Infralimbic cortex plays a similar role in the punishment and extinction of instrumental behavior.

Learning to stop responding is a fundamental process in instrumental learning. Animals may learn to stop responding under a variety of conditions that include punishment-where the response earns an aversive stimulus in addition to a reinforcer-and extinction-where a reinforced response now earns nothing at all. Recent research suggests that punishment and extinction may be related manifestations of a common retroactive interference process. In both paradigms, animals learn to stop performing a specific response in a specific context, suggesting direct inhibition of the response by the context. This process may depend on the infralimbic cortex (IL), which has been implicated in a variety of interference-based learning paradigms including extinction and habit learning. Despite the behavioral parallels between extinction and punishment, a corresponding role for IL in punishment has not been identified. Here we report that, in a simple arrangement where either punishment or extinction was conducted in a context that differed from the context in which the behavior was first acquired, IL inactivation reduced response suppression in the inhibitory context, but not responding when it "renewed" in the original context. In a more complex arrangement in which two responses were first trained in different contexts and then extinguished or punished in the opposite one, IL inactivation had no effect. The results advance our understanding of the effects of IL in retroactive interference and the behavioral mechanisms that can produce suppression of a response.

The anterior retrosplenial cortex is required for short-term object in place recognition memory retrieval: Role of ionotropic glutamate receptors in male and female Long-Evans rats.

The anterior retrosplenial cortex (aRSC) integrates multimodal sensory information into cohesive associative recognition memories. Little is known about how information is integrated during different learning phases (i.e., encoding and retrieval). Additionally, sex differences are observed in performance of some visuospatial memory tasks; however, inconsistent findings warrant more research. We conducted three experiments using the 1-h delay object-in-place (1-h OiP) test to assess recognition memory retrieval in male and female Long-Evans rats. (i) We found both sexes performed equally in three repeated 1-h OiP test sessions. (ii) We showed infusions of a mixture of muscimol/baclofen (GABAA/B receptor agonists) into the aRSC ~15-min prior to the test phase disrupted 1-h OiP in both sexes. (iii) We assessed the role of aRSC ionotropic glutamate receptors in 1-h OiP retrieval using another squad of cannulated rats and confirmed that infusions of either the competitive AMPA/Kainate receptor antagonist CNQX (3 mM) or competitive NMDA receptor antagonist AP-5 (30 mM) (volumes = 0.50 uL/side) significantly impaired 1-h OiP retrieval in both sexes compared to controls. Taken together, findings challenge reported sex differences and clearly establish a role for aRSC ionotropic glutamate receptors in short-term visuospatial recognition memory retrieval. Thus, modulating neural activity in the aRSC may alleviate some memory processing impairments in related disorders.

Additive effect of histamine and muscimol upon induction of antinociceptive and antidepressant effects in mice.

We investigated the effects of histamine and GABA A receptor agents on pain and depression-like behaviors and their interaction using a tail-flick test and the forced swimming test (FST) in male mice. Our data revealed that intraperitoneal administration of muscimol (0.12 and 0.25 mg/kg) increased the percentage of maximum possible effect (%MPE) and area under the curve (AUC) of %MPE, indicating an antinociceptive response. Intraperitoneal injection of bicuculline (0.5 and 1 mg/kg) decreased %MPE and AUC of %MPE, suggesting hyperalgesia. Moreover, muscimol by reducing the immobility time of the FST elicited an antidepressant-like response but bicuculline by enhancing the immobility time of the FST caused a depressant-like response. Intracerebroventricular (i.c.v.) microinjection of histamine (5 µg/mouse) enhanced %MPE and AUC of %MPE. i.c.v. infusion of histamine (2.5 and 5 µg/mouse) decreased immobility time in the FST. Co-administration of different doses of histamine along with a sub-threshold dose of muscimol potentiated antinociceptive and antidepressant-like responses produced by histamine. Cotreatment of different doses of histamine plus a noneffective dose of bicuculline reversed antinociception and antidepressant-like effects elicited by histamine. Cotreatment of histamine, muscimol, and bicuculline reversed antinociceptive and antidepressant-like behaviors induced by the drugs. The results demonstrated additive antinociceptive and antidepressant-like effects between histamine and muscimol in mice. In conclusion, our results indicated an interaction between the histaminergic and GABAergic systems in the modulation of pain and depression-like behaviors.

Activation of Beta-adrenergic Receptors Upregulates the Signal-to-Noise Ratio of Auditory Input in the Medial Prefrontal Cortex and Mediates Auditory Fear Conditioning.

Norepinephrine (NE) is involved in auditory fear conditioning (AFC) in posttraumatic stress disorder (PTSD). However, it is still unclear how it acts on neurons. We aimed to investigate whether the activation of the ß-adrenergic receptor (ß-AR) improves AFC by sensitization of the prelimbic (PL) cortex at the animal, cellular, and molecular levels. In vivo single-cell electrophysiological recording was used to characterize the changes in neurons in the PL cortex after AFC. Then, PL neurons were locally administrated by the ß-AR agonist isoproterenol (ISO), the GABAaR agonist muscimol, or intervened by optogenetic method, respectively. Western blotting and immunohistochemistry were finally used to assess molecular changes. Noise and low-frequency tones induced similar AFC. The expression of ß-ARs in PL cortex neurons was upregulated after fear conditioning. Microinjection of muscimol into the PL cortex blocked the conformation of AFC, whereas ISO injection facilitated AFC. Moreover, PL neurons can be distinguished into two types, with type I but not type II neurons responding to conditioned sound and being regulated by ß-ARs. Our results showed that ß-ARs in the PL cortex regulate conditional fear learning by activating type I PL neurons.

The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats.

In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors.

Inactivation of the paraventricular nucleus attenuates the cardiogenic sympathetic afferent reflex in the spontaneously hypertensive rat.

BACKGROUND: Myocardial ischemia causes the release of bradykinin, which stimulates cardiac afferents, causing sympathetic excitation and chest pain. Glutamatergic activation of the paraventricular hypothalamic nucleus (PVN) in the spontaneously hypertensive rat (SHR) drives elevated basal sympathetic activity. Thus, we tested the hypothesis that inactivation of the PVN attenuates the elevated reflex response to epicardial bradykinin in the SHR and that ionotropic PVN glutamate receptors mediate the elevated reflex. METHODS: We recorded the arterial pressure and renal sympathetic nerve activity (RSNA) response to epicardial bradykinin application in anesthetized SHR and Wistar Kyoto (WKY) rats before and after PVN microinjection of GABA A agonist muscimol or ionotropic glutamate receptor antagonist kynurenic acid. RESULTS: Muscimol significantly decreased the arterial pressure response to bradykinin from 180.4 ±â€Š5.8 to 119.5 ±â€Š6.9 mmHg in the SHR and from 111.8 ±â€Š7.0 to 84.2 ±â€Š8.3 mmHg in the WKY and the RSNA response from 186.2 ±â€Š7.1 to 142.7 ±â€Š7.3% of baseline in the SHR and from 201.0 ±â€Š11.5 to 160.2 ±â€Š9.3% of baseline in the WKY. Kynurenic acid significantly decreased the arterial pressure response in the SHR from 164.5 ±â€Š5.0 to 126.2 ±â€Š7.7 mmHg and the RSNA response from 189.9 ±â€Š13.7to 168.5 ±â€Š12.7% of baseline but had no effect in the WKY. CONCLUSION: These results suggest that tonic PVN activity is critical for the full manifestation of the CSAR in both the WKY and SHR. Glutamatergic PVN activity contributes to the augmented CSAR observed in the SHR.

Analysis of the Ibotenic Acid, Muscimol, and Ergosterol Content of an Amanita Muscaria Hydroalcoholic Extract with an Evaluation of Its Cytotoxic Effect against a Panel of Lung Cell Lines In Vitro.

The fungus Amanita muscaria is universally recognizable for its iconic appearance; it is also widely regarded as poisonous, inedible, and even deadly. In spite of that, there have been documented cases of use of A. muscaria-containing preparations against various diseases, including cancer, to no apparent ill effect. The search for compounds that can be used to treat cancer among various plants and fungi has been intensifying in recent years. In light of this, we describe an HPLC HILIC analytical method for the evaluation of the content of the anticancer compound ergosterol (ERG) and the neuroactive alkaloids ibotenic acid (IBO) and muscimol (MUS) that contribute significantly to the unpleasant physiological syndrome associated with A. muscaria consumption. A 'homemade' A. muscaria tincture made using 80-proof rye vodka as the solvent, an A. muscaria extract made with a standardized water-ethanol solution as the solvent, and fractions obtained from the second extract via liquid-liquid extraction with nonpolar solvents were analyzed. The study also presents the results of capillary zone electrophoresis with contactless conductivity detection and UHPLC-MS/MS analyses of the IBO and MUS content of the two native A. muscaria extracts and an evaluation of the standardized extract's cytotoxic effect against a small panel of lung cell cultures in vitro. Our results show that the standardized extract has a significant cytotoxic effect and does not contain the compounds of interest in any significant quantity.

A thalamo-parietal cortex circuit is critical for place-action coordination.

The anterior and lateral thalamus (ALT) contains head direction cells that signal the directional orientation of an individual within the environment. ALT has direct and indirect connections with the parietal cortex (PC), an area hypothesized to play a role in coordinating viewer-dependent and viewer-independent spatial reference frames. This coordination between reference frames would allow an individual to translate movements toward a desired location from memory. Thus, ALT-PC functional connectivity would be critical for moving toward remembered allocentric locations. This hypothesis was tested in rats with a place-action task that requires associating an appropriate action (left or right turn) with a spatial location. There are four arms, each offset by 90°, positioned around a central starting point. A trial begins in the central starting point. After exiting a pseudorandomly selected arm, the rat had to displace the correct object covering one of two (left versus right) feeding stations to receive a reward. For a pair of arms facing opposite directions, the reward was located on the left, and for the other pair, the reward was located on the right. Thus, each reward location had a different combination of allocentric location and egocentric action. Removal of an object was scored as correct or incorrect. Trials in which the rat did not displace any objects were scored as "no selection" trials. After an object was removed, the rat returned to the center starting position and the maze was reset for the next trial. To investigate the role of the ALT-PC network, muscimol inactivation infusions targeted bilateral PC, bilateral ALT, or the ALT-PC network. Muscimol sessions were counterbalanced and compared to saline sessions within the same animal. All inactivations resulted in decreased accuracy, but only bilateral PC inactivations resulted in increased non selecting, increased errors, and longer latency responses on the remaining trials. Thus, the ALT-PC circuit is critical for linking an action with a spatial location for successful navigation.

Prelimbic cortex inactivation prevents ABA renewal based on stress state.

Our recent research suggests that the interoceptive state associated with stress can function as a contextual stimulus for operant behavior. In the present experiment, we investigated the role of the rodent prelimbic cortex (PL), a brain region that is critical in contextual control of operant behavior, in the ability of a stressed state to produce ABA renewal of an extinguished operant response. Rats were trained to perform a lever press response for a food pellet reward during daily sessions that followed exposure to a stressor that changed each day. The response was then extinguished in the absence of stress. ABA renewal of extinguished responding occurred following exposure to another stressor (different from any used during acquisition) in control rats but not in rats that received a PL-inactivating infusion (baclofen/muscimol). Results confirm that the interoceptive state of stress can play the role of a contextual stimulus and initiate renewal (relapse) of an inhibited behavior when stress has previously been associated with the behavior. In conjunction with our previous work, the present results support the hypothesis that the PL is important for contexts, both exteroceptive and interoceptive, to exert such control over operant behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties.

Herbal products found in nature can serve as great systems of study for drug design. The Amanita muscaria mushroom is native to many parts of the Northern Hemisphere and has a very distinctive appearance with its red cap and white spotted warts. The mushroom comprises several pharmacologically active alkaloids, including muscazone, muscarine, ibotenic acid, and muscimol, the latter two compounds being potent GABA agonists. Muscimol has served as a backbone in the design of GABA agonists devoid of effects on the GABA-metabolizing enzyme, GABA transaminase, and GABA uptake systems. In this sense, several analogs of muscimol have been synthesized and studied including THIP, THPO, iso-THIP, iso-THAZ and 4-PIOL which all interact with the GABA receptors much differently. The growing pharmacological and toxicological interest based on many conflicting opinions on the use of the neuroprotective role of muscimol analogs against some neurodegenerative diseases, its potent role in the treatment of cerebral ischemia and other socially significant health conditions provided the basis for this review.

Muscimol inhibits plasma membrane rupture and ninjurin-1 oligomerization during pyroptosis.

Pyroptosis is a cell death process that causes inflammation and contributes to numerous diseases. Pyroptosis is mediated by caspase-1 family proteases that cleave the pore-forming protein gasdermin D, causing plasma membrane rupture and release of pathogenic cellular contents. We previously identified muscimol as a small molecule that prevents plasma membrane rupture during pyroptosis via an unidentified mechanism. Here, we show that muscimol has reversible activity to prevent cellular lysis without affecting earlier pyroptotic events. Although muscimol is a well-characterized agonist for neuronal GABAA receptors, muscimol protection is not altered by GABAA receptor antagonists or recapitulated by other GABAA agonists, suggesting that muscimol acts via a novel mechanism. We find that muscimol blocks oligomerization of ninjurin-1, which is required for plasma membrane rupture downstream of gasdermin D pore formation. Our structure-activity relationship studies reveal distinct molecular determinants defining inhibition of pyroptotic lysis compared to GABAA binding. In addition, we demonstrate that muscimol reduces lethality during LPS-induced septic shock. Together, these findings demonstrate that ninjurin-1-mediated plasma membrane rupture can be pharmacologically modulated and pave the way toward identification of therapeutic strategies for pathologic conditions associated with pyroptosis.

Social affective behaviors among female rats involve the basolateral amygdala and insular cortex.

The ability to detect, appraise, and respond to another's emotional state is essential to social affective behavior. This is mediated by a network of brain regions responsible for integrating external cues with internal states to orchestrate situationally appropriate behavioral responses. The basolateral amygdala (BLA) and the insular cortex are reciprocally connected regions involved in social cognition and prior work in male rats revealed their contributions to social affective behavior. We investigated the functional role of these regions in female rats in a social affective preference (SAP) test in which experimental rats approach stressed juvenile but avoid stressed adult conspecifics. In separate experiments, the BLA or the insula were inhibited by local infusion of muscimol (100ng/side in 0.5µL saline) or vehicle prior to SAP tests. In both regions, muscimol interfered with preference for the stressed juvenile and naive adult, indicating that these regions are necessary for appropriate social affective behavior. In male rats, SAP behavior requires insular oxytocin but there are noteworthy sex differences in the oxytocin receptor distribution in rats. Oxytocin (500nM) administered to the insula did not alter social behavior but oxytocin infusions to the BLA increased social interaction. In sum, female rats appear to use the same BLA and insula regions for social affective behavior but sex differences exist in contribution of oxytocin in the insula.

Determination of ibotenic acid and muscimol in species of the genus Amanita section Amanita from China.

The genus Amanita sect. Amanita harbors approximately 150 species in the world, and 27 species have been recognized in China. Some of the species in China have continuously caused poisoning. The responsible toxins should be ibotenic acid (IBO) and muscimol (MUS). However, species of the section Amanita containing IBO and MUS and their systematic positions are unclear. In this study, the contents of IBO and MUS in 84 samples of 24 species in section Amanita were detected using UPLC‒MS/MS, and the distribution of toxin-containing species in the molecular phylogeny was analyzed by the combined (ITS, nrLSU, RPB2, TUB2 and TEF1-α) dataset using maximum likelihood (ML) analysis and Bayesian inference (BI). Our results indicated that 10 of the 24 species contained IBO and MUS ranging from 0.6125 to 32.0932 and 0.0056-5.8685 g/kg dry weight, respectively. Among these 10 species, the toxins of eight species, including Amanita altipes, A. concentrica, A. flavopantherina, A. griseopantherina, A. pseudopantherina, A. rubrovolvata, A. subglobosa and A. sychnopyramis, were detected for the first time. In addition, the IBO and MUS contents of A. subglobosa in different growth stages showed that both toxins decreased in the mature stage. The phylogenetic analysis showed that all species of sect. Amanita from China were divided into 5 groups. And IBO- and MUS-containing species were gathered in clades Ⅰ and Ⅳ, but not all of the species in the two clades contain the toxins. No presence of IBO and MUS in the species of clades Ⅱ, Ⅲ and Ⅴ were confirmed.

Regulation of vagally-evoked respiratory responses by the lateral parabrachial nucleus in the mouse.

Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the localised effects of modulating lateral parabrachial nucleus (LPB) activity on vagally-evoked changes in breathing pattern. In isoflurane-anaesthetised and instrumented mice, electrical stimulation of the vagus nerve (eVNS) produced stimulation frequency-dependent changes in diaphragm electromyograph (dEMG) activity with an evoked tachypnoea and apnoea at low and high stimulation frequencies, respectively. Muscimol microinjections into the LPB significantly attenuated eVNS-evoked respiratory rate responses. Notably, muscimol injections reaching the caudal LPB, previously unrecognised for respiratory modulation, potently modulated eVNS-evoked apnoea, whilst muscimol injections reaching the intermediate LPB selectively modulated the eVNS-evoked tachypnoea. The effects of muscimol on eVNS-evoked breathing rate changes occurred without altering basal eupneic breathing. These results highlight novel roles for the LPB in regulating vagally-evoked respiratory reflexes.

A new large pantherine and a sabre-toothed cat (Mammalia, Carnivora, Felidae) from the late Miocene hominoid-bearing Khorat sand pits, Nakhon Ratchasima Province, northeastern Thailand.

We describe two large predators from the hominoid-bearing Khorat sand pits, Nakhon Ratchasima Province, northeastern Thailand: a new genus of pantherine, Pachypanthera n. gen., represented by partial mandible and maxilla and an indeterminate sabre-toothed cat, represented by a fragment of upper canine. The morphological characters of Pachypanthera n. gen., notably the large and powerful canine, the great robustness of the mandibular body, the very deep fossa for the m. masseter, the zigzag HSB enamel pattern, indicate bone-cracking capacities. The genus is unique among Felidae as it has one of the most powerful and robust mandibles ever found. Moreover, it may be the oldest known pantherine, as other Asian pantherines are dated back to the early Pliocene. The taxa we report here are the only carnivorans known from the late Miocene of Thailand. Although the material is rather scarce, it brings new insights to the evolutionary history of Neogene mammals of Southeast Asia, in a geographic place which is partly "terra incognita."

Controllable Stress Increases Rapid Eye Movement Sleep in Rats: Regulation by the Central Nucleus of the Amygdala.

BACKGROUND: Training with inescapable shock (IS; uncontrollable stressor) is followed by significant decreases in rapid eye movement sleep (REM). However, controllability is important in the effects of stress. We examined the effects of escapable shock (ES; controllable stressor) on sleep and whether the central nucleus of the amygdala (CNA) plays a role in regulating these effects. METHODS: Six Wistar rats implanted with a cannula located in CNA underwent two days of ES training (20 shock presentations; 0.5 mA; 5.0 s maximum duration; 1.0 min interstimulus interval). Five days later, they were re-exposed to the shock context. RESULTS: Following shock training, REM was significantly increased in both light and dark periods. Non-REM (NREM) and total sleep (TS) duration were decreased during the light period. Similar effects on REM and NREM were observed following re-exposure to the training context alone. Microinjections of saline into CNA immediately following ES also produced similar increases in REM, whereas microinjections of muscimol (MUS; GABAA (γ-aminobutyric acid) antagonist) subsequent to ES blocked the increases in REM. CONCLUSIONS: These data, along with previous work with ES and IS, demonstrate that stressor controllability is important in determining how stress impacts sleep. Moreover, the results of the microinjection study indicate that the effects of ES on REM are regulated through the CNA.

The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice.

Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABAARs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABAAR agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABAAR inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of "M2" cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication.

Effects of bile duct ligation on the inhibitory control of supraoptic vasopressin neurons.

Dilutional hyponatremia due to increased plasma arginine vasopressin (AVP) is associated with liver cirrhosis. However, plasma AVP remains elevated despite progressive hypoosmolality. This study investigated changes to inhibitory control of supraoptic nucleus (SON) AVP neurons during liver cirrhosis. Experiments were conducted with adult male Sprague-Dawley rats. Bile duct ligation was used as a model of chronic liver cirrhosis. An adeno-associated virus containing a construct with an AVP promoter and either green fluorescent protein (GFP) or a ratiometric chloride indicator, ClopHensorN, was bilaterally injected into the SON of rats. After 2 weeks, rats received either BDL or sham surgery, and liver cirrhosis was allowed to develop for 4 weeks. In vitro, loose patch recordings of action potentials were obtained from GFP-labeled and unlabeled SON neurons in response to a brief focal application of the GABAA agonist muscimol (100 µM). Changes to intracellular chloride ([Cl]i) following muscimol application were determined by changes to the fluorescence ratio of ClopHensorN. The contribution of cation chloride cotransporters NKCC1 and KCC2 to changes in intracellular chloride was investigated using their respective antagonists, bumetanide (BU, 10 µM) and VU0240551 (10 µM). Plasma osmolality and hematocrit were measured as a marker of dilutional hyponatremia. The results showed reduced or absent GABAA -mediated inhibition in a greater proportion of AVP neurons from BDL rats as compared to sham rats (100% inhibition in sham vs. 47% in BDL, p = .001). Muscimol application was associated with increased [Cl]i in most cells from BDL as compared to cells from sham rats (χ2 = 30.24, p < .001). NKCC1 contributed to the impaired inhibition observed in BDL rats (p < .001 BDL - BU vs. BDL + BU). The results show that impaired inhibition of SON AVP neurons and increased intracellular chloride contribute to the sustained dilutional hyponatremia in liver cirrhosis.

Muscimol inactivation of dorsal striatum in young and aged male rats does not affect paired associates learning performance.

Improving cognitive health for older adults requires understanding the neurobiology of age-related cognitive decline and the mechanisms underlying preserved cognition in old age. During spatial learning tasks, aged humans and rodents shift navigation preferences in favor of a stimulus-response learning strategy. This has been hypothesized to result from competitive interactions of the caudate nucleus/dorsal striatum (DS) memory system with the hippocampus (HPC)-dependent spatial/allocentric memory system. In support of this hypothesis, a recent study reported that inactivation of the DS in aged rodents rescued HPC-dependent spatial learning on a T-maze (Gardner, Gold, & Korol, 2020). Currently, it is unclear whether a shift from HPC-dependent to DS-dependent behavior also contributes to age-related cognitive decline outside of spatial learning and memory. To test the hypothesis that inactivation of the DS can restore age-related cognitive function outside of spatial behavior, the present study bilaterally inactivated the DS of young (n = 8) and aged (n = 7) rats during visuospatial paired associates learning (PAL). This study found that inactivation of the DS did not alter PAL performance in young or aged rats, but did alter a positive control, DS-dependent spatial navigation task. This observation suggests that elevated DS activity does not play a role in the decline of HPC-dependent PAL performance in aged male rats. Given the persistent tendencies of aged rodents toward DS-dependent learning, it will be worthwhile to explore further the coordination dynamics between the HPC and DS that may contribute to age-related cognitive decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pharmacological evaluation of lateral habenula and rostromedial tegmental nucleus in the expression of ethanol-induced place preference.

Although ethanol administration produces a range of physiological effects, the rewarding aspect associated with its consumption is a major contributory factor to its abuse liability. Recently, lateral habenula (LHb) has been shown to be engaged by both rewarding and aversive stimuli. Its major glutamatergic output, the fasciculus retroflexus, projects to the rostromedial tegmental nucleus (RMTg) and controls the activity of the ventral tegmental area (VTA) dopaminergic system to promote reward circuitry. While several attempts have been made to understand the relationship between LHb and addiction, there is still a lack of knowledge in relation to ethanol addiction. In the present study, by pharmacologically exacerbating or inhibiting the LHb or RMTg neuronal activity during a post-conditioning test, we investigated the role of LHb-RMTg fasciculus retroflexus in ethanol-induced reward behavior using the conditioned place preference (CPP) test. We found that activation of LHb glutamatergic system by intra-LHb administration of l-trans-2,4-pyrrolidine dicarboxylate (PDC) (glutamate transporter inhibitor) significantly decreased CPP score; on the contrary, lamotrigine (inhibits glutamate release) significantly increased CPP score and showed a rewarding effect in CPP. Instead, intra-RMTg administration of muscimol (GABAA receptor agonist) significantly increased CPP score, whereas bicuculline (GABAA antagonist) treatment decreased CPP score. In immunohistochemistry, we found that PDC administration significantly decreased, whereas lamotrigine treatment significantly increased tyrosine hydroxylase immunoreactivity (TH-ir) in VTA and nucleus accumbens (NAc). Furthermore, while intra-RMTg administration of muscimol increased, the bicuculline treatment significantly decreased the TH-ir in VTA and NAc. Together, our behavioral and immunohistochemical results signify the role of LHb and RMTg in the expression of ethanol-conditioned reward behavior.