Role Of GABAA Receptors Research Articles

Cross state-dependent memory retrieval between tramadol and ethanol: involvement of dorsal hippocampal GABAA receptors.

Tramadol and ethanol, as psychoactive agents, are often abused. Discovering the molecular pathways of drug-induced memory creation may contribute to preventing drug addiction and relapse. The tramadol- and ethanol-induced state-dependent memory (SDM) and cross-SDM retrieval between tramadol and ethanol were examined in this study. Moreover, because of the confirmed involvement of GABAA receptors and GABAergic neurotransmission in memory retrieval impairment, we assessed cross-SDM retrieval between tramadol and ethanol with a specific emphasis on the role of the GABAA receptors. The first hypothesis of this study was the presence of cross-SDM between tramadol and ethanol, and the second hypothesis was related to possible role of GABAA receptors in memory retrieval impairment within the dorsal hippocampus. The cannulae were inserted into the hippocampal CA1 area of NMRI mice, and a step-down inhibitory avoidance test was used to evaluate state dependence and memory recovery. The post-training and/or pre-test administration of tramadol (2.5 and 5 mg/kg, i.p.) and/or ethanol (0.5 and 1 g/kg, i.p.) induced amnesia, which was restored after the administration of the drugs 24 h later during the pre-test period, proposing ethanol and tramadol SDM. The pre-test injection of ethanol (0.25 and 0.5 g/kg, i.p.) with tramadol at an ineffective dose (1.25 mg/kg) enhanced tramadol SDM. Moreover, tramadol injection (1.25 and 2.5 mg/kg) with ethanol at the ineffective dose (0.25 g/kg) promoted ethanol SDM. Furthermore, the pre-test intra-CA1 injection of bicuculline (0.0625, 0.125, and 0.25 μg/mouse), a GABAA receptor antagonist, 5 min before the injection of tramadol (5 mg/kg) or ethanol (1 g/kg) inhibited tramadol- and ethanol-induced SDM dose-dependently. The findings strongly confirmed cross-SDM between tramadol and ethanol and the critical role of dorsal hippocampal GABAA receptors in the cross-SDM between tramadol and ethanol.

GABAA receptor availability relates to emotion-induced BOLD responses in the medial prefrontal cortex: simultaneous fMRI/PET with [11C]flumazenil.

The fMRI BOLD response to emotional stimuli highlighting the role of the medial prefrontal cortex (MPFC) has been thoroughly investigated. Recently, the relationship between emotion processing and GABA levels has been studied using MPFC proton magnetic resonance spectroscopy (1H-MRS). However, the role of GABAA receptors in the MPFC during emotion processing remains unexplored. Using [11C]flumazenil PET, we investigated the relationship between the binding potential of GABAA receptors and emotion processing as measured using simultaneous fMRI BOLD. We hypothesized a correlation between the percent signal change in the BOLD signal and the binding potential of GABAA receptors in the MPFC. In a combined simultaneous fMRI and [11C]flumazenil-PET study, we analyzed the data from 15 healthy subjects using visual emotional stimuli. Our task comprised two types of emotional processing: passive viewing and appraisal. Following the administration of a bolus plus infusion protocol, PET and fMRI data were simultaneously acquired in a hybrid 3 T MR-BrainPET. We found a differential correlation of BOLD percent signal change with [11C]flumazenil binding potential in the MPFC. Specifically, [11C]flumazenil binding potential in the ventromedial prefrontal cortex (vMPFC) correlated with passive viewing of emotionally valenced pictures. In contrast, the [11C]flumazenil binding potential and the BOLD signal induced by picture appraisal did show a correlation in the paracingulate gyrus. Our data deliver first evidence for a relationship between MPFC GABAA receptors and emotion processing in the same region. Moreover, we observed that GABAA receptors appear to play different roles in emotion processing in the vMPFC (passive viewing) and paracingulate gyrus (appraisal).

AGABRacadabra: A surprising new role for GABAA receptors in cortical development

In this issue of Neuron, Babij, Ferrer, and colleagues provide new evidence that β3 subunit of GABAA receptors is critical for the maturation of functional networks in the neonatal somatosensory cortex.

Dihydromyricetin Protects Against Ethanol-Induced Toxicity in SH-SY5Y Cell Line: Role of GABAA Receptor.

Toxicity induced by binge alcohol drinking, particularly in adolescent and young adults, is of major medical and social consequence. Recently, we reported that butyrate, a short chain fatty acid, can protect against ethanol (ETOH)-induced toxicity in an in vitro model. In this study, we sought to evaluate the potential effectiveness of dihydromyricetin (DHM), a natural bioactive flavonoid, alone or in combination with butyrate in the same model. Exposure of SH-SY5Y cells for 24h to 500mM ETOH resulted in approximately 40% reduction in cell viability, which was completely prevented by 0.1 μM DHM. Combinations of DHM and butyrate provided synergistic protection against alcohol toxicity. Whereas butyrate effect was shown to be mediated primarily through fatty acid receptor 3 activation, DHM protection appears to be mediated primarily via benzodiazepine receptor site of GABAA receptor. This is based on the finding that DHM's effect could be completely prevented by pretreatment with flumazenil, a selective antagonist at this site, but not by bicuculline, a selective antagonist at the actual GABAA receptor binding site. These findings suggest potential utility of DHM alone or in combination with butyrate against ETOH-induced toxicity.

The regulatory role of GABAA receptor in Actinia equina nervous system and the possible effect of global ocean acidification

Global warming and connected acidification of the world ocean attract a substantial amount of research efforts, in particular in a context of their impact on behaviour and metabolism of marine organisms, such as Cnidaria. Nevertheless, mechanisms underlying Cnidarians’ neural signalling and behaviour and their (possible) alterations due to the world ocean acidification remain poorly understood. Here we researched for the first time modulation of GABAA receptors (GABAARs) in Actinia equina (Cnidaria: Anthozoa) by pH fluctuations within a range predicted by the world ocean acidification scenarios for the next 80–100 years and by selective pharmacological activation. We found that in line with earlier studies on vertebrates, both changes of pH and activation of GABAARs with a selective allosteric agonist (diazepam) modulate electrical charge transfer through GABAAR and the whole-cell excitability. On top of that, diazepam modifies the animal behavioural reaction on startle response. However, despite behavioural reactions displayed by living animals are controlled by GABAARs, changes of pH do not alter them significantly. Possible mechanisms underlying the species resistance to acidification impact are discussed.

Dopamine neurons in the ventral periaqueductal gray modulate isoflurane anesthesia in rats.

AimsGeneral anesthesia has been applied in surgery for more than 170 years, and there is little doubt that GABAA receptors have an important role as anesthetic molecular targets, but its neural mechanisms remain unclear. Increasing researchers have shown that dopaminergic pathways in the brain are crucial for sleep and wake. General anesthesia‐induced unconsciousness and natural sleep share some neural correlates. However, the role of GABAA receptors in ventral periaqueductal gray (vPAG) dopamine (DA) neurons in the isoflurane‐induced unconsciousness has yet to be identified.MethodsIn the present study, we used calcium fiber photometry recording to explore that the activity of ventral periaqueductal gray (vPAG) neurons. Then, rats were unilaterally microinjected with 6‐hydroxydopamine into the vPAG area to determine the role of vPAG‐DA neurons in isoflurane‐induced‐anesthesia. Furthermore, thirty SD rats were divided into three groups: a GABAAR agonist‐muscimol group, a GABAAR antagonist‐gabazine group, and a control group. Finally, whole‐cell patch clamp was used to examine the effects of isoflurane and GABAA receptor agonist/antagonist on vPAG‐DA neurons.ResultsThe vPAG neurons were markedly inhibited during isoflurane anesthesia induction and that these neurons were activated during emergence from isoflurane anesthesia. Lesion to the vPAG‐DA neurons shortened the induction time and prolonged the emergence time while increasing δ power in isoflurane anesthesia. Intracerebral injection of the GABAA receptor agonist (muscimol) into the vPAG accelerated the induction of anesthesia and delayed recovery from isoflurane anesthesia, with a decrease of δ power and an augment of β power. Injection of GABAA receptor antagonist gabazine generated the opposite effects. Isoflurane enhanced GABAergic transmission, and GABAA receptor agonist partly increased isoflurane‐induced inhibition of vPAG‐DA neurons, while GABAA receptor antagonist evidently attenuated GABAergic transmission.ConclusionOur results suggest that vPAG‐DA neurons are involved in isoflurane anesthesia through activation of the GABAA receptor.

Role of GABAA receptors in EEG activity and spatial recognition memory in aged APP and PS1 double transgenic mice

Alzheimer's disease (AD) is a leading cause of dementia, with no effective treatment currently available. However, targeting the aging mechanism may improve outcomes and γ-aminobutyric acid (GABA) system alteration could have implications for treatment of cognitive decline in old age. We studied the effects of the GABA system on brain activity in aged APP and PS1 transgenic mice. Low dose (0.1 mg/kg i.p.) GABAA agonist muscimol and antagonist bicuculline were administered for moderate system activation and inhibition, respectively. EEGs from the hippocampus (Hip) and prefrontal cortex (PFC) were recorded under spontaneous state and during Y-maze performance. Basally, AD mice exhibited increased spontaneous EEG delta (2–4 Hz) and decreased spontaneous EEG alpha (8–12 Hz) activity in the Hip, and decreased Y-maze EEG theta (4–8 Hz) activity in the PFC. Interestingly, GABAA activation and inhibition in AD mice reduced EEG delta activity and increased EEG theta activity in the PFC, and behaviorally improved spatial recognition memory during Y-maze testing. Decreased spontaneous EEG delta activity was also observed in the PFC. Specifically, GABAA activation primarily affected low frequency EEG (2–12 Hz) activity in the PFC, whereas inhibition affected EEG activity across many frequencies in the PFC and Hip. These data provide evidence for slower brain activity in AD mice. Importantly, improved spatial memory after GABAA activation and inhibition may be explained by brain rhythm recovery in certain regions. Our study highlights the potential clinical use of GABAA drugs to improve cognitive disorders and restore neural network activity in AD.

Role of GABAA receptors in sevoflurane-induced inhibition of discharge activities of inspiratory neurons in medullary respiratory center of neonatal rats

Objective To evaluate the role of GABAA receptors in sevoflurane-induced inhibition of the discharge activities of inspiratory neurons in the medullary respiratory center of neonatal rats. Methods The medulla oblongata slices of neonatal rats(aged 0-4 days)including the medial region of the nucleus retrofacialis with the hypoglossal nerve rootlets retained were prepared.The slices were perfused with artificial cerebrospinal fluid(ACSF), and the activity of the inspiratory neurons in the medial region of the nucleus retrofacialis and the respiratory rhythmical discharge activity of the hypoglossal nerve rootlets were simultaneously recorded using microelectrodes and suction electrodes, respectively.The ACSF, 5% sevoflurane, GABAA receptor blocker bicuculline 10 μmol/L and combination of 5% sevoflurane and 10 μmol/L bicuculline were added to the perfusion liquid after the discharge activity was stable.The respiratory cycle(RC), inspiratory time(TI), integral amplitude(IA)and changes in peak frequency(PFn)of the inspiratory neurons were recorded. Results Compared with that after giving ACSF, RC was significantly prolonged, TI was shortened, and IA and PFn were decreased after giving sevoflurane, and RC was significantly shortened, IA and PFn were increased(P 0.05). Compared with that after giving sevoflurane, RC was significantly shortened, TI was prolonged, and IA and PFn were increased after giving sevoflurane and bicuculline(P<0.05). Conclusion Sevoflurane inhibits the discharge activities of inspiratory neurons through GABAA receptors in the medullary respiratory center of neonatal rats. Key words: Anesthetics, Inhalation; Respiratory Center; Neurons

Role of GABAA Receptors of Parafacial Respiratory Group in Control of Respiration in Rats.

The role of GABAergic inhibition in the regulation of activity of the parafacial respiratory group was studied on narcotized mature rats. Microinjections of GABAA agonist muscimol into the parafacial respiratory group inhibited external respiration and bioelectrical activity of the diaphragmatic muscle resulting in diminished tidal volume and decreased respiration rate accompanied by prolonged inspiration, expiration, and intervals between the inspiratory bursts in the phrenic electromyogram. In contrast, microinjections of GABAA antagonist bicuculline into this group stimulated respiration and markedly increased its volumetric parameters. In addition, blockade of GABAA receptors affected the expiratory phase and interburst intervals in the phrenic electromyogram, but produced no effect on respiration rate. These findings attested to contribution of GABAA-mediated inhibition into the performance of parafacial respiratory group. The study revealed different roles of GABAA receptors in modulation of the mechanisms of respiration rate control in mature rats and formation of inspiratory motor outputs originating from the parafacial respiratory group.

Physiological implications of ocean acidification for marine fish: emerging patterns and new insights.

Ocean acidification (OA) is an impending environmental stress facing all marine life, and as such has been a topic of intense research interest in recent years. Numerous detrimental effects have been documented in marine fish, ranging from reduced mortality to neurosensory impairment, and the prevailing opinions state that these effects are largely the downstream consequences of altered blood carbon dioxide chemistry caused by respiratory acid-base disturbances. While the respiratory acid-base disturbances are consistent responses to OA across tested fish species, it is becoming increasingly clear that there is wide variability in the degree of downstream impairments between species. This can also be extended to intraspecies variability, whereby some individuals have tolerant physiological traits, while others succumb to the effects of OA. This review will synthesize relevant literature on marine fish to highlight consistent trends of impairment, as well as observed interspecies variability in the responses to OA, and the potential routes of physiological acclimation. In all cases, whole animal responses are linked to demonstrated or proposed physiological impairments. Major topics of focus include: (1) respiratory acid-base disturbances; (2) early life survival and growth; (3) the implications for metabolic performance, activity, and reproduction; and (4) emerging physiological theories pertaining to neurosensory impairment and the role of GABAA receptors. Particular emphasis is placed on the importance of understanding the underlying physiological traits that confer inter- and intraspecies tolerance, as the abundance of these traits will decide the long-term outlook of marine fish.

The Role of GABAA Receptor δ Subunit and its Agonist THIP in Thermal Hypersensitivity in a Mouse Model of Neuropathic Pain

Decreased gamma-aminobutyric acid (GABA)-mediated phasic inhibitory transmission in the spinal cord is thought to be responsible for the development of neuropathic pain. However, the role of GABAergic tonic current in substantia gelatinosa (SG) neurons remains to be fully elucidated. Using real-time polymerase chain reaction, we investigated the expression of the GABAA receptor δ subunit, which contributes to tonic current in the SG, in chronic constriction injury (CCI; a well-known model of neuropathic pain) and naive mice. The expression of the δ subunit mRNA was reduced by 40% in the ipsilateral SG of the dorsal horn of CCI mice compared to naive mice. We also performed behavioral experiments to assess the effect of the δ subunit-preferring agonist 4,5,6,7- tetrahydroisoxazolo(5,4-c)pyridine-3-ol (THIP) on thermal hypersensitivity with the Hargreaves test. Intrathecal administration of THIP significantly improved thermal thresholds of the ipsilateral hindpaw (4.55 ± 0.78 to 6.56 ± 1.09 s from baseline to after injection, respectively, P<0.005), while normal saline did not (4.41 ± 0.86 to 4.46 ± 1.1 s, P>0.1). GABAA receptor δ subunit-mediatedtonic current contributes to thermal hypersensitivity of CCI mice, and THIP may represent a therapeutic tool to improve thermal hypersensitivity.

Motor Alterations Induced by Chronic 4-Aminopyridine Infusion in the Spinal Cord In vivo: Role of Glutamate and GABA Receptors.

Motor neuron (MN) degeneration is the pathological hallmark of MN diseases, a group of neurodegenerative disorders clinically manifested as muscle fasciculations and hyperreflexia, followed by paralysis, respiratory failure, and death. Ample evidence supports a role of glutamate-mediated excitotoxicity in motor death. In previous work we showed that stimulation of glutamate release from nerve endings by perfusion of the K+-channel blocker 4-aminopyridine (4-AP) in the rat hippocampus induces seizures and neurodegeneration, and that AMPA infusion in the spinal cord produces paralysis and MN death. On these bases, in this work we have tested the effect of the chronic infusion of 4-AP in the spinal cord, using implanted osmotic minipumps, on motor activity and on MN survival, and the mechanisms underlying this effect. 4-AP produced muscle fasciculations and motor deficits assessed in two motor tests, which start 2–3 h after the implant, which ameliorated spontaneously within 6–7 days, but no neurodegeneration. These effects were prevented by both AMPA and NMDA receptors blockers. The role of GABAA receptors was also explored, and we found that chronic infusion of bicuculline induced moderate MN degeneration and enhanced the hyperexcitation produced by 4-AP. Unexpectedly, the GABAAR agonist muscimol also induced motor deficits and failed to prevent the MN death induced by AMPA. We conclude that motor alterations induced by chronic 4-AP infusion in the spinal cord in vivo is due to ionotropic glutamate receptor overactivation and that blockade of GABAergic neurotransmission induces MN death under chronic conditions. These results shed light on the role of glutamatergic and GABAergic neurotransmission in the regulation of MN excitability in the spinal cord.

Ectopic Expression of α6 and δ GABAA Receptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus.

In contrast to many hippocampal interneurons, somatostatin (SOM) neurons in the hilus of the dentate gyrus have very low levels of nonsynaptic GABAARs and exhibit very little tonic inhibition. In an effort to increase tonic inhibition selectively in these interneurons, we used Cre-dependent viral vectors in SOM-Cre mice to achieve interneuron-specific expression of the nonsynaptic GABAAR subunits (α6 and δ) in vivo. We show, for the first time, that such recombinant GFP-tagged GABAAR subunits are expressed robustly, assemble to form functional receptors, substantially increase tonic inhibition in SOM interneurons, and alter circuit activity within the dentate gyrus.

Inhibition of microglia in the basolateral amygdala enhanced morphine-induced antinociception: Possible role of GABAA receptors

In clinical medicine, morphine is widely used to relieve many types of pain, but it has several side effects such as the development of tolerance and dependence. In order to decrease the side effects of morphine administration for the treatment of pain, the combination of minocycline as a glial inhibitor and morphine has been suggested in previous studies. It is important to understand which synaptic mechanisms are involved in the potentiative effect of minocycline on morphine antinociception. To this aim, male Wistar rats were bilaterally cannulated in the basolateral amygdala by srereotaxic instrument. A tail-flick apparatus was used to measure the pain threshold. The results revealed that intraperitoneal injection of morphine (2.5–7.5mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of minocycline (5–10µg/rat) by itself had no effect on tail-flick latency, while the microinjection of the same doses of minocycline with an ineffective dose of morphine (5mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of different doses of muscimol (0.001–0.005µg/rat) increased the minocycline-induced potentioation on morphine response in the tail-flick test. Intra-basolateral amygdala microinjection of muscimol by itself had no effect on tail-flick latency. On the other hand, intra-basolateral amygdala microinjection of bicuculline (0.01–0.1µg/rat) inhibited minocycline-induced potentiation of morphine antinociception. It should be noted that intra-basolateral amygdala bicucculine by itself had no effect on tail-flick latency. It can thus be concluded that intra-basolateral amygdala minocycline potentiates morphine response in the tail-flick test. Moreover, basolateral amygdala GABAergic system may be involved in the minocycline-induced potentiation of morphine response via GABAA receptors.

The role of GABAA receptors on ethanol-induced type 1 IP3 receptor up-regulation

The role of GABAA receptors on ethanol-induced type 1 IP3 receptor up-regulation

Role of GABAA receptor in modulation of acute thermal pain using a rat model of cholestasis

Increased activity of the endogenous opioid system in cholestasis results in analgesia. GABAA receptors have been ascribed both pronociceptive and antinociceptive roles in pain modulation. Considering the elevated endogenous opioid tone in cholestasis and the existence of close interaction between the GABAergic and opioidergic systems in pain control, the involvement of GABAA receptors in modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated using muscimol and bicuculline as selective GABAA receptor agonist and antagonist respectively. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct between them. Cholestatic rats had increased tail-flick latencies (TFLs) compared to non-cholestatic rats. Administration of muscimol (0.2 and 0.4mg/kg, s.c.) and bicuculline (0.5 and 1mg/kg, s.c.) to the cholestatic groups significantly increased and decreased respectively TFLs compared to the saline treated cholestatic group. Muscimol antinociception in cholestatic animals was attenuated by co-administration of naloxone or bicuculline. Furthermore, the combination of bicuculline and naloxone completely reversed the increased TFLs of cholestatic rats back to the level of unoperated animals. Muscimol and bicuculline injections into non-cholestatic animals did not alter TFLs. At the doses used here, none of the drugs impaired motor coordination, as revealed by the rotarod test. This study shows the involvement of GABAA receptors in pain modulation during cholestasis in rats.

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

Fetal alcohol exposure (FAE) can lead to a variety of behavioral and physiological disturbances later in life. Understanding how alcohol (ethanol, EtOH) affects fetal brain development is essential to guide the development of better therapeutics for FAE. One of EtOH's many pharmacological targets is the γ-aminobutyric acid type A receptor (GABAAR), which plays a prominent role in early brain development. Acute EtOH potentiates inhibitory currents carried by certain GABAAR subtypes, whereas chronic EtOH leads to persistent alterations in GABAAR subunit composition, localization and function. We recently introduced a flavonoid compound, dihydromyricetin (DHM), which selectively antagonizes EtOH's intoxicating effects in vivo and in vitro at enhancing GABAAR function as a candidate for alcohol abuse pharmacotherapy. Here, we studied the effect of FAE on physiology, behavior and GABAAR function of early adolescent rats and tested the utility of DHM as a preventative treatment for FAE-induced disturbances. Gavage administration of EtOH (1.5, 2.5, or 5.0g/kg) to rat dams on day 5, 8, 10, 12, and 15 of pregnancy dose-dependently reduced female/male offspring ratios (largely through decreased numbers of female offspring) and offspring body weights. FAE (2.5g/kg) rats tested on postnatal days (P) 25-32 also exhibited increased anxiety and reduced pentylenetetrazol (PTZ)-induced seizure threshold. Patch-clamp recordings from dentate gyrus granule cells (DGCs) in hippocampal slices from FAE (2.5g/kg) rats at P25-35 revealed reduced sensitivity of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and tonic current (Itonic) to potentiation by zolpidem (0.3μM). Interestingly, potentiation of mIPSCs by gaboxadol increased, while potentiation of Itonic decreased in DGCs from FAE rats. Co-administration of EtOH (1.5 or 2.5g/kg) with DHM (1.0mg/kg) in pregnant dams prevented all of the behavioral, physiological, and pharmacological alterations observed in FAE offspring. DHM administration alone in pregnant rats had no adverse effect on litter size, progeny weight, anxiety level, PTZ seizure threshold, or DGC GABAAR function. Our results indicate that FAE induces long-lasting alterations in physiology, behavior, and hippocampal GABAAR function and that these deficits are prevented by DHM co-treatment of EtOH-exposed dams. The absence of adverse side effects and the ability of DHM to prevent FAE consequences suggest that DHM is an attractive candidate for development as a treatment for prevention of fetal alcohol spectrum disorders.

Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. We tested the hypothesis that DRN GABAA receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP). First, we tested if activation of GABAA receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABAA receptors in the DRN would attenuate swim stress-induced reinstatement of morphine CPP. CPP was induced by morphine (5mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABAA receptor agonist muscimol (50ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABAA receptor antagonist bicuculline (75ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP. Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement. These data provide evidence that GABAA receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP.

1277 – The role of GABA-A receptor in the synergism between SSRI and antipsychotics in schizophrenia

Currently available antipsychotics are often effective against positive symptoms of schizophrenia but have limited effect in treating core features such as negative or cognitive symptoms. New drugs developed on the basis of current dogmas have shown no breakthroughs in effectiveness and novel understandings of the mechanisms responsible for symptom productions and treatment response are needed. Clinical studies have shown that resistant negative symptoms may improve when antipsychotics are augmented with selective serotonin reuptake inhibitor (SSRI). This augmenting effect cannot be explained by summating pharmacological effects of the individual drugs. We reasoned that study of this synergism may reveal novel mechanisms relevant to the core features of schizophrenia and their treatment. Here we present results of in vitro and in vivo laboratory studies showing that the SSRI-Antipsychotic combination, produces unique changes in gamma-aminobutyric acid (GABA)-A receptor and its regulating system which are different from each individual drug. The changes include GABAA receptor phosphorylation, and cellular compartment distribution and changes in proteins modulating GABAA activity including PKC, GSK, ERK and BDNF. Results are also presented from clinical studies showing that SSRI augmentation in schizophrenia patients results in changes in blood mononuclear cell mRNA encoding for GABAA receptor and related proteins which are similar to those observed in the laboratory and associated with clinical improvement. Taken together these findings support the view that GABA A receptor modulation may be part of the mechanism mediating SSRI-antipsychotic synergistic effect ameliorating some core features of schizophrenia.

The Role of GABA-A Receptor in the Synergism Between SSRI and Antipsychotic in Schizophrenia; Implications for Antipsychotic Modes of Actions

The Role of GABA-A Receptor in the Synergism Between SSRI and Antipsychotic in Schizophrenia; Implications for Antipsychotic Modes of Actions