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Pharmacological Inhibition of the Nucleus Accumbens Increases Dyadic Social Interaction in Macaques.ENeuro Apr 2024The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties...
The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties of social stimuli have a vital role in guiding behavior (both in humans and nonhuman animals), the NAc is likely to contribute to the brain circuitry controlling social behavior. In rodents, prior studies have found that focal pharmacological inhibition of NAc and/or elevation of dopamine in NAc increases social interactions. However, the role of the NAc in social behavior in nonhuman primates remains unknown. We measured the social behavior of eight dyads of male macaques following (1) pharmacological inhibition of the NAc using the GABA agonist muscimol and (2) focal application of quinpirole, an agonist at the D2 family of dopamine receptors. Transient inhibition of the NAc with muscimol increased social behavior when drug was infused in submissive, but not dominant partners of the dyad. Focal application of quinpirole was without effect on social behavior when infused into the NAc of either dominant or submissive subjects. Our data demonstrate that the NAc contributes to social interactions in nonhuman primates.
PubMed: 38575350
DOI: 10.1523/ENEURO.0085-24.2024 -
BioRxiv : the Preprint Server For... Mar 2024The hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates...
The hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates the context-dependence of signaled active avoidance (SAA) in rats. Here, we explore whether the VH mediates intertrial responses (ITRs), which are putative unreinforced avoidance responses that occur between trials. First, we examined whether VH inactivation would affect ITRs. Male rats underwent SAA training and subsequently received intra-VH infusions of saline or muscimol before retrieval tests in the training context. Rats that received muscimol performed significantly fewer ITRs, but equivalent avoidance responses, compared to controls. Next, we asked whether chemogenetic VH activation would increase ITR vigor. In male and female rats expressing excitatory (hM3Dq) DREADDs, systemic CNO administration produced a robust ITR increase that was not due to nonspecific locomotor effects. Then, we examined whether chemogenetic VH activation potentiated ITRs in an alternate (non-training) test context and found it did. Finally, to determine if context-US associations mediate ITRs, we exposed rats to the training context for three days after SAA training to extinguish the context. Rats submitted to context extinction did not show a reliable decrease in ITRs during a retrieval test, suggesting that context-US associations are not responsible for ITRs. Collectively, these results reveal an important role for the VH in context-dependent ITRs during SAA. Further work is required to explore the neural circuits and associative basis for these responses, which may be underlie pathological avoidance that occurs in humans after threat has passed.
PubMed: 38562746
DOI: 10.1101/2024.03.18.585627 -
BioRxiv : the Preprint Server For... Mar 2024The frontal cortex plays a critical role in decision-making. One specific frontal area, the anterior cingulate cortex, has been identified as crucial for setting a...
The frontal cortex plays a critical role in decision-making. One specific frontal area, the anterior cingulate cortex, has been identified as crucial for setting a threshold for how much evidence is needed before a choice is made (Domenech & Dreher, 2010). Threshold is a key concept in drift diffusion models, a popular framework used to understand decision-making processes. Here, we investigated the role of the prelimbic cortex, part of the rodent cingulate cortex, in decision making. Male and female rats learned to choose between stimuli associated with high and low value rewards. Females learned faster, were more selective in their responses, and integrated information about the stimuli more quickly. By contrast, males learned more slowly and showed a decrease in their decision thresholds during choice learning. Inactivating the prelimbic cortex in female and male rats sped up decision making without affecting choice accuracy. Drift diffusion modeling found selective effects of prelimbic cortex inactivation on the decision threshold, which was reduced with increasing doses of the GABA-A agonist muscimol. Stimulating the prelimbic cortex through mu opioid receptors slowed the animals' choice latencies and increased the decision threshold. These findings provide the first causal evidence that the prelimbic cortex directly influences decision processes. Additionally, they suggest possible sex-based differences in early choice learning.
PubMed: 38562679
DOI: 10.1101/2024.03.18.585593 -
Neuroscience Letters Apr 2024The primary somatosensory cortex (S1) is responsible for processing information related to tactile stimulation, motor learning and control. Despite its significance, the...
The primary somatosensory cortex (S1) is responsible for processing information related to tactile stimulation, motor learning and control. Despite its significance, the connection between S1 and the primary motor cortex (M1), as well as its role in motor learning, remains a topic of ongoing exploration. In the present study, we silenced S1 by the GABA receptor agonist muscimol to study the potential roles of S1 in motor learning and task execution. Our results show that the inhibition of S1 leads to an immediate impairment in performance during the training session and also a substantial reduction in performance improvement during post-test session on the subsequent day. To understand the underlying mechanism, we used intravital two-photon imaging to investigate the dynamics of dendritic spines of layer V pyramidal neurons and the calcium activities of pyramidal neurons in M1 after inhibition of S1. Notably, S1 inhibition reduces motor training-induced spine formation and facilitates the elimination of existing spines of layer V pyramidal neurons in M1. The calcium activities in M1 exhibit a significant decrease during both resting and running periods following S1 inhibition. Furthermore, inhibition of S1, but not M1, significantly impairs the execution of the acquired motor task in the well-trained animals. Together, these findings reveal that S1 plays important roles in motor learning and task execution.
Topics: Animals; Somatosensory Cortex; Calcium; Pyramidal Cells; Inhibition, Psychological
PubMed: 38554843
DOI: 10.1016/j.neulet.2024.137753 -
Frontiers in Pharmacology 2024The plant-based alkaloid muscimol is a potent agonist of inhibitory GABA-neurotransmitter receptors. GABA receptors are a heterogeneous family of pentameric complexes,...
The plant-based alkaloid muscimol is a potent agonist of inhibitory GABA-neurotransmitter receptors. GABA receptors are a heterogeneous family of pentameric complexes, with 5 out of 19 subunits assembling around the central anion pore. Muscimol is considered to bind to all receptor subtypes at the orthosteric drug binding site at the β+/α- interface. Recently, we observed that the antipsychotic drugs clozapine (CLZ), loxapine (LOX) and chlorpromazine (CPZ) although exerting functional inhibition on multiple GABA receptor subtypes showed diverging results in displacing 3H-muscimol. While a complete displacement could be observed in hippocampal membranes by bicuculline (BIC), and no displacement with CPZ, the compounds CLZ and LOX competed partially. Non-sigmoidal, complex dose response curves were indicative of multiple sites. In the current study we now aimed to investigate more extensively this heterogeneity of bicuculline sensitive muscimol sites in rat brain. We tested membranes from four different brain regions (hippocampus, cerebellum, thalamus and striatum) and selected recombinantly expressed subunit combinations with displacement assays. 3H-muscimol displacement was tested with BIC, LOX, CLZ and CPZ. ligand structural analysis and computational docking was performed. We observed a unique pharmacology of each tested compound in the studied brain regions. Combining two of the tested ligands suggests that in striatum all CLZ sites are contained in the pool of LOX sites, while the CPZ sites may in part be non-overlapping with LOX sites. Experiments on recombinantly expressed receptors indicate, that BIC can displace 3H-muscimol from all tested receptors, while LOX and CLZ display different and variable competition indicative of multiple sites. Molecular docking produced structural correlates of the observed diversity of muscimol sites on the basis of bicuculline bound experimental structures. These findings indicate that 3H-muscimol binding sites in rat brain are heterogeneous, with different populations of receptors, which are CPZ, LOX or CLZ sensitive or insensitive. These binding sites show a varying distribution in different rat brain regions. Molecular docking suggests that the so-called loop F region of α subunits drives the observed differences.
PubMed: 38549678
DOI: 10.3389/fphar.2024.1368527 -
Journal of Biomolecular Structure &... Mar 2024Gamma-aminobutyric acid (GABA) signaling is the principal inhibitory pathway in the central nervous system. It is critical in neuronal cell proliferation and fate...
Gamma-aminobutyric acid (GABA) signaling is the principal inhibitory pathway in the central nervous system. It is critical in neuronal cell proliferation and fate determination. Any aberration in GABA inhibition results in psychiatric and neurological diseases. Thus, modulating GABAergic neurotransmission has become the basis of drug therapy for psychiatric and several neurological diseases. Though GABA and muscimol are classical inhibitors of GABA receptors, the search for novel inhibitors continues unabated. In this study, the binding mechanism of GABA and muscimol was elucidated and applied in the search for small molecule GABAergic inhibitors using comprehensive computational techniques. It was revealed that a high-affinity binding of GABA and muscimol was mediated by a water molecule involving αThr129 and then stabilized by strong interactions including salt bridges with βGlu155 and αArg66 amidst hydrogen bonds, π-π stacking, and π -cation interactions with other residues. The binding of GABA and muscimol was also characterized by stability and deeper penetration into the hydrophobic core of the protein which resulted in conformational changes of the binding pocket and domain, by inducing correlated motions of the residues. Thermodynamics analysis showed GABA and muscimol exhibited total binding free energies of -19.85 ± 8.83 Kcal/mol and -26.55 ± 3.42 Kcal/mol, respectively. A pharmacophore model search, based on the energy contributions of implicating binding residues, resulted in the identification of ZINC68604167, ZINC19735138, ZINC04202466, ZINC00901626, and ZINC01532854 as potential GABA-mimetic compounds from metabolites and natural products libraries. This study has elucidated the binding mechanisms of GABA and muscimol and successfully applied in the identification of GABA-mimetic compounds.Communicated by Ramaswamy H. Sarma.
PubMed: 38520326
DOI: 10.1080/07391102.2024.2331088 -
Neuropsychopharmacology : Official... Mar 2024Evidence indicates that the anterior (aIC), but not posterior (pIC), insular cortex promotes cued reinstatement of cocaine seeking after extinction in rats. It is...
Evidence indicates that the anterior (aIC), but not posterior (pIC), insular cortex promotes cued reinstatement of cocaine seeking after extinction in rats. It is unknown whether these subregions also regulate heroin seeking and whether such involvement depends on prior extinction learning. To address these questions, we used baclofen and muscimol (BM) to inactivate the aIC or pIC bilaterally during a seeking test after extinction or prolonged withdrawal from heroin. Male Sprague-Dawley rats in the extinction groups underwent 10+ days of heroin self-administration, followed by 6+ days of extinction sessions, and subsequent cued or heroin-primed reinstatement. Results indicate that aIC inactivation increased cued reinstatement of heroin seeking after extinction, whereas pIC inactivation prevented cued reinstatement. To determine whether these effects were extinction-dependent, we conducted a subsequent study using both sexes with prolonged withdrawal. Male and female rats in the withdrawal groups underwent 10+ days of heroin self-administration, followed by cued seeking tests after 1 and 14 days of homecage withdrawal to measure incubation of heroin craving. In this case, the findings indicate that aIC inactivation had no effect on incubation of heroin craving after withdrawal in either sex, whereas pIC inactivation decreased heroin craving only in males. These findings suggest that the aIC and pIC have opposing roles in suppressing vs promoting cued heroin seeking after extinction and that these roles are distinct from those in cocaine seeking. Moreover, the incubation of craving results suggest that new contingency learning is necessary to recruit the aIC in cued heroin seeking.
PubMed: 38499719
DOI: 10.1038/s41386-024-01846-x -
Behavioural Brain Research May 2024The anterior insular cortex (AIC) comprises a region of sensory integration. It appears to detect salient events in order to guide goal-directed behavior, code tracking...
The anterior insular cortex (AIC) comprises a region of sensory integration. It appears to detect salient events in order to guide goal-directed behavior, code tracking errors, and estimate the passage of time. Temporal processing in the AIC may be instantiated by the integration of representations of interoception. Projections between the AIC and the medial prefrontal cortex (mPFC) - found both in rats and humans - also suggest a possible role for these structures in the integration of autonomic responses during ongoing behavior. Few studies, however, have investigated the role of AIC and mPFC in decision-making and time estimation tasks. Moreover, their findings are not consistent, so the relationship between temporal decision-making and those areas remains unclear. The present study employed bilateral inactivations to explore the role of AIC and prelimbic cortex (PL) in rats during a temporal decision-making task. In this task, two levers are available simultaneously (but only one is active), one predicting reinforcement after a short, and the other after a long-fixed interval. Optimal performance requires a switch from the short to the long lever after the short-fixed interval elapsed and no reinforcement was delivered. Switch behavior from the short to the long lever was dependent on AIC and PL. During AIC inactivation, switch latencies became more variable, while during PL inactivation switch latencies became both more variable and less accurate. These findings point to a dissociation between AIC and PL in temporal decision-making, suggesting that the AIC is important for temporal precision, and PL is important for both temporal accuracy and precision.
Topics: Humans; Rats; Animals; Cerebral Cortex; Prefrontal Cortex; Gambling; Insular Cortex
PubMed: 38494127
DOI: 10.1016/j.bbr.2024.114961 -
Communications Biology Mar 2024
PubMed: 38467884
DOI: 10.1038/s42003-024-05975-3 -
IBRO Neuroscience Reports Jun 2024There is evidence that both the GABAergic system and serotonin reuptake inhibitor (SSRI) such as citalopram are involved in the modulation of anxiety and depression...
BACKGROUND
There is evidence that both the GABAergic system and serotonin reuptake inhibitor (SSRI) such as citalopram are involved in the modulation of anxiety and depression processes. In this research, we examined the effects of GABA receptor agents and citalopram on anxiety- and depression-related behaviors and their interaction in male mice.
METHODS
For intracerebroventricular (i.c.v.) infusion, a guide cannula was implanted in the left lateral ventricle. Anxiety and depression behaviors were evaluated using the elevated plus-maze (EPM) and forced swimming test (FST).
RESULTS
The results revealed that i.c.v. microinjection of muscimol (1 µg/mouse) enhanced % OAT (open arm time) and % OAE (open arm entries) in the EPM test and decreased immobility time in the FST without affecting locomotor activity, presenting anxiolytic- and antidepressant-like behaviors in the EPM and FST, respectively. On the other hand, i.c.v. microinjection of bicuculline (1 µg/mouse) reduced % OAT and % OAE without affecting locomotor activity and immobility time, presenting an anxiogenic-like effect. Moreover, i.p. administration of citalopram (8 mg/kg) increased %OAT and %OAE and reduced immobility time with no effect on locomotor activity, showing anxiolytic- and antidepressant-like responses in male mice. Furthermore, i.c.v. infusion of an ineffective dosage of muscimol potentiated the anxiolytic- and antidepressant-like responses induced by i.p. injection of citalopram in male mice. When citalopram and bicuculline were co-injected, a non-significant dose of bicuculline reversed the anxiolytic-like effect of citalopram in male mice. Also, the data revealed synergistic anxiolytic- and antidepressant-like behaviors between citalopram and muscimol in male mice.
CONCLUSIONS
The results suggested an interaction between citalopram and GABAergic agents on the modulation of anxiety and depression behaviors in male mice.
PubMed: 38415182
DOI: 10.1016/j.ibneur.2024.02.003