The Dissociative Subtype of Posttraumatic Stress Disorder: Unique Resting-State Functional Connectivity of Basolateral and Centromedial Amygdala Complexes

Previous studies point towards differential connectivity patterns among basolateral (BLA) and centromedial (CMA) amygdala regions in patients with posttraumatic stress disorder (PTSD) as compared with controls. Here we describe the first study to compare directly connectivity patterns of the BLA and CMA complexes between PTSD patients with and without the dissociative subtype (PTSD+DS and PTSD−DS, respectively). Amygdala connectivity to regulatory prefrontal regions and parietal regions involved in consciousness and proprioception were expected to differ between these two groups based on differential limbic regulation and behavioral symptoms. PTSD patients (n=49) with (n=13) and without (n=36) the dissociative subtype and age-matched healthy controls (n=40) underwent resting-state fMRI. Bilateral BLA and CMA connectivity patterns were compared using a seed-based approach via SPM Anatomy Toolbox. Among patients with PTSD, the PTSD+DS group exhibited greater amygdala functional connectivity to prefrontal regions involved in emotion regulation (bilateral BLA and left CMA to the middle frontal gyrus and bilateral CMA to the medial frontal gyrus) as compared with the PTSD−DS group. In addition, the PTSD+DS group showed greater amygdala connectivity to regions involved in consciousness, awareness, and proprioception—implicated in depersonalization and derealization (left BLA to superior parietal lobe and cerebellar culmen; left CMA to dorsal posterior cingulate and precuneus). Differences in amygdala complex connectivity to specific brain regions parallel the unique symptom profiles of the PTSD subgroups and point towards unique biological markers of the dissociative subtype of PTSD.     

Resting-State Functional Connectivity of Antero-Medial Prefrontal Cortex Sub-Regions in Major Depression and Relationship to Emotional Intelligence

Background:

Major depressive disorder has been associated with abnormal resting-state functional connectivity (FC), especially in cognitive processing and emotional regulation networks. Although studies have found abnormal FC in regions of the default mode network (DMN), no study has investigated the FC of specific regions within the anterior DMN based on cytoarchitectonic subdivisions of the antero-medial pre-frontal cortex (PFC). Studies from different areas in the field have shown regions within the anterior DMN to be involved in emotional intelligence. Although abnormalities in this region have been observed in depression, the relationship between the ventromedial PFC (vmPFC) function and emotional intelligence has yet to be investigated in depressed individuals.

Methods:

Twenty-one medication-free, non–treatment resistant, depressed patients and 21 healthy controls underwent a resting state functional magnetic resonance imaging session. The participants also completed an ability-based measure of emotional intelligence: the Mayer-Salovey-Caruso Emotional Intelligence Test. FC maps of Brodmann areas (BA) 25, 10m, 10r, and 10p were created and compared between the two groups.

Results:

Mixed-effects analyses showed that the more anterior seeds encompassed larger areas of the DMN. Compared to healthy controls, depressed patients had significantly lower connectivity between BA10p and the right insula and between BA25 and the perigenual anterior cingulate cortex. Exploratory analyses showed an association between vmPFC connectivity and emotional intelligence.

Conclusions:

These results suggest that individuals with depression have reduced FC between antero-medial PFC regions and regions involved in emotional regulation compared to control subjects. Moreover, vmPFC functional connectivity appears linked to emotional intelligence.     

PI3K-Akt Signaling in the Basolateral Amygdala Facilitates Traumatic Stress Enhancements in Fear Memory

BackgroundA core symptom of posttraumatic stress disorder is persistent fear memory, which can be defined as fear memory that is resistant to updating, inhibition, or extinction. posttraumatic stress disorder emerges after traumatic stress exposure, but neurobiological mechanisms via which traumatic stress leads to persistent fear memory are not well defined. Akt signaling within the amygdala (Amy) is enhanced with traumatic stress, and phosphatidylinositol kinase 3 (PI3K) activation of Akt within the basolateral Amy (BLA) has been implicated as critical to fear memory formation. These findings raise the possibility that traumatic stress enhances PI3K→Akt signaling in the BLA, which leads to persistent fear memory.MethodsTo test this hypothesis, rats were exposed to traumatic stress using the single prolonged stress model, and changes in Akt phosphorylation were assayed in the Amy at 0 and 30 minutes after fear conditioning (FC). In a separate experiment, we inhibited PI3K→Akt signaling in the BLA prior to FC and observed the effect this had on acquisition, expression, and extinction of FC in stressed and control rats.ResultsEnhanced Akt phosphorylation in the Amy at both time points was observed in stressed rats, but not in control rats. PI3K→Akt inhibition in the BLA had no effect on freezing in control rats but decreased freezing during extinction training and testing in stressed rats.ConclusionThese findings suggest that PI3K→Akt signaling in the BLA could be a mechanism via which traumatic stress leads to fear memory that is resistant to extinction.     

Astrocytic NMDA Receptors in the Basolateral Amygdala Contribute to Facilitation of Fear Extinction

BackgroundEnhancement of N-methyl-D-aspartate (NMDA) receptor function using glycine-site agonist D-cycloserine is known to facilitate fear extinction, providing a means to augment cognitive behavioral therapy in anxiety disorders. A novel class of glycine-site agonists has recently been identified, and we have found that the prototype, AICP, is more effective than D-cycloserine in modulating neuronal function.MethodsUsing novel glycine-site agonist AICP, local infusion studies, and genetic models, we elucidated the role of GluN2C-containing receptors in fear extinction.ResultsWe tested the effect of intracerebroventricular injection of AICP on fear extinction and found a robust facilitation of fear extinction. This effect was dependent on GluN2C subunit, consistent with superagonist action of AICP at GluN2C-containing receptors. Local infusion studies in wild-type and GluN2C knockout mice suggested that AICP produces its effect via GluN2C-containing receptors in the basolateral amygdala (BLA). Furthermore, consistent with astrocytic expression of GluN2C subunit in the amygdala, we found that AICP did not facilitate fear extinction in mice with conditional deletion of obligatory GluN1 subunit from astrocytes. Importantly, chemogenetic activation of astrocytes in the basolateral amygdala facilitated fear extinction. Acutely, AICP was found to facilitate excitatory neurotransmission in the BLA via presynaptic GluN2C-dependent mechanism. Immunohistochemical studies suggest that AICP-mediated facilitation of fear extinction involves synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor GluA1 subunit.ConclusionThese results identify a unique role of astrocytic NMDA receptors composed of GluN2C subunit in extinction of conditioned fear memory and demonstrate that further development of recently identified superagonists of GluN2C-containing receptors may have utility for anxiety disorders.     

Voxel-wise Functional Connectivity of the Default Mode Network in Epilepsies: A Systematic Review and Meta-Analysis

Background:Default Mode Network (DMN) is recognized to be involved in the generation and propagation of epileptic activities in various epilepsies. Converging evidence has suggested disturbed Functional Connectivity (FC) in epilepsies, which was inferred to be related to underlying pathological mechanisms. However, abnormal changes of FC in DMN revealed by different studies are controversial, which obscures the role of DMN in distinct epilepsies.Objective:The present work aims to investigate the voxel-wise FC in DMN across epilepsies.Methods:A systematic review was conducted on 22 published articles before October 2020, indexed in PubMed and Web of Science. A meta-analysis with a random-effect model was performed using the effect-size signed differential mapping approach. Subgroup analyses were performed in three groups: Idiopathic Generalized Epilepsy (IGE), mixed Temporal Lobe Epilepsy (TLE), and mixed Focal Epilepsy (FE) with different foci.Results:The meta-analysis suggested commonly decreased FC in mesial prefrontal cortices across different epilepsies. Additionally decreased FC in posterior DMN was observed in IGE. The TLE showed decreased FC in temporal lobe regions and increased FC in the dorsal posterior cingulate cortex. Interestingly, an opposite finding in the ventral and dorsal middle frontal gyrus was observed in TLE. The FE demonstrated increased FC in the cuneus.     

Differential Role of Muscarinic Transmission within the Entorhinal Cortex and Basolateral Amygdala in the Processing of Irrelevant Stimuli

Cholinergic projections to the entorhinal cortex (EC) and basolateral amygdala (BLA) mediate distinct cognitive processes through muscarinic acetylcholine receptors (mAChRs). In this study, we sought to further differentiate the role of muscarinic transmission in these regions in cognition, using the latent inhibition (LI) phenomenon. LI is a cross-species phenomenon manifested as poorer conditioning to a stimulus experienced as irrelevant during an earlier stage of repeated non-reinforced pre-exposure to that stimulus, and is considered to index the ability to ignore, or to in-attend to, irrelevant stimuli. Given our recent findings that systemic administration of the mAChR antagonist scopolamine can produce two contrasting LI abnormalities in rats, ie, abolish LI under conditions yielding LI in non-treated controls, or produce abnormally persistent LI under conditions preventing its expression in non-treated controls, we tested whether mAChR blockade in the EC and BLA would induce LI abolition and persistence, respectively. We found that intra-EC scopolamine infusion (1, 10 μg per hemisphere) abolished LI when infused in pre-exposure or both pre-exposure and conditioning, but not in conditioning alone, whereas intra-BLA scopolamine infusion led to persistent LI when infused in conditioning or both stages, but not in pre-exposure alone. Although cholinergic innervation of the EC and BLA has long been implicated in attention to novel stimuli and in processing of motivationally significant stimuli, respectively, our results provide evidence that EC mAChRs also have a role in the development of inattention to stimuli, whereas BLA mAChRs have a role in re-attending to previously irrelevant stimuli that became motivationally relevant.     

Lateral Paracapsular GABAergic Synapses in the Basolateral Amygdala Contribute to the Anxiolytic Effects of ��3 Adrenoceptor Activation

Norepinephrine (NE) is known to play an integral role in the neurobiological response to stress. Exposure to stressful stimuli increases NE levels in brain regions that regulate stress and anxiety, like the basolateral amygdala (BLA). NE is thought to increase excitability in these areas through α- and β-adrenoceptors (ARs), leading to increased anxiety. Surprisingly, recent studies have shown that systemic β3-AR agonist administration decreases anxiety-like behaviors, suggesting that β3-ARs may inhibit excitability in anxiety-related brain regions. Therefore, in this study we integrated electrophysiological and behavioral approaches to test the hypothesis that the anxiolytic effects of β3-AR agonists may be mediated by an increase in BLA GABAergic inhibition. We examined the effect of a selective β3-AR agonist, BRL37344 (BRL), on GABAergic synapses arising from local circuit interneurons and inhibitory synapses originating from a recently described population of cells called lateral paracapsular (LPCS) interneurons. Surprisingly, BRL selectively enhanced LPCS-evoked inhibitory postsynaptic currents (eIPSCs) with no effect on local GABAergic inhibition. BRL also had no effect on glutamatergic synaptic excitation within the BLA. BRL potentiation of LPCS eIPSCs was blocked by the selective β3-AR antagonist, SR59230A, or by intracellular dialysis of Rp-CAMPS (cAMP-dependent protein kinase inhibitor), and this enhancement was not associated with any changes in spontaneous IPSCs or LPCS paired-pulse ratio. BRL also increased the amplitude of unitary LPCS IPSCs (uIPSCs) with no effect on uIPSC failure rate. Finally, bilateral BLA microinjection of BRL reduced anxiety-like behaviors in an open-field assay and the elevated plus-maze. Collectively, these data suggest that β3-AR activation selectively enhances LPCS, but not local, BLA GABAergic synapses, and that increases in LPCS-mediated inhibition may contribute to the anxiolytic profile of β3-AR agonists.     

Basolateral Amygdala SIRT1/PGC-1α Mitochondrial Biogenesis Pathway Mediates Morphine Withdrawal-Associated Anxiety in Mice

BackgroundAnxiety is a negative emotion that contributes to craving and relapse during drug withdrawal. Sirtuins 1 (SIRT1) has been reported to be critical in both negative emotions and drug addiction. However, it remains incompletely elucidated whether SIRT1 is involved in morphine withdrawal-associated anxiety.MethodsWe established a mouse model of anxiety-like behaviors induced by morphine withdrawal and then detected neuronal activity with immunofluorescence and mitochondrial morphology with electron microscopy, mitochondrial DNA contents with quantitative real-time PCR, and mitochondrial function with the ATP content detection kit and the Mitochondrial Complex IV Activity Kit in the basolateral amygdala (BLA). The mitochondrial molecules were detected by western blot. Then we used virus-mediated downregulation and overexpression of SIRT1 in BLA to investigate the effect of SIRT1 on anxiety and mitochondrial function. Finally, we examined the effects of pharmacological inhibition of SIRT1 on anxiety and mitochondrial function.ResultsWe found that BLA neuronal activity, mitochondrial function, and mtDNA content were significantly higher in morphine withdrawal mice. Furthermore, the expression levels of mitochondrial molecules increased in BLA cells. Virus-mediated downregulation of SIRT1 in BLA prevented anxiety-like behaviors in morphine withdrawal mice, whereas overexpression of SIRT1 in BLA facilitated anxiety-like behaviors in untreated mice through the SIRT1/ peroxisome proliferator activated receptor gamma coactivator 1-alpha pathway. Intra-BLA infusion of selective SIRT1 antagonist EX527 effectively ameliorated anxiety-like behaviors and mitochondrial dysfunction in mice with morphine withdrawal.ConclusionOur results implicate a causal role for SIRT1 in the regulation of anxiety through actions on mitochondrial biogenesis. Inhibitors targeting SIRT1 may have therapeutic potential for the treatment of opioid withdrawal-associated anxiety.     

Enkephalin Knockdown in the Basolateral Amygdala Reproduces Vulnerable Anxiety-Like Responses to Chronic Unpredictable Stress

The endogenous enkephalins (ENKs) are potential candidates participating in the naturally occurring variations in coping styles and determining the individual capacities for adaptation during chronic stress exposure. Here we demonstrate that there is a large variance in individual behavioral, as well as in physiological outcomes, in a population of Sprague–Dawley rats subjected to 3 weeks of chronic unpredictable stress (CUS). Separation of resilient and vulnerable subpopulations reveals specific long-term neuroadaptation in the ENKergic brain circuits. ENK mRNA expression was greatly reduced in the posterior basolateral nucleus of amygdala (BLAp) in vulnerable individuals. In contrast, ENK mRNA levels were similar in resilient and control (unstressed) individuals. Another group of rats were used for lentiviral-mediated knockdown of ENK to assess whether a decrease of ENK expression in the BLAp reproduces the behavioral disturbances found in vulnerable individuals. ENK knockdown specifically located in the BLAp was sufficient to increase anxiety in the behavioral tests, such as social interaction and elevated plus maze when compared with control individuals. These results show that specific neuroadaptation mediated by the ENKergic neurotransmission in the BLAp is a key regulator of resilience, whereas a decrease of the ENK in the BLAp is a maladaptation mechanism, which mediates the behavioral dichotomy observed between vulnerable and resilient following 3 weeks of CUS.     

Postsynaptic Adenosine A2A Receptors Modulate Intrinsic Excitability of Pyramidal Cells in the Rat Basolateral Amygdala

Background:

The basolateral amygdala plays a critical role in the etiology of anxiety disorders and addiction. Pyramidal neurons, the primary output cells of this region, display increased firing following exposure to stressors, and it is thought that this increase in excitability contributes to stress responsivity and the expression of anxiety-like behaviors. However, much remains unknown about the underlying mechanisms that regulate the intrinsic excitability of basolateral amygdala pyramidal neurons.

Methods:

Ex vivo gramicidin perforated patch recordings were conducted in current clamp mode where hyper- and depolarizing current steps were applied to basolateral amygdala pyramidal neurons to assess the effects of adenosine A_2A receptor modulation on intrinsic excitability.

Results:

Activation of adenosine A_2A receptors with the selective A_2A receptor agonist CGS-21680 significantly increased the firing rate of basolateral amygdala pyramidal neurons in rat amygdala brain slices, likely via inhibition of the slow afterhyperpolarization potential. Both of these A_2A receptor-mediated effects were blocked by preapplication of a selective A_2A receptor antagonist (ZM-241385) or by intra-pipette infusion of a protein kinase A inhibitor, suggesting a postsynaptic locus of A_2A receptors on basolateral amygdala pyramidal neurons. Interestingly, bath application of the A_2A receptor antagonist alone significantly attenuated basolateral amygdala pyramidal cell firing, consistent with a role for tonic adenosine in the regulation of the intrinsic excitability of these neurons.

Conclusions:

Collectively, these data suggest that adenosine, via activation of A_2A receptors, may directly facilitate basolateral amygdala pyramidal cell output, providing a possible balance for the recently described inhibitory effects of adenosine A₁ receptor activation on glutamatergic excitation of basolateral amygdala pyramidal cells.     

Cannabinoid Modulation of Amygdala Subregion Functional Connectivity to Social Signals of Threat

Background:

Δ⁹-Tetrahydrocannabinol has been shown to modulate anxiety and facilitate the extinction of fear by inhibiting amygdala reactivity. Since functional coupling between the amygdala and prefrontal cortex is implicated in affective processes, it is possible that Δ⁹-tetrahydrocannabinol affects amygdala-prefrontal cortex functional connectivity in ways that differ across amygdala subregions: basolateral, centromedial, and superficial.

Methods:

The aim of the study was to examine the effects of Δ⁹-tetrahydrocannabinol on functional connectivity between amygdala subregions and the prefrontal cortex during socio-emotional threat in healthy adults using a double-blind, placebo-controlled, within-subjects design. Sixteen subjects completed a functional magnetic resonance imaging task designed to probe amygdala responses to social threat. Amygdala subregion-prefrontal cortex functional connectivity was compared between Δ⁹-tetrahydrocannabinol and placebo using generalized psychophysiological interaction analyses.

Results:

Findings indicated that Δ⁹-tetrahydrocannabinol enhanced basolateral and superficial amygdala connectivity to the rostral anterior cingulate/medial prefrontal cortex.

Conclusion:

These effects, including Δ⁹-tetrahydrocannabinol’s potential ability to reduce threat perception or enhance socio-emotional regulation, may help understand the neurocircuitry of affect.     

PI3K/Akt Signaling Pathway in the Basolateral Amygdala Mediates the Rapid Antidepressant-like Effects of Trefoil Factor 3

Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.     

Interaction of the Basolateral Amygdala and Orbitofrontal Cortex is Critical for Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

The basolateral amygdala (BLA) and lateral orbitofrontal cortex (OFC) are critical elements of the neural circuitry that regulates drug context-induced reinstatement of cocaine-seeking behavior. Given the existence of dense reciprocal anatomical connections between these brain regions, this study tested the hypothesis that serial information processing by the BLA and OFC is necessary for drug context-induced cocaine-seeking behavior. Male Sprague–Dawley rats were trained to lever press for un-signaled cocaine infusions (0.15 mg/infusion, i.v.) in a distinct environment (cocaine-paired context) then underwent extinction training in a different environment (extinction context). During four subsequent test sessions, rats were re-exposed to the cocaine-paired and extinction contexts in order to assess cocaine-seeking behavior (non-reinforced active lever responding). Immediately before each test session, rats received microinfusions of the GABA_A/GABA_B agonist cocktail, baclofen+muscimol (BM: 1.0/.01 mM), or vehicle unilaterally into the BLA plus the contralateral or ipsilateral OFC, or unilaterally into the OFC alone. Exposure to the previously cocaine-paired context, but not the extinction context, reinstated extinguished cocaine-seeking behavior. BM-induced unilateral OFC inactivation failed to alter this behavior, similar to the effect of unilateral BLA inactivation in our previous study (Fuchs et al, 2007). Conversely, neural inactivation of the BLA plus the contralateral or ipsilateral OFC equally attenuated drug context-induced cocaine seeking without altering food-reinforced instrumental responding, relative to vehicle pretreatment. These findings suggest that the BLA and OFC co-regulate drug context-induced motivation for cocaine either through sequential information processing via intra- and interhemispheric connections or by providing converging input to a downstream brain region.     

No Laughing Matter: Intranasal Oxytocin Administration Changes Functional Brain Connectivity during Exposure to Infant Laughter

Infant laughter is a rewarding experience. It activates neural reward circuits and promotes parental proximity and care, thus facilitating parent–infant attachment. The neuropeptide oxytocin might enhance the incentive salience of infant laughter by modulating neural circuits related to the perception of infant cues. In a randomized controlled trial with functional magnetic resonance imaging we investigated the influence of intranasally administered oxytocin on functional brain connectivity in response to infant laughter. Blood oxygenation level-dependent responses to infant laughter were measured in 22 nulliparous women who were administered oxytocin and 20 nulliparous women who were administered a placebo. Elevated oxytocin levels reduced activation in the amygdala during infant laughter and enhanced functional connectivity between the amygdala and the orbitofrontal cortex, the anterior cingulate, the hippocampus, the precuneus, the supramarginal gyri, and the middle temporal gyrus. Increased functional connectivity between the amygdala and regions involved in emotion regulation may reduce negative emotional arousal while enhancing the incentive salience of the infant laughter.     

Comorbid Posttraumatic Stress Disorder and Opiate Addiction: A Literature Review

Treatment of comorbid posttraumatic stress disorder (PTSD) and opioid dependence has been a challenge for many clinicians. There are limited evidence-based guidelines for treatment of this comorbidity. Symptoms of PTSD and opiate dependence may converge, and it is sometimes difficult to differentiate between both conditions. For example, opioid withdrawal symptoms may mimic the hypervigilance and exacerbated startle response of patients with PTSD. A common neurobiologic circuit is suggested for the pathophysiologic mechanism of this comorbidity. There is evidence that opioid substitution therapy may improve treatment outcomes for opioid addiction in patients with comorbid PTSD and opioid dependence. Evidence-based psychotherapeutic intervention is recommended for this population to improve the psychological outcome as well. Combining opioid substitution therapy with evidence-based cognitive behavioral therapy designed for individuals with comorbid PTSD and substance abuse (e.g., Seeking Safety) may improve treatment outcomes in this population. More research is needed to understand the underlying mechanisms for this comorbidity and to improve treatment response.     

Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder

Generalized social anxiety disorder (GSAD) is characterized by aberrant patterns of amygdala-frontal connectivity to social signals of threat and at rest. The neuropeptide oxytocin (OXT) modulates anxiety, stress, and social behaviors. Recent functional neuroimaging studies suggest that these effects are mediated through OXT''s effects on amygdala reactivity and/or amygdala-frontal connectivity. The aim of the current study was to examine OXT''s effects on amygdala-frontal resting-state functional connectivity (rsFC) in GSAD patients and healthy controls (HCs). In a randomized, double-blind, cross-over design, 18 GSAD and 18 HC participants received intranasal OXT (24 IU or 40.32 μg) or placebo (PBO) before resting-state functional magnetic resonance imaging. In individuals with GSAD, OXT enhanced rsFC of the left and right amygdala with rostral anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC), and in doing so, reversed (ie, ‘normalized'') the reduced amygdala-frontal connectivity observed relative to HCs evident on PBO. Higher social anxiety severity in GSAD subjects correlated with lower amygdala-ACC/mPFC connectivity on PBO and higher social anxiety also correlated with greater enhancement in amygdala-frontal connectivity induced by OXT. These findings show that OXT modulates a neural circuit known for social threat processing and emotion regulation, suggesting a neural mechanism by which OXT may have a role in the pathophysiology and treatment of social anxiety disorder.     

Extracellular Signal-Regulated Kinase in the Basolateral Amygdala,but not the Nucleus Accumbens Core,is Critical for Context-Response-Cocaine Memory Reconsolidation in Rats

The reconsolidation of cocaine memories following retrieval is necessary for the sustained ability of a cocaine-paired environmental context to elicit cocaine seeking. Extracellular signal-regulated kinase (ERK) is an intracellular signaling molecule involved in nucleus accumbens core (NACc)-mediated reconsolidation of Pavlovian cocaine memories. Here, we used a rodent model of drug context-elicited relapse to test the hypothesis that ERK would be similarly required for the reconsolidation of context-response-cocaine memories that underlie drug context-induced reinstatement of instrumental cocaine-seeking behavior, with a focus on the NACc and on the basolateral amygdala (BLA), another important locus for the reconsolidation of cocaine memories. We show that the mitogen-activated protein kinase (MEK)/ERK1/2 inhibitor, U0126 (1.0 μg/0.5 μl/hemisphere), microinfused bilaterally into the BLA—but not the NACc—immediately after brief re-exposure to a previously cocaine-paired context (that is, cocaine-memory reactivation), significantly attenuated subsequent drug context-induced cocaine seeking relative to vehicle (VEH). This effect in the BLA was associated with a transient inhibition of ERK1/2 phosphorylation, and it depended on memory reactivation given that U0126 administered following exposure to a novel context did not alter subsequent cocaine seeking. Furthermore, similar to U0126, baclofen+muscimol-induced (B+M; 106.8/5.7 ng/0.5 μl/hemisphere) neural inactivation of the NACc, following cocaine-memory reactivation, failed to alter subsequent cocaine seeking. These findings demonstrate that ERK activation in the BLA, but not the NACc, is required for the reconsolidation of context-response-cocaine associative memories. Together with prior research, these results suggest that contextual drug-memory reconsolidation in Pavlovian and instrumental settings involves distinct neuroanatomical mechanisms.     

Negative Affect Mediates the Association between Posttraumatic Cognitions and Craving in Veterans with Posttraumatic Stress Disorder and Alcohol Use Disorder

Abstract

Objective: The co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common. Individuals with PTSD/AUD commonly drink to cope with PTSD symptoms, which maintains PTSD/AUD, and may result in increased craving for alcohol. Negative affect is implicated in negative reinforcement models of craving. Further, Emotional Processing Theory posits that posttraumatic cognitions lead to the experience of negative affect, which may result in increased craving in PTSD/AUD. The current study aims to advance the understanding of craving in PTSD/AUD by evaluating if specific posttraumatic cognitions (e.g., cognitions about the self, world, and self-blame) are associated with increased negative affect, and whether higher negative affect is associated with heightened craving. Methods: Three separate simple mediation models were utilized to test if negative affect mediated the relationship between each specific posttraumatic cognition type and craving among 136 treatment-seeking veterans with PTSD/AUD. Results: We found that negative affect mediated the association between all posttraumatic cognition types and craving. Specifically, viewing oneself as being unable to handle PTSD-related distress, viewing the world as very dangerous, and blaming oneself for one’s role in a traumatic event were all associated with increased negative affect, which was related to higher craving. Conclusions: Given that posttraumatic cognitions improve via trauma-focused treatment for PTSD, future work should evaluate whether improvements in posttraumatic cognitions via trauma-focused treatment lead to decreased negative affect and craving in PTSD/AUD.     

Posttraumatic Stress Disorder,Gender, and Problem Profiles in Substance Dependent Patients

Patients with a chronic and severe substance-use disorder who also have a history of posttraumatic stress disorder (PTSD) are thought to have a unique set of problems. The present study assessed psychiatric disorders, psychosocial problems, and traumatic events with structured interviews in 747 men and 693 women enrolling in urban opioid substitution treatment programs from 1995 to 2001. Participants with versus without a history of PTSD were more likely to have a history of many other psychiatric disorders and demonstrated more current and historical medical, employment, family/social, and psychiatric problems. PTSD was generally unrelated to substance-use disorder severity or diagnoses, with the exception of an increased risk of alcohol dependence. Women were more likely than men to have experienced sexual assault, and less likely to have been physically assaulted, although these events precipitated PTSD at equivalent rates across gender. In contrast, witnessing or hearing about the death or injury of others was more likely to precipitate PTSD in women than men. Female gender, exposure to combat, sexual assault, or physical assault, and a history of major mood or anxiety disorder were the best predictors of PTSD in this group. Study limitations are noted.