces divergent neuronal Ca2+ responses in the suprachiasmatic nucleus network

Intercellular communication between γ-aminobutyric acid (GABA)ergic suprachiasmatic nucleus (SCN) neurons facilitates light-induced phase changes and synchronization of individual neural oscillators within the SCN network. We used ratiometric Ca²⁺ imaging techniques to record changes in the intracellular calcium concentration ([Ca²⁺]_i) to study the role of GABA in interneuronal communication and the response of the SCN neuronal network to optic nerve stimulations that mimic entraining light signals. Stimulation of the retinohypothalamic tract (RHT) evoked divergent Ca²⁺ responses in neurons that varied regionally within the SCN with a pattern that correlated with those evoked by pharmacological GABA applications. GABA_A and GABA_B receptor agonists and antagonists were used to evaluate components of the GABA-induced changes in [Ca²⁺]_i. Application of the GABA_A receptor antagonist gabazine induced changes in baseline [Ca²⁺]_i in a direction opposite to that evoked by GABA, and similarly altered the RHT stimulation-induced Ca²⁺ response. GABA application induced Ca²⁺ responses varied in time and region within the SCN network. The NKCC1 cotransporter blocker, bumetanide, and L-type calcium channel blocker, nimodipine, attenuated the GABA-induced rise of [Ca²⁺]_i. These results suggest that physiological GABA induces opposing effects on [Ca²⁺]_i based on the chloride equilibrium potential, and may play an important role in neuronal Ca²⁺ balance, synchronization and modulation of light input signaling in the SCN network.     

Age-Dependent Effects of γ-Aminobutyric Acid Agents on Flurothyl Seizures

Summary: Behavioral characteristics of seizures have age-dependent features, which suggests that effective treatment of seizures may be age-specific as well. In experiments that used the flurothyl seizure model, we examined the effects of several drugs that affect GAB Aergic neurotransmission in rats of various ages. Systemic administration of phenobarbital (PB, a drug that enhances GABA, receptor-mediated inhibition) was anticonvulsant in most age groups. In contrast, γ- vinyl GAB_A (VGB, a drug that increases endogenous GABA levels and enhances both GABA_A and GABA_B, receptor transmission) did not have anticonvulsant effects. Baclofen (a GABA_B receptor agonist) was proconvulsant in 9-day-old rat pups, and anticonvulsant in 15–30-day-old rats and lost its anticonvulsant activity in 60-day-old rats. CGP 35348 (a GABA_B receptor antagonist) was proconvulsant in developing rats but not in 60-day-old rats. A novel GABA, receptor antagonist, CGP 36742, was proconvulsant in 9- and 15-day-old rats but had no effects in 30- and 60-day-old rats. These results indicate that the effects of presumed GAB Aergic agents are not uniform across the age span. The differences may reflect age-dependent maturational changes of GAB A receptor subtypes, differential action of the drugs on pre- and postsynaptic sites and possible non-GAB Aergic effects.     

Antiepileptic Drug Mechanisms of Action

Summary: Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, γ-ami-nobutyric acid type A (GABA_A) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABA_A receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underlie the clinical efficacy of VGB.     

Effect of a γ-Aminobutyric Acid Uptake Inhibitor, NNC-711, on Spontaneous Postsynaptic Currents in Cultured Rat Hippocampal Neurons: Implications for Antiepileptic Drug Development

Summary: The effect of a novel γ-aminobutyric acid (GABA) uptake inhibitor, NNC-711, on spontaneous postsynaptic currents was studied in cultured rat hippocampal neurons by the whole cell patch clamp method. NNC-711 decreased the amplitude of inhibitory postsynaptic currents (IPSCs) and did not prolong the decay. NNC-711 also decreased the amplitude of excitatory PSCs (EPSCs). The GABA_B receptor antagonist 2-OH saclofen abolished the effect on both IPSCs and EPSCs. NNC-711 itself induced no current and had no effect on currents induced by exogenously applied GABA. These findings suggest that duration of GABA_A-receptor mediated IPSCs is not determined by GABA uptake and that GABA uptake inhibitors may work by allowing GABA to remain in the synaptic area long enough to activate presynaptic GABA_B receptors.     

Developmental Patterns in the Regulation of Chloride Homeostasis and GABAA Receptor Signaling by Seizures

Summary:  GABA_A receptors have dual functions during development. They depolarize immature neurons but hyperpolarize more mature neurons. This functional switch has been attributed to age-related differences in the relative abundance of cation chloride cotransporters, such as KCC2 and NKCC1, which regulate chloride homeostasis. Certain insults, such as trauma, ischemia, and seizures, if they occur when GABA_Aergic signaling is hyperpolarizing, such as in the adult brain, can lead to reappearance of the immature, depolarizing synaptic responses to GABA_A receptor activation. In certain cases, this has been associated with either reduced expression of KCC2 or increase in NKCC1. In epilepsy, the depolarizing effects of GABA_A receptors have been proposed to be important for the acquisition and/or maintenance of the epileptic state. Using the kainic acid model of status epilepticus, we have studied the effects of repetitive neonatal episodes of status epilepticus on the expression of cation chloride cotransporter KCC2 in the neonatal hippocampus. In contrast to adults, seizures increased KCC2 mRNA expression in the CA3 region of the neonatal hippocampus. The contrasting patterns of regulation of KCC2 by seizures in mature and immature neurons may be one of the age-related factors that protect the neonatal brain against the development of epilepsy.     

Synchronous GABAA-receptor-dependent potentials in limbic areas of the in-vitro isolated adult guinea pig brain

Epileptiform discharges are known to reflect the hypersynchronous glutamatergic activation of cortical neurons. However, experimental evidence has revealed that epileptiform synchronization is also contributed to by population events mediated by GABA_A receptors. Here, we analysed the spatial distribution of GABA_A-receptor-dependent interictal events in the hippocampal/parahippocampal region of the adult guinea pig brain isolated in vitro . We found that arterial perfusion of this preparation with 4-aminopyridine caused the appearance of glutamatergic-independent interictal potentials that were reversibly abolished by GABA_A receptor antagonism. Laminar profiles and current source density analysis performed in different limbic areas demonstrated that these GABA_A-receptor-mediated events were independently generated in different areas of the hippocampal/parahippocampal formation (most often in the medial entorhinal cortex) and propagated between interconnected limbic structures of both hemispheres. Finally, intracellular recordings from principal neurons of the medial entorhinal cortex demonstrated that the GABAergic field potential correlated to inhibitory postsynaptic potentials (membrane potential reversal, −68.12 ± 8.01 mV, n  = 5) that were interrupted by ectopic spiking. Our findings demonstrate that, in an acute seizure model developed in the adult guinea pig brain, hypersynchronous GABA_A-receptor-mediated interictal events are generated from independent sources and propagate within limbic cortices in the absence of excitatory synaptic transmission. As spared or enhanced inhibition was reported in models of epilepsy, our data may support a role of GABA-mediated signaling in ictogenesis and epileptogenesis.     

Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood?

Serotonin [5-hydroxytryptamine (5-HT)] and 5-HT receptors are involved in sleep and in waking functions such as cognition and mood. Animal and human studies support a particular role for the 5-HT_2A receptor in sleep, which has led to renewed interest in this receptor subtype as a target for the development of novel pharmacological agents to treat insomnia. Focusing primarily on findings in healthy human volunteers, a review of the available data suggests that antagonistic interaction with 5-HT_2A receptors (and possibly also 5-HT_2C receptors) prolongs the duration of slow wave sleep and enhances low-frequency (< 7 Hz) activity in the sleep electroencephalogram (EEG), a widely accepted marker of sleep intensity. Despite certain differences, the changes in sleep and the sleep EEG appear to be remarkably similar to those of physiologically more intense sleep after sleep deprivation. It is currently unclear whether these changes in sleep are associated with improved vigilance, cognition and mood during wakefulness. While drug-induced interaction with sleep must be interpreted cautiously, too few studies are available to provide a clear answer to this question. Moreover, functional relationships between sleep and waking functions may differ between healthy controls and patients with sleep disorders. A multimodal approach investigating subjective and objective aspects of sleep and wakefulness provides a promising research avenue for shedding light on the complex relationships among 5-HT_2A/2C receptor-mediated effects on sleep, the sleep EEG, cognition and mood in health and various diseases associated with disturbed sleep and waking functions.