应激诱发复吸的动物模型及其神经生物学基础

复吸是药物成瘾的重要特征,应激是诱发复吸的因素之一。该文介绍了用于研究应激诱发复吸的动物恢复模型,阐述了涉及应激诱发复吸的神经生物学基础。大量研究结果表明,下丘脑外侧的终纹床核与杏仁核内的促肾上腺皮质激素释放因子和去甲肾上腺素是参与应激诱发复吸的重要神经递质。内侧前额叶皮层可能是介导应激、药物点燃及药物相关线索等各类因素诱发复吸的共同通路     

Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety

Stress initiates a series of neuronal responses that prepare an organism to adapt to new environmental challenges. However, chronic stress may lead to maladaptive responses that can result in psychiatric syndromes such as anxiety and depressive disorders. Corticotropin-releasing factor (CRF) has been identified as a key neuropeptide responsible for initiating many of the endocrine, autonomic and behavioral responses to stress. The amygdala expresses high concentrations of CRF receptors and is itself a major extrahypothalamic source of CRF containing neurons. Within the amygdala, the basolateral nucleus (BLA) has an important role in regulating anxiety and affective responses. During periods of stress, CRF is released into the amygdala and local CRF receptor activation has been postulated as a substrate for stress-induced alterations in affective behavior. Previous studies have suggested that synaptic plasticity in the BLA contributes to mechanisms underlying long-term changes in the regulation of affective behaviors. Several studies have shown that acute glutamate receptor-mediated activation, by either GABA-mediated disinhibition or CRF-mediated excitation, induces long-term synaptic plasticity and increases the excitability of BLA neurons. This review summarizes some of the data supporting the hypotheses that stress induced plasticity within the amygdala may be a critical step in the pathophysiology of the development of chronic anxiety states. It is further proposed that such a change in the limbic neural circuitry is involved in the transition from normal vigilance responses to pathological anxiety, leading to syndromes such as panic and post-traumatic stress disorders.     

The central amygdala nucleus via corticotropin-releasing factor is necessary for time-limited consolidation processing but not storage of contextual fear memory

The central nucleus of the amygdala (CeA) is traditionally portrayed in fear conditioning as the key neural output that relays conditioned information established in the basolateral amygdala complex to extra-amygdalar brain structures that generate emotional responses. However, several recent studies have questioned this serial processing view of the amygdalar fear conditioning circuit by showing an influence of the CeA on memory consolidation. We previously reported that inhibition of endogenous CeA secretion of corticotropin-releasing factor (CRF) at the time of contextual training effectively impaired fear memory consolidation. However, the time-dependent range of CeA CRF secretion in facilitating consolidation processing has not been examined. Therefore, to address this issue, we performed CeA site-specific microinjections of CRF antisense oligonucleotides (CRF ASO) at several post-training time intervals. Rats microinjected with CRF ASO at post-training intervals up to 24-h subsequently exhibited significant impairments in contextual freezing retention in contrast to animals treated 96-h after training. To further establish the validity of the results, CeA fiber-sparing lesions were made at two distinct post-training periods (24-h and 96-h), corresponding respectively to the temporal intervals when CeA CRF ASO administration disrupted or had no significant effects on memory consolidation. Similar to the CeA CRF ASO results, CeA lesions made 24-h, but not 96-h, after training induced significant freezing deficits in the retention test. In conclusion, the current results demonstrate: (1) an extended involvement of CeA CRF in contextual memory consolidation and (2) that contextual fear memory storage is not dependent on a functional CeA.     

Hypothalamo-Pituitary-Adrenocortical Regulation Following Lesions of the Central Nucleus of the Amygdala

Previous reports indicate that the central nucleus of the amygdala (CeA) stimulates adrenocorticotropin and corticosterone secretion, suggesting a role for this region in central hypothalamo-pituitary-adrenocortical (HPA) stress regulation. To evaluate this hypothesis, this study assessed the impact of CeA lesion on the response of hypophysiotrophic paraventricular nucleus (PVN) neurons to acute restraint and chronic unpredictable stress exposure. In contrast to previous reports, CeA lesions did not affect corticosterone or ACTH secretion induced by acute stress. Acute restraint increased PVN corticotropin releasing hormone (CRH) mRNA expression, increased the number of parvocellular PVN neurons expressing the co-secretagogue arginine vasopressin (AVP), and induced cFOS mRNA expression in the parvocellular PVN. However, there was no additional effect of CeA lesion on any measure of PVN activation. Chronic unpredictable stress exposure induced long-term activation of the HPA axis, noted by thymic involution, adrenal hypertrophy and increased PVN CRH mRNA expression. Stress-induced changes in thymus and adrenal weights were not affected by CeA lesion. Further, CeA lesion rats did not differ from controls in post-stress CRH mRNA expression. However, basal CRH mRNA expression was increased in the PVN of CeA rats, suggesting that the CeA plays a role in long-term inhibition of the PVN. The results of these studies are not consistent with the hypothesis that the CeA is necessary for stress-induced pituitary-adrenocortical activation. Rather, this region may play a stressor-specific modulatory role in regulation of HPA function.     

The central nucleus of the amygdala; a conduit for modulation of HPA axis responses to an immune challenge?

Physical stressors such as infection, inflammation and tissue injury elicit activation of the hypothalamic-pituitary-adrenal (HPA) axis. This response has significant implications for both immune and central nervous system function. Investigations in rats into the neural substrates responsible for HPA axis activation to an immune challenge have predominantly utilized an experimental paradigm involving the acute administration of the pro-inflammatory cytokine interleukin- 1β (IL-1β). It is well recognized that medial parvocellular corticotrophin-releasing factor cells of the paraventricular nucleus (mPVN CRF) are critical in generating HPA axis responses to an immune challenge but little is known about how peripheral immune signals can activate and/or modulate the mPVN CRF cells. Studies that have examined the afferent control of the mPVN CRF cell response to systemic IL-1β have centred largely on the inputs from brainstem catecholamine cells. However, other regulatory neuronal populations also merit attention and one such region is a component of the limbic system, the central nucleus of the amygdala (CeA). A large number of CeA cells are recruited following systemic IL-lβ administration and there is a significant body of work indicating that the CeA can influence HPA axis function. However, the contribution of the CeA to HPA axis responses to an immune challenge is only just beginning to be addressed. This review examines three aspects of HPA axis control by systemic IL-1β: (i) whether the CeA has a role in generating HPA axis responses to systemic IL-1β, (ii) the identity of the neural connections between the CeA and mPVN CRF cells that might be important to HPA axis responses and(iii) the mechanisms by which systemic IL-Iβ triggers the recruitment of CeA cells.     

Neural systems involved in fear and anxiety measured with fear-potentiated startle

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala (BLA). The BLA projects to the central (CeA) and medial (MeA) nuclei of the amygdala, which project indirectly to a particular part of the acoustic startle pathway in the brainstem. N-methyl-D-aspartate (NMDA) receptors, as well as various intracellular cascades in the amygdala, are critical for fear learning, which is then mediated by glutamate acting in the CeA. Less predictable stimuli, such as a long-duration bright light or a fearful context, activate the BLA, which projects to the bed nucleus of the stria terminalis (BNST), which projects to the startle pathway much as the CeA does. The anxiogenic peptide corticotropin-releasing hormone increases startle by acting directly in the BNST. CeA-mediated behaviors may represent stimulus-specific fear, whereas BNST-mediated behaviors are more akin to anxiety. NMDA receptors are also involved in extinction of conditioned fear, and both extinction in rats and exposure-based psychotherapy in humans are facilitated by an NMDA-partial agonist called D-cycloserine. ((c) 2006 APA, all rights reserved).     

Mitogen-activated protein kinase in the amygdala plays a critical role in lithium chloride-induced taste aversion learning

The intracellular mitogen-activated protein kinase (MAPK) pathway in the brain is necessary for the formation of a variety of memories including conditioned taste aversion (CTA) learning. However, the functional role of MAPK activation in the amygdala during lithium chloride (LiCl)-induced CTA learning has not been established. In the present study, we investigated if local microinjection of SL327, a MAPK kinase inhibitor, into the rat amygdala could alleviate LiCl-induced CTA learning. Our results revealed that acute administration of a high dose of LiCl (0.15M, 12 ml/kg, i.p.) rapidly increased the level of phosphorylated MAPK (pMAPK)-positive cells in the central nucleus of the amygdala (CeA) and nucleus of the solitary tract (NTS) of rats as measured by immunohistochemistry. Local microinjection of SL327 (1 μg/0.5 μl/hemisphere) into the CeA 10 min before LiCl administration decreased both the strength of LiCl-induced CTA paired with 0.125% saccharin and the level of LiCl-induced pMAPK-positive cells in the CeA, but not in the NTS. Our data suggest that the intracellular signaling cascade of the MAPK pathway in the CeA plays a critical role in the processing of visceral information induced by LiCl for CTA learning.     

The role of corticotrophin-releasing hormone receptors in the calcitonin gene-related peptide-induced suppression of pulsatile luteinising hormone secretion in the female rat

Corticotrophin-releasing hormone (CRH) plays a pivotal role in the suppression of the gonadotrophin-releasing hormone (GRH) pulse generator in response to stress and intracerebroventricular (i.c.v.) administration of calcitonin gene-related peptide (CGRP). We have previously shown both CRH receptor subtypes, CRH-R1 and CRH-R2, are involved in the stress-induced suppression of LH pulses. The aims of the present study were to examine the role of CRH-R1 and CRH-R2 in CGRP-induced suppression of LH pulses, and to investigate the effects of CGRP on CRH expression in the paraventricular nucleus (PVN) and central nucleus of the amygdala (CeA), which have prominent CRH neurone populations that receive dense CGRP innervations. The suppression of LH pulses by CGRP (1.5 microg i.c.v.) was completely prevented by intravenous administration of the CRH-R1 antagonist SSR125543Q (7.5 mg/rat i.v., 30 min before CGRP), but was not affected by the CRH-R2 antagonist, astressin(2)-B (100 microg i.c.v., 10 min before CGRP). CGRP increased the CRH mRNA expression in PVN and CeA. These results provide evidence of a role for CRH-R1 in mediating the suppressive effects of CGRP on pulsatile LH secretion in the female rat, and additionally raise the possibility of an involvement of PVN and CeA CRH neuronal populations in this suppression.     

The bed nucleus of the stria terminalis is required for the expression of contextual but not auditory freezing in rats with basolateral amygdala lesions

Previous data suggest that overtraining can overcome fear conditioning deficits in rats with lesions of the basolateral complex of the amygdala (BLA). We have previously shown that the central nucleus of the amygdala (CEA) is essential for the acquisition and expression of conditional fear to both contextual and auditory conditioned stimuli (CSs) after overtraining. This provides strong evidence that the CEA can compensate for the loss of the BLA. Another brain area that may compensate for the loss of the BLA is the bed nucleus of the stria terminalis (BNST). We explored this possibility by examining the consequences of lesions or reversible inactivation of the BNST on the expression of overtrained fear in rats with BLA lesions. We demonstrate that lesions or inactivation of the BNST block the expression of freezing to the conditioning context, but not to an auditory conditional stimulus. These results reveal that the BNST has a critical role in the expression of contextual fear, but not fear to an auditory CS, and is therefore not the essential locus of compensation for fear learning in the absence of the BLA.     

Neuronal substrates of relapse to cocaine-seeking behavior: role of prefrontal cortex

The return to drug seeking, even after prolonged periods of abstinence, is a defining feature of cocaine addiction. The neural circuitry underlying relapse has been identified in neuropharmacological studies of experimental animals, typically rats, and supported in brain imaging studies of human addicts. Although the nucleus accumbens (NAcc), which has long been implicated in goal-directed behavior, plays a critical role in this circuit, the prefrontal cortex (PFC) appears to process the events that directly trigger relapse: exposure to acute stress, cues previously associated with the drug, and the drug itself. In this paper, we review animal models of relapse and what they have revealed about the mechanisms underlying the involvement of the NAcc and PFC in cocaine-seeking behavior. We also present electrophysiological data from PFC illustrating how the hedonic, motor, motivational, and reinforcing effects of cocaine can be analyzed at the neuronal level. Our preliminary findings suggest a role for PFC in processing information related to cocaine seeking but not the hedonic effects of the drug. Further use of this recording technology can help dissect the functions of PFC and other components of the neural circuitry underlying relapse.     

The hippocampus and amygdala mediate the locomotor stimulating effects of corticotropin-releasing factor in mice

We have previously demonstrated that both stress manipulations and corticotropin-releasing factor (CRF) elevate locomotor activity in mice primarily in the center region of an open field. In the present study, other than confirming these findings, we have further examined the roles of the dentate gyrus of the hippocampus, the amygdala, and the caudate nucleus in mediating the locomotor-stimulating effect of CRF. Results indicate that among the areas examined, the hippocampus is the most important neural substrate of the action of CRF. The amygdala is also partly responsible for the behavioral effect produced by CRF. The caudate nucleus, however, although is important in the expression of gross motor activity, is not involved in the effect of CRF on locomotion in mice. The results are compared with those obtained in rats and are discussed in terms of the interactions between CRF and stress.     

Glutamate-mediated neuroplasticity in a limbic input to the hypothalamus

Emotionally-salient stressors are processed by cortical and limbic circuits that provide important regulatory input to the hypothalamic-pituitary-adrenal (HPA) axis. However, exposure to chronic or severe stress may cause disregulation of the axis and a variety of physiological and psychological symptoms. The mechanisms that underlie stress-induced alterations in HPA axis function are not well characterized, but one possibility is that severe stress causes plastic changes in limbic inputs to the hypothalamus. We examined plasticity within the bed nucleus of stria terminalis (BNST) and the hypothalamic paraventricular nucleus (PVN) with a stimulating electrode in the BNST and a recording electrode in the PVN. High-frequency BNST stimulation produced long-lasting suppression of evoked field potentials recorded from the PVN, and this effect was blocked by administration of MK-801. Accordingly, rapid glutamate-mediated neuroplasticity in the BNST to PVN neurocircuitry may contribute to plasticity in limbic regulation of the HPA axis.     

Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry

Palatable food intake reduces stress responses, suggesting that individuals may consume such ?comfort? food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid ergic signaling is critical for both reward and stress regulation, suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the present study (1) determines how palatable ?comfort? food alters stress-induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry and (2) identifies candidate brain regions that may underlie comfort food-mediated stress reduction. We used a model of palatable ?snacking? in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis buffering following palatable snacking. Specifically, palatable snacking alone decreased pro-enkephalin-A (ENK) mRNA expression in the anterior bed nucleus of the stria terminalis (BST) and the nucleus accumbens, and decreased GAD65 mRNA in the posterior BST. Chronic stress alone increased ENK mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and BST; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, BST, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can mitigate many of the neurochemical alterations induced by chronic stress.     

The relationship between the amygdala and bed nucleus of the stria terminalis in the cat: an evoked potential and single cell study

The effects of amygdala stimulation on excitability of cells in the bed nucleus of the stria terminalis (BNST) were investigated in the cat. The predominant effect of stimulation was to excite cells localized in the lateral BNST. Cells responded either with single spikes to a stimulus pulse or in short bursts. Spontaneous firing of cells after a pulse to the amygdala was observed to both increase and decrease over a 4-s interval. Increases in firing rate, however, were the predominant response. Cells in more anterior locations in the BNST responded with latencies shorter than those of cells in more posterior locations, reflecting either differences in conduction time of excitation from the amygdala or differences in transmitters mediating the excitatory effects. Associated with increases in cell firing was a compound field potential with an initial negative component and a later positive component. These components may be generated by different cell types within the BNST. The negative component likely represents a field EPSP. Effective sites of amygdala stimulation were restricted to the posterior basal amygdala, and effects observed in the BNST were restricted to the lateral BNST. These data correspond well with anatomical studies showing a monosynaptic projection of basal amygdala to lateral BNST in the cat. This study suggests that this projection is predominantly excitatory.     

The role of neuropeptide Y in the amygdala on corticotropin-releasing factor receptor-mediated behavioral stress responses in the rat

Neuropeptide Y (NPY) is one of the most abundant peptides in the brain and has been shown to be a critical regulator of emotionality, most notably for its effect in decreasing anxiety-like behaviors. The stress response in both humans and animals has been shown to involve a cascade of biological events initiated by corticotropin releasing factor (CRF), another centrally acting peptide. Interestingly, NPY and CRF are present in similar brain regions mediating stress responses and may act in an opposing fashion. The basolateral nucleus of the amygdala (BLA) is a distinct division of the amygdala and contains CRF receptors and the highest concentration of NPY neurons. The current study investigates the behavioral effects in rodents when NPY is injected directly into the BLA prior to the pharmacological stressor, urocortin I (Ucn; a CRF receptor agonist) or the emotional stressor, restraint. The animals that underwent restraint were evaluated in the social interaction (SI) test, while those injected with Ucn into the BLA were assessed in the two floor choice test, a modified version of the conditioned-place avoidance paradigm. The results showed that injections of NPY into the BLA prior to Ucn significantly blocked the development of the avoidance behavior in the two floor choice test and the decrease in SI time that is usually seen following restraint stress. These results provide further support that an interaction between NPY and CRF within the BLA may be critical for maintaining a normal homeostatic emotional state.     

Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala

The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA.     

Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala

Stress can profoundly affect memory and alter the functioning of the hippocampus and amygdala. Studies have also shown that the antidepressant tianeptine can block the effects of stress on hippocampal and amygdala morphology and synaptic plasticity. We examined the effects of acute predator stress and tianeptine on long-term potentiation (LTP; induced by 100 pulses in 1 s) and primed burst potentiation (PB; a low threshold form of LTP induced by only five physiologically patterned pulses) in CA1 and in the basolateral nucleus (BLA) of the amygdala in anesthetized rats. Predator stress blocked the induction of PB potentiation in CA1 and enhanced LTP in BLA. Tianeptine blocked the stress-induced suppression of PB potentiation in CA1 without affecting the stress-induced enhancement of LTP in BLA. In addition, tianeptine administered under non-stress conditions enhanced PB potentiation in the hippocampus and LTP in the amygdala. These findings support the hypothesis that acute stress impairs hippocampal functioning and enhances amygdaloid functioning. The work also provides insight into the actions of tianeptine with the finding that it enhanced electrophysiological measures of plasticity in the hippocampus and amygdala under stress, as well as non-stress, conditions.     

PACAP centrally mediates emotional stress-induced corticosterone responses in mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide widely distributed in the nervous system. Recently, PACAP was shown to be involved in restraint stress-induced corticosterone release and concomitant expression of the genes involved in hypothalamic-pituitary-adrenal (HPA) axis activation. Therefore, in this study, we have addressed the types of stressors and the levels of the HPA axis in which PACAP signaling is involved using mice lacking PACAP (PACAP?/?). Among four different types of stressors, open-field exposure, cold exposure, ether inhalation, and restraint, the corticosterone response to open-field exposure and restraint, which are categorized as emotional stressors, but not the other two, was markedly attenuated in PACAP?/? mice. Peripheral administration of corticotropin releasing factor (CRF) or adrenocorticotropic hormone induced corticosterone increase similarly in PACAP?/? and wild-type mice. In addition, the restraint stress-induced c-Fos expression was significantly decreased in the paraventricular nucleus (PVN) and medial amygdala (MeA), but not the medial prefrontal cortex, in PACAP?/? mice. In the PVN of PACAP?/? mice, the stress-induced c-Fos expression was blunted in the CRF neurons. These results suggest that PACAP is critically involved in activation of the MeA and PVN CRF neurons to centrally regulate the HPA axis response to emotional stressors.