Effects of chronic stress on dendritic arborization in the central and extended amygdala

A differential role has been suggested for two important areas in the neural circuitry of stress, central nucleus of the amygdala (CeA) and bed nucleus of stria terminalis (BNST) in the extended amygdala, in regulating fear versus anxiety. Since chronic stress enhances anxiety and consolidation of aversive memories, we examined the effects of chronic immobilization stress (CIS) on neuronal morphology in the CeA and BNST of rats. In contrast to previous reports of stress-induced atrophy in the hippocampus, CIS does not cause dendritic atrophy in CeA and BNST neurons. While dendritic arborization in CeA neurons remains unaffected, it increases in BNST neurons after CIS. These results suggest a role for dendritic remodeling of BNST neurons in stress-induced facilitation of anxiety.     

Plasticity of inhibitory synaptic network interactions in the lateral amygdala upon fear conditioning in mice

After fear conditioning, plastic changes of excitatory synaptic transmission occur in the amygdala. Fear‐related memory also involves the GABAergic system, although no influence on inhibitory synaptic transmission is known. In the present study we assessed the influence of Pavlovian fear conditioning on the plasticity of GABAergic synaptic interactions in the lateral amygdala (LA) in brain slices prepared from fear‐conditioned, pseudo‐trained and naïve adult mice. Theta‐burst tetanization of thalamic afferent inputs to the LA evoked an input‐specific potentiation of inhibitory postsynaptic responses in projection neurons; the cortical input was unaffected. Philanthotoxin (10 µm ), an antagonist of Ca²⁺‐permeable AMPA receptors, disabled this plastic phenomenon. Surgical isolation of the LA, extracellular application of a GABA_B receptor antagonist (CGP 55845A, 10 µm ) or an NMDA receptor antagonist (APV, 50 µm ), or intracellular application of BAPTA (10 mm ), did not influence the plasticity. The plasticity also showed as a potentiation of monosynaptic excitatory responses in putative GABAergic interneurons. Pavlovian fear conditioning, but not pseudo‐conditioning, resulted in a significant reduction in this potentiation that was evident 24 h after training. Two weeks after training, the potentiation returned to control levels. In conclusion, a reduction in potentiation of inhibitory synaptic interactions occurs in the LA and may contribute to a shift in synaptic balance towards excitatory signal flow during the processes of fear‐memory acquisition or consolidation.     

Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia

Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories.     

Differential activation of CRF receptor subtypes removes stress-induced memory deficit and anxiety

The objective of this study was to investigate the role of corticotropin-releasing factor receptors 1 (CRF(1)) and 2 (CRF(2)) in anxiety-like behavior and learning of C57BL/6J mice after exposure to a stressful stimulus. When C57BL/6J mice were exposed to immobilization (1 h) serving as stressful stimulus, context- and tone-dependent fear conditioning were impaired if the training followed immediately after immobilization. The stress-induced impairment of context-dependent fear conditioning was prevented by specific blockade of CRF(2) of the lateral septum (LS) with anti-sauvagine-30. Immobilization did not only affect conditioned fear, but also enhanced, through CRF(2) of the LS, anxiety-like behavior determined with the elevated plus maze. Recovery from stress-induced anxiety and impairment of context-dependent fear conditioning was observed after 1 h delay of training and required hippocampal CRF(1), as indicated by the finding that this recovery was prevented by blockade of intrahippocampal CRF(1). It was concluded that exposure to a stressor initially affected both anxiety-like behavior and contextual conditioned fear through septal CRF(2), while the later activation of hippocampal CRF(1) resulted in the return to baseline levels of both processes. Intraventricular injection of mouse urocortin 2, a CRF(2)-selective agonist, removed the stress-induced anxiety and learning impairment, but did not reduce the activation of the hypothalamic pituitary adrenal axis indicative of the hormonal stress response. We propose that the enhanced anxiety is the component of the stress response responsible for the memory deficit.     

Placing prediction into the fear circuit

Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review recent electrophysiological, molecular and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray region, can be linked to prediction error and expectation modulation of fear learning, as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signaling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure-based treatments for clinical anxiety. This aversive prediction error circuit might represent a conserved mechanism for regulating fear learning in mammals.     

The Roles of Basolateral Amygdala Parvalbumin Neurons in Fear Learning

The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV)-expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, activity profiles of these interneurons across the course of fear learning, and whether or how these change across the course of learning all remain poorly understood. Here, we used PV cell-type-specific recording and manipulation approaches in male transgenic PV-Cre rats during pavlovian fear conditioning to address these issues. We show that activity of BLA PV neurons during the moments of aversive reinforcement controls fear learning about aversive events, but activity during moments of nonreinforcement does not control fear extinction learning. Furthermore, we show expectation-modulation of BLA PV neurons during fear learning, with greater activity to an unexpected than expected aversive unconditioned stimulus (US). This expectation-modulation was specifically because of BLA PV neuron sensitivity to aversive prediction error. Finally, we show that BLA PV neuron function in fear learning is conserved across these variations in prediction error. We suggest that aversive prediction-error modulation of PV neurons could enable BLA fear-learning circuits to retain selectivity for specific sensory features of aversive USs despite variations in the strength of US inputs, thereby permitting the rapid updating of fear associations when these sensory features change.SIGNIFICANCE STATEMENT The capacity to learn about sources of danger in the environment is essential for survival. This learning depends on complex microcircuitries of inhibitory interneurons in the basolateral amygdala. Here, we show that parvalbumin-positive GABAergic interneurons in the rat basolateral amygdala are important for fear learning during moments of danger, but not for extinction learning during moments of safety, and that the activity of these neurons is modulated by expectation of danger. This may enable fear-learning circuits to retain selectivity for specific aversive events across variations in expectation, permitting the rapid updating of learning when aversive events change.     

NMDA receptors are essential for the acquisition, but not expression, of conditional fear and associative spike firing in the lateral amygdala

We examined the contribution of N-methyl-D-aspartate (NMDA) receptors (NMDARs) to the acquisition and expression of amygdaloid plasticity and Pavlovian fear conditioning using single-unit recording techniques in behaving rats. We demonstrate that NMDARs are essential for the acquisition of both behavioral and neuronal correlates of conditional fear, but play a comparatively limited role in their expression. Administration of the competitive NMDAR antagonist +/--3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) prior to auditory fear conditioning completely abolished the acquisition of conditional freezing and conditional single-unit activity in the lateral amygdala (LA). In contrast, CPP given prior to extinction testing did not affect the expression of conditional single-unit activity in LA, despite producing deficits in conditional freezing. Administration of CPP also blocked the induction of long-term potentiation in the amygdala. Together, these data suggest that NMDARs are essential for the acquisition of conditioning-related plasticity in the amygdala, and that NMDARs are more critical for regulating synaptic plasticity and learning than routine synaptic transmission in the circuitry supporting fear conditioning.     

Modulation of glutamatergic synaptic transmission in the bed nucleus of the stria terminalis

Glutamate, catecholamine and neuropeptide signaling within the bed nucleus of the stria terminalis (BNST) have all been identified as key participants in anxiety-like behaviors and behaviors related to withdrawal from exposure to substances of abuse. The BNST is thought to serve as a key relay between limbic cognitive centers and reward, stress and anxiety nuclei. Human studies and animal models have demonstrated that stressors and drugs of abuse can result in long term behavioral modifications that can culminate in psychological diseases such as addiction and post-traumatic stress disorder. The ability of catecholamines and neuropeptides to influence synaptic glutamatergic transmission (stemming from cognitive centers) within the BNST may have profound consequences over these behaviors. In this review we highlight studies examining synaptic plasticity and modulation of excitatory transmission within the BNST, emphasizing how such modulation may result in alterations in anxiety and reward related behavior.     

EphrinA4 mimetic peptide targeted to EphA binding site impairs the formation of long-term fear memory in lateral amygdala

Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathologies conditions such as phobias and posttraumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). EphrinA4 and its cognate Eph receptors are intimately involved in regulating neuronal morphogenesis, synaptic transmission and plasticity. To assess possible roles of ephrinA4 in fear memory formation we designed and used a specific inhibitory ephrinA4 mimetic peptide (pep-ephrinA4) targeted to EphA binding site. We show that this peptide, composed of the ephrinA4 binding domain, interacts with EphA4 and inhibits ephrinA4-induced phosphorylation of EphA4. Microinjection of the pep-ephrinA4 into rat LA 30 min before training impaired long- but not short-term fear conditioning memory. Microinjection of a control peptide derived from a nonbinding E helix site of ephrinA4, that does not interact with EphA, had no effect on fear memory formation. Microinjection of pep-ephrinA4 into areas adjacent to the amygdala had no effect on fear memory. Acute systemic administration of pep-ephrinA4 1 h after training also impaired long-term fear conditioning memory formation. These results demonstrate that ephrinA4 binding sites in LA are essential for long-term fear memory formation. Moreover, our research shows that ephrinA4 binding sites may serve as a target for pharmacological treatment of fear and anxiety disorders.     

Towards a better preclinical model of PTSD: Characterizing animals with weak extinction,maladaptive stress responses and low plasma corticosterone

Most of the available preclinical models of PTSD have focused on isolated behavioural aspects and have not considered individual variations in response to stress. We employed behavioural criteria to identify and characterize a subpopulation of rats that present several features analogous to PTSD-like states after exposure to classical fear conditioning. Outbred Sprague-Dawley rats were segregated into weak- and strong-extinction groups on the basis of behavioural scores during extinction of conditioned fear responses. Animals were subsequently tested for anxiety-like behaviour in the open-field test (OFT), novelty supressed feeding (NSF) and elevated plus maze (EPM). Baseline plasma corticosterone was measured prior to any behavioural manipulation. In a second experiment, rats underwent OFT, NSF and EPM prior to being subjected to fear conditioning to ascertain whether or not pre-stress levels of anxiety-like behaviours could predict extinction scores. We found that 25% of rats exhibit low extinction rates of conditioned fear, a feature that was associated with increased anxiety-like behaviour across multiple tests in comparison to rats showing strong extinction. In addition, weak-extinction animals showed low levels of corticosterone prior to fear conditioning, a variable that seemed to predict extinction recall scores. In a separate experiment, anxiety measures taken prior to fear conditioning were not predictive of a weak-extinction phenotype, suggesting that weak-extinction animals do not show detectable traits of anxiety in the absence of a stressful experience. These findings suggest that extinction impairment may be used to identify stress-vulnerable rats, thus providing a useful model for elucidating mechanisms and investigating potential treatments for PTSD.     

Administration of moclobemide facilitates fear extinction and attenuates anxiety-like behaviors by regulating synaptic-associated proteins in a rat model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a long-lasting mental disorder and accompanied by worse fear extinction. Enhanced fear memory or poor fear extinction are typical features of PTSD. Dysfunction of the serotonergic neurotransmitter system is involved in numerous mental and behavioral disorders. Monoamine oxidase A (MAOA) is important in the metabolism of serotonin and play an important role in behavious. The aim of this study was to explore the change of MAOA and effect of MAOA on fear memory in PTSD. We used single prolonged stress (SPS) to create animal model of PTSD. A startle/fear box and elevated plus maze were used to observe fear memory and anxiety level, respectively. We examined the expression of MAOA and synaptic marker protein, as well as the immunological activity of MAOA in the infralimbic cortex (IL) area, which is a critical brain region involved in emotions, especially fear regulation. We found increased anxiety-like behavior, dysfunction in fear extinction, and increased MAOA in SPS rats. After treatment with moclobemide (a selective inhibitor of MAOA), SPS rats showed significantly improved fear memory and decreased anxiety-like behavior, which indicated that moclobemide could reverse fear extinction deficit and attenuate abnormally increased levels of anxiety caused by SPS in short term. On the contrary, decreased PSD-95 and SYN1 expression in the IL region were also reversed by moclobemide. These results suggest that increased MAOA play a negative role in fear extinction and levels of anxiety in PTSD, which may be involved in change in PSD-95 and SYN1.     

Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice

The endocannabinoid system (ECS) tightly controls emotional responses to acute aversive stimuli. Repeated stress alters ECS activity but the role played by the ECS in the emotional consequences of repeated stress has not been investigated in detail. This study used social defeat stress, together with pharmacology and genetics to examine the role of cannabinoid type-1 (CB(1)) receptors on repeated stress-induced emotional alterations. Seven daily social defeat sessions increased water (but not food) intake, sucrose preference, anxiety, cued fear expression, and adrenal weight in C57BL/6N mice. The first and the last social stress sessions triggered immediate brain region-dependent changes in the concentrations of the principal endocannabinoids anandamide and 2-arachidonoylglycerol. Pretreatment before each of the seven stress sessions with the CB(1) receptor antagonist rimonabant prolonged freezing responses of stressed mice during cued fear recall tests. Repeated social stress abolished the increased fear expression displayed by constitutive CB(1) receptor-deficient mice. The use of mutant mice lacking CB(1) receptors from cortical glutamatergic neurons or from GABAergic neurons indicated that it is the absence of the former CB(1) receptor population that is responsible for the fear responses in socially stressed CB(1) mutant mice. In addition, stress-induced hypolocomotor reactivity was amplified by the absence of CB(1) receptors from GABAergic neurons. Mutant mice lacking CB(1) receptors from serotonergic neurons displayed a higher anxiety but decreased cued fear expression than their wild-type controls. These mutant mice failed to show social stress-elicited increased sucrose preference. This study shows that (i) release of endocannabinoids during stress exposure impedes stress-elicited amplification of cued fear behavior, (ii) social stress opposes the increased fear expression and delayed between-session extinction because of the absence of CB(1) receptors from cortical glutamatergic neurons, and (iii) CB(1) receptors on central serotonergic neurons are involved in the sweet consumption response to repeated stress.     

Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical–amygdala pathway and fear memory

Deep brain stimulation (DBS) of the amygdala has been demonstrated to modulate hyperactivity of the amygdala, which is responsible for the symptoms of post-traumatic stress disorder (PTSD), and thus might be used for the treatment of PTSD. However, the underlying mechanism of DBS of the amygdala in the modulation of the amygdala is unclear. The present study investigated the effects of DBS of the amygdala on synaptic transmission and synaptic plasticity at cortical inputs to the amygdala, which is critical for the formation and storage of auditory fear memories, and fear memories. The results demonstrated that auditory fear conditioning increased single-pulse-evoked field excitatory postsynaptic potentials in the cortical–amygdala pathway. Furthermore, auditory fear conditioning decreased the induction of paired-pulse facilitation and long-term potentiation, two neurophysiological models for studying short-term and long-term synaptic plasticity, respectively, in the cortical–amygdala pathway. In addition, all these auditory fear conditioning-induced changes could be reversed by DBS of the amygdala. DBS of the amygdala also rescued auditory fear conditioning-induced enhancement of long-term retention of fear memory. These findings suggested that DBS of the amygdala alleviating fear conditioning-induced alterations in synaptic plasticity in the cortical–amygdala pathway and fear memory may underlie the neuromodulatory role of DBS of the amygdala in activities of the amygdala.     

Extinction of cued fear memory involves a distinct form of depotentiation at cortical input synapses onto the lateral amygdala

The amygdala is known to be a critical storage site of conditioned fear memory. Among the two major pathways to the lateral amygdala (LA), the cortical pathway is known to display a presynaptic long‐term potentiation which is occluded with fear conditioning. Here we show that fear extinction results in a net depression of conditioning‐induced potentiation at cortical input synapses onto the LA (C‐LA synapses). Fear conditioning induced a significant potentiation of excitatory postsynaptic currents at C‐LA synapses compared with naïve and unpaired controls, whereas extinction apparently reversed this potentiation. Paired‐pulse low‐frequency stimulation (pp‐LFS) induced synaptic depression in the C‐LA pathway of fear‐conditioned rats, but not in naïve or unpaired controls, indicating that the pp‐LFS‐induced depression is specific to associative learning‐induced changes (pp‐LFS‐induced depotentiation_{ex vivo}). Importantly, extinction occluded pp‐LFS‐induced depotentiation_{ex vivo}, suggesting that extinction shares some mechanisms with the depotentiation. pp‐LFS‐induced depotentiation_{ex vivo} required NMDA receptor (NMDAR) activity, consistent with a previous finding that blockade of amygdala NMDARs impaired fear extinction. In addition, pp‐LFS‐induced depotentiation_{ex vivo} required activity of group II metabotropic glutamate receptors (mGluRs), known to be present at presynaptic terminals, but not AMPAR internalization, consistent with a presynaptic mechanism for pp‐LFS‐induced depotentiation_{ex vivo}. This result is in contrast with another form of ex vivo depotentiation in the thalamic pathway that requires both group I mGluR activity and AMPAR internalization. We thus suggest that extinction of conditioned fear involves a distinct form of depotentiation at C‐LA synapses, which depends upon both NMDARs and group II mGluRs.     

Fear learning induces persistent facilitation of amygdala synaptic transmission

In the maintenance phase of fear memory, synaptic transmission is potentiated and the stimulus requirements and signalling mechanisms are altered for long-term potentiation (LTP) in the cortico-lateral amygdala (LA) pathway. These findings link amygdala synaptic plasticity to the coding of fear memories. Behavioural experiments suggest that the amygdala serves to store long-term fear memories. Here we provide electrophysiological evidence showing that synaptic alterations in rats induced by fear conditioning are evident in vitro 10 days after fear conditioning. We show that synaptic transmission was facilitated and that high-frequency stimulation dependent LTP (HFS-LTP) of the cortico-lateral amygdala pathway remained attenuated 10 days following fear conditioning. Additionally, we found that the low-frequency stimulation dependent LTP (LFS-LTP) measured 24 h after fear conditioning was absent 10 days post-training. The persistent facilitation of synaptic transmission and occlusion of HFS-LTP suggests that, unlike hippocampal coding of contextual fear memory, the cortico-lateral amygdala synapse is involved in the storage of long-term fear memories. However, the absence of LFS-LTP 10 days following fear conditioning suggests that amygdala physiology 1 day following fear learning may reflect a dynamic state during memory stabilization that is inactive during the long-term storage of fear memory. Results from these experiments have significant implications regarding the locus of storage for maladaptive fear memories and the synaptic alterations induced by these memories.     

Resilience against predator stress and dendritic morphology of amygdala neurons

Individual differences in coping response lie at the core of vulnerability to conditions like post-traumatic stress disorder (PTSD). Like humans, not all animals exposed to severe stress show lasting change in affect. Predator stress is a traumatic experience inducing long-lasting fear, but not in all rodents. Thus, individual variation may be a cross species factor driving responsiveness to stressful events. The present study investigated neurobiological bases of variation in coping with severe stress. The amygdala was studied because it modulates fear and its function is affected by stress. Moreover, stress-induced plasticity of the amygdala has been related to induction of anxiety, a comorbid symptom of psychiatric conditions like PTSD. We exposed rodents to predator stress and grouped them according to their adaptability based on a standard anxiety test (the elevated plus maze). Subsequently we investigated if well-adapted (less anxious) and mal-adapted (extremely anxious) stressed animals differed in the structure of dendritic trees of their output neurons of the right basolateral amygdala (BLA). Two weeks after exposure to stress, well-adapted animals showed low anxiety levels comparable to unstressed controls, whereas mal-adapted animals were highly anxious. In these same animals, Golgi analysis revealed that BLA neurons of well-adapted rats exhibited more densely packed and shorter dendrites than neurons of mal-adapted or unstressed control animals, which did not differ. These data suggest that dendritic hypotrophy in the BLA may be a resilience marker against lasting anxiogenic effects of predator stress.     

Mild traumatic brain injury in the rat alters neuronal number in the limbic system and increases conditioned fear and anxiety-like behaviors

Recent reports suggest that experiencing a mild closed head trauma or mild traumatic brain injury (mTBI) is associated with a greater incidence of anxiety disorders. Dysfunction of limbic structures, such as the medial prefrontal cortex, amygdala and hippocampus, is associated with the symptoms of anxiety disorders. Therefore, the goal of the current studies was to characterize the consequences of closed mTBI on these limbic structures and associated fear and anxiety-related behaviors. A weight-drop procedure was employed to induce mTBI in male rats. Rats were transcardically perfused 4 or 9 days following exposure to mTBI or control procedures, and neuronal number, brain region area, and the number of apoptotic cells in each region were determined. In separate groups of rats, the effects of mTBI on anxiety-like behaviors, motor function, nociception, and acquisition, retention and extinction of contextual fear were also assessed. Findings suggest that mTBI was associated with significant neuronal cell loss in the CA1 region of the dorsal hippocampus and increased cell number in subregions of the amygdala, both of which appear to be related to alterations to apoptosis in these regions following mTBI. Furthermore, mTBI increased expression of anxiety-like behaviors and conditioned fear, with no effect on motor performance or nociception. Overall, a single impact to the skull to mimic mTBI in rats produces discrete alterations to neuronal numbers within the limbic system and specific emotional deficits, providing a potential neurobiological link between mTBI and anxiety disorders.     

Intra-amygdaloid microinjection of neuropeptide glutamic acid-isoleucine induces anxiety-like behavior

The amygdaloid complex is involved in anxiety or fear responses to stressful stimuli. In this study the effect of neuropeptide-EI on anxiety-like behavior and its influence on adrenocortical function was tested in male Wistar rats that were injected bilaterally in the basolateral amygdala with neuropeptide-EI (1 μg/1 μl) or artificial cerebrospinal fluid and placed on the plus maze. The plasma corticosterone levels were analyzed in controls and plus-maze exposed animals. Neuropeptide-EI in the basolateral amygdala significantly decreased the time spent in open arms but had no effect on locomotor activity, showing an anxiogenic effect. However, neuropeptide administration did not change serum corticosterone levels compared with vehicle controls. Our results suggest that the anxiogenic effect of neuropeptide-EI could be independent of the hypothalamic-pituitary-adrenocortical system response.     

Effects of stress and aversion on dopamine neurons: Implications for addiction

Stress plays a key role in modulating the development and expression of addictive behavior, and is a major cause of relapse following periods of abstinence. In this review we focus our attention on recent advances made in understanding how stress, aversive events, and drugs of abuse, cocaine in particular, interact directly with dopamine neurons in the ventral tegmental area, and how these interactions may be involved in stress-induced relapse. We start by outlining how dopamine neurons respond to aversive stimuli and stress, particularly in terms of firing activity and modulation of excitatory synaptic inputs. We then discuss some of the cellular mechanisms underlying the effects of cocaine on dopamine neurons, again with a selective focus on synaptic plasticity. Finally, we examine how the effects of stress and cocaine interact and how these cellular mechanisms in ventral tegmental area dopamine neurons may be engaged in stress-induced relapse.     

Effects of stress and aversion on dopamine neurons: Implications for addiction

Stress plays a key role in modulating the development and expression of addictive behavior, and is a major cause of relapse following periods of abstinence. In this review we focus our attention on recent advances made in understanding how stress, aversive events, and drugs of abuse, cocaine in particular, interact directly with dopamine neurons in the ventral tegmental area, and how these interactions may be involved in stress-induced relapse. We start by outlining how dopamine neurons respond to aversive stimuli and stress, particularly in terms of firing activity and modulation of excitatory synaptic inputs. We then discuss some of the cellular mechanisms underlying the effects of cocaine on dopamine neurons, again with a selective focus on synaptic plasticity. Finally, we examine how the effects of stress and cocaine interact and how these cellular mechanisms in ventral tegmental area dopamine neurons may be engaged in stress-induced relapse.