Passive Avoidance Behavior Research Articles

Protective effects of high Tryptophan diet on aging-induced passive avoidance impairment and hippocampal apoptosis.

In our previous work we have shown that L-Tryptophan (TrP) enriched diet prevents the age-induced decline of hippocampal Serotonin (5-HT) production. Considering that loss or reduction in 5-HT neurotransmission may contribute to age-related cognitive decline, here we have investigated the effect of such diet on passive avoidance (PA) behavior, cell death, pro- and anti- apoptotic molecules (BAX, Bcl-2 and Caspase-3) and an important transcription factor involved in synaptic plasticity and memory (CREB). The increase in 5-HT neurotransmission in the Hippocampus (Hp) of aged rats was induced by 1 month of high TrP administration. In the first phase of our study we found that high TrP diet improves PA behaviour of aged rats and this correlated with a decrease of TUNEL positive cells in all hippocampal regions tested (CA1, CA2, CA3, DG). Interestingly, the Hp of aged animals fed with high TrP diet showed a significant downregulation of proapoptotic proteins, caspase-3 and BAX, and an increase of antiapoptotic molecules Bcl-2 as indicated by Western Blot and immunohistochemical analyses. Also, high TrP diet partially rescued the age-induced inhibition of hippocampal CREB phosphorylation. Altogether, our data suggest that enhanced TrP intake, and in consequence a potential increase in 5-HT neurotransmission, might be beneficial in preventing age-related detrimental features by inhibition of hippocampal apoptosis.

An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior

Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l, a component of a histone methyltransferase complex. We therefore examined genome-wide changes in H3K4 tri-methylation, a mark induced by the Ash2l complex associated with increased gene transcription. A significant number of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4 tri-methylation. Knockdown of Ash2l or Mef2c abolishes nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuates nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimics nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a novel target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.

Pair exposure with conspecific during fear conditioning induces the link between freezing and passive avoidance behaviors in rats

Social factor plays an important role in dealing with posttraumatic stress disorder related to excessive physiological fear response and insufficient fear memory extinction of the brain. However, although social circumstances occurred not only during contextual retrieval but also during fear conditioning, most previous studies focused on the advantageous aspects of social buffering in fear retrieval period. To demonstrate the association between fear responses and fear memory from social stimuli during fear conditioning, pair exposed rats with conspecific as social buffering were subjected to a fear conditioning of passive avoidance test to evaluate memory function and freezing behavior. Whereas single exposed rats showed the significant increase of freezing behaviors and passive avoidance behaviors compared to control rats, pair exposed rats showed significant alleviation of the freezing behaviors and passive avoidance behaviors compared to single exposed rats. Furthermore, we determined a significant correlation between freezing and passive avoidance behavioral alteration in pair exposed rats. Taken together, we suggest that pair exposure with conspecific during fear conditioning helps to cope with both freezing response and fear memory systems and their reciprocal interaction has a crucial potential as a resource for the relief of unreasonable stress responses in posttraumatic stress disorder.

Acute modulation of the cholinergic system in the mouse brain detected by pharmacological resting-state functional MRI

IntroductionThe cholinergic system is involved in learning and memory and is affected in neurodegenerative disorders such as Alzheimer's disease. The possibility of non-invasively detecting alterations of neurotransmitter systems in the mouse brain would greatly improve early diagnosis and treatment strategies. The hypothesis of this study is that acute modulation of the cholinergic system might be reflected as altered functional connectivity (FC) and can be measured using pharmacological resting-state functional MRI (rsfMRI). Material and methodsPharmacological rsfMRI was performed on a 9.4T MRI scanner (Bruker BioSpec, Germany) using a gradient echo EPI sequence. All mice were sedated with medetomidine. C57BL/6 mice (N=15/group) were injected with either saline, the cholinergic antagonist scopolamine, or methyl-scopolamine, after which rsfMRI was acquired. For an additional group (N=8), rsfMRI scans of the same mouse were acquired first at baseline, then after the administration of scopolamine and finally after the additional injection of the cholinergic agonist milameline. Contextual memory was evaluated with the same setup as the pharmacological rsfMRI using the passive avoidance behavior test. ResultsScopolamine induced a dose-dependent decrease of FC between brain regions involved in memory. Scopolamine-induced FC deficits could be recovered completely by milameline for FC between the hippocampus–thalamus, cingulate–retrosplenial, and visual–retrosplenial cortex. FC between the cingulate–rhinal, cingulate–visual and visual–rhinal cortex could not be completely recovered by milameline. This is consistent with the behavioral outcome, where milameline only partially recovered scopolamine-induced contextual memory deficits. Methyl-scopolamine administered at the same dose as scopolamine did not affect FC in the brain. ConclusionThe results of the current study are important for future studies in mouse models of neurodegenerative disorders, where pharmacological rsfMRI may possibly be used as a non-invasive read-out tool to detect alterations of neurotransmitter systems induced by pathology or treatment.

TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment.

The adolescent brain undergoes important dynamic and plastic cell changes, including overproduction of axons and synapses, followed by rapid pruning along with ongoing axon myelination. These developmental changes make the adolescent brain particularly vulnerable to neurotoxic and behavioral effects of alcohol. Although the mechanisms of these effects are largely unknown, we demonstrated that ethanol by activating innate immune receptors toll-like receptor 4 (TLR4), induces neuroinflammation and brain damage in adult mice. The present study aims to evaluate whether intermittent ethanol treatment in adolescence promotes TLR4-dependent pro-inflammatory processes, leading to myelin and synaptic dysfunctions, and long-term cognitive impairments. Using wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3.0g/kg) for 2weeks, we show that binge-like ethanol treatment activates TLR4 signaling pathways (MAPK, NFκB) leading to the up-regulation of cytokines and pro-inflammatory mediators (COX-2, iNOS, HMGB1), impairing synaptic and myelin protein levels and causing ultrastructural alterations. These changes were associated with long-lasting cognitive dysfunctions in young adult mice, as demonstrated with the object recognition, passive avoidance and olfactory behavior tests. Notably, elimination of TLR4 receptors prevented neuroinflammation along with synaptic and myelin derangements, as well as long-term cognitive alterations. These results support the role of the neuroimmune response and TLR4 signaling in the neurotoxic and behavioral effects of ethanol in adolescence.

BDNF-Dependent Plasticity Induced by Peripheral Inflammation in the Primary Sensory and the Cingulate Cortex Triggers Cold Allodynia and Reveals a Major Role for Endogenous BDNF As a Tuner of the Affective Aspect of Pain

Painful experiences are multilayered, composed of sensory, affective, cognitive and behavioral facets. Whereas it is well accepted that the development of chronic pain is due to maladaptive neuronal changes, the underlying molecular mechanisms, their relationship to the different pain modalities, and indeed the localization of these changes are still unknown. Brain-derived neurotrophic factor (BDNF) is an activity-dependent neuromodulator in the adult brain, which enhances neuronal excitability. In the spinal cord, BDNF underlies the development and maintenance of inflammatory and neuropathic pain. Here, we hypothesized that BDNF could be a trigger of some of these plastic changes. Our results demonstrate that BDNF is upregulated in the anterior cingulate cortex (ACC) and the primary sensory cortex (S1) in rats with inflammatory pain. Injections of recombinant BDNF (into the ACC) or a viral vector synthesizing BDNF (into the ACC or S1) triggered both neuronal hyperexcitability, as shown by elevated long-term potentiation, and sustained pain hypersensitivity. Finally, pharmacological blockade of BDNF-tropomyosin receptor kinase B (TrkB) signaling in the ACC, through local injection of cyclotraxin-B (a novel, highly potent, and selective TrkB antagonist) prevented neuronal hyperexcitability, the emergence of cold hypersensitivity, and passive avoidance behavior. These findings show that BDNF-dependent neuronal plasticity in the ACC, a structure known to be involved in the affective-emotional aspect of pain, is a key mechanism in the development and maintenance of the emotional aspect of chronic pain.

Elimination of Kalrn expression in POMC cells reduces anxiety-like behavior and contextual fear learning

Kalirin, a Rho GDP/GTP exchange factor for Rac1 and RhoG, is known to play an essential role in the formation and maintenance of excitatory synapses and in the secretion of neuropeptides.Mice unable to express any of the isoforms of Kalrn in cells that produce POMC at any time during development (POMC cells) exhibited reduced anxiety-like behavior and reduced acquisition of passive avoidance behavior, along with sex-specific alteration in the corticosterone response to restraint stress. Strikingly, lack of Kalrn expression in POMC cells closely mimicked the effects of global Kalrn knockout on anxiety-like behavior and passive avoidance conditioning without causing the other deficits noted in Kalrn knockout mice. Our data suggest that deficits in excitatory inputs onto POMC neurons are responsible for the behavioral phenotypes observed.

Human Hippocampus Arbitrates Approach-Avoidance Conflict

SummaryAnimal models of human anxiety often invoke a conflict between approach and avoidance [1, 2]. In these, a key behavioral assay comprises passive avoidance of potential threat and inhibition, both thought to be controlled by ventral hippocampus [2–6]. Efforts to translate these approaches to clinical contexts [7, 8] are hampered by the fact that it is not known whether humans manifest analogous approach-avoidance dispositions and, if so, whether they share a homologous neurobiological substrate [9]. Here, we developed a paradigm to investigate the role of human hippocampus in arbitrating an approach-avoidance conflict under varying levels of potential threat. Across four experiments, subjects showed analogous behavior by adapting both passive avoidance behavior and behavioral inhibition to threat level. Using functional magnetic resonance imaging (fMRI), we observe that threat level engages the anterior hippocampus, the human homolog of rodent ventral hippocampus [10]. Testing patients with selective hippocampal lesions, we demonstrate a causal role for the hippocampus with patients showing reduced passive avoidance behavior and inhibition across all threat levels. Our data provide the first human assay for approach-avoidance conflict akin to that of animal anxiety models. The findings bridge rodent and human research on passive avoidance and behavioral inhibition and furnish a framework for addressing the neuronal underpinnings of human anxiety disorders, where our data indicate a major role for the hippocampus.

Effects of the Novel Anti-Asthenic Drug Ladasten on Behavior and T-Cell Subsets Alterations in a Social Defeat Animal Model of Depression

The aim of the present study was to investigate the effects of the anti-asthenic drug ladasten on behavioral patterns and T-cell subsets in blood, spleen, and thymus in socially stressed male C57Bl/6 mice. Mice subjected to social defeat stress (SDS) for 25 days developed a depressive-like phenotype. The submissive SDS animals were assigned to one of two treatment groups: one group was treated with ladasten (30 mg/kg, i.p.) for up to 5 days, and the other one was administered vehicle as a control. Twenty four hours after the last injection, behavioral parameters were tested, and trunk blood and tissue samples were collected. SDS mice from the vehicle-treated group showed a subordinate and passive avoidance behavior with significantly decreased spontaneous locomotor activity (SLA) and exhibited impaired parameters in the forced swimming test (FST). Changes in behavioral status were correlated with an increase spleen weight, a decrease in thymic index and a shift in the CD4/CD8 balance toward T-cytotoxic cells. The behavior parameters were reversed in the group treated with ladasten compared to the untreated SDS group and were similar to those of unstressed mice. Treatment of socially stressed mice with ladasten normalized the amount of T-lymphocyte cells in the blood, spleen, and thymus. These findings support the notion that depression is accompanied by cell-mediated immune activation and that targeting this pathway may be a new therapeutic approach for treatment. Furthermore, our data support further investigations of ladasten as a potent anti-depressive drug which can be used alone as well as in combination with other anti-depressants.

Tobacco Use and Environmental Smoke Exposure among Taiwanese Pregnant Smokers and Recent Quitters: Risk Perception, Attitude, and Avoidance Behavior

In this study, we conducted an empirical survey of the avoidance behaviors and risk perceptions of active and passive smoking pregnant smokers and recent quitters. We employed an online questionnaire survey by recruiting 166 voluntary participants from an online parenting community in Taiwan. The results of the empirical survey revealed that three-fourths of smokers quit smoking during pregnancy and one-fourth continued smoking. All pregnant women who continued smoking had partners or lived with relatives who smoked. Current smokers and quitters differed significantly in their risk perceptions and attitudes toward smoking during pregnancy. Most pregnant smokers and quitters adopted passive smoking avoidance behaviors at home and in public. Nevertheless, one-fifth of pregnant women chose not to avoid passive smoking. We concluded that most women stop smoking during pregnancy; however, most women continue to be exposed to passive-smoking environments. Perceived fetal health risks and attitudes toward smoking during pregnancy are critical predictors of the anti-smoking behaviors of pregnant women.

Lithium treatment alleviates impaired cognition in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is caused by suppressed expression of fragile X mental retardation protein (FMRP), which results in intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity, seizures and autistic-like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with lithium has been reported to ameliorate locomotor hyperactivity, prevent hypersensitivity to audiogenic seizures, improve passive avoidance behavior and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is cognitive impairment, we tested if lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to lithium differed in adolescent and adult mice and tested if therapeutic effects persisted after discontinuation of lithium administration. Fmr1 KO mice displayed impaired cognition in the novel object detection task, temporal ordering for objects task and coordinate and categorical spatial processing tasks. Chronic lithium treatment of adolescent (from 4 to 8 weeks of age) and adult (from 8 to 12 weeks of age) mice abolished cognitive impairments in all four cognitive tasks. Cognitive deficits returned after lithium treatment was discontinued for 4 weeks. These results show that Fmr1 KO mice exhibit severe impairments in these cognitive tasks, that lithium is equally effective in normalizing cognition in these tasks whether it is administered to young or adult mice and that lithium administration must be continued for the cognitive improvements to be sustained. These findings provide further evidence that lithium administration may be beneficial for individuals with FXS.

Single dose of H3 receptor antagonist - ciproxifan - abolishes negative effects of chronic stress on cognitive processes in rats

The role of histamine neurons in stress evoked cognitive impairments remains unclear. Previous research has indicated that the blockade of H(3)-type histamine receptors may improve attention and memory in naïve rodents. The purpose of this study was to determine if ciproxifan, (cyclopropyl-(4-(3-1H-imidazol-4-yl) propyloxy) phenyl) ketone, an H(3) receptor antagonist, could alleviate cognitive deficits observed in chronically stressed rats. Specifically, we attempted to characterize the preventive action of single dose of ciproxifan (3 mg/kg, i.p.) against an impairment caused by chronic restraint stress (2 h daily for 21 days) on recognition memory tested in an object recognition task and on the long-term memory tested in a passive avoidance test. We found that administration of ciproxifan potently prevented deleterious effects of chronic restraint stress, when administered prior to learning, or immediately after learning, or before retrieval on both the recognition (p<0.001) and the passive avoidance behavior (p<0.001). These data support the idea that modulation of H(3) receptors represents a novel and viable therapeutic strategy in the treatment of stress evoked cognitive impairments.

A study on the hematological parameters and brain acetylcholine esterase activity in immobilization induced stress and co-treatment with Centella asiatica leaves extract to wistar rats

Aim: Our aim was to evaluate the anti-stress activities of aqueous leaf extract of Centella asiatica (CA) in immobilization-induced stress in rats. The anti-stress activities of CA were assessed by monitoring the changes in the behavior, counts of red blood cells (RBCs) and white blood cells (WBCs) (Lymphocytes, Monocytes, Neutrophils, Esinophils) and change in the level of brain acetylcholine esterase (AChEs) activity in immobilization-induced stress in male albino Wistar rats. Materials and Methods: Immobilization stress was induced in rats by placing in 20 cm × 7 cm plastic tubes for 2 h/day for 21 days. Aqueous leaf extract of CA was co-administered orally to the experimental rats at a dose of 200 mg/kg body weight daily for the 21 days. Results: Stress induced by immobilization in the rats for 21 days decreased the passive avoidance behavior, total counts of RBCs, WBCs and brain AChEs activity. Upon co-administration of CA leaves extract to the stressed animals significantly reverted the changes to near normal levels when compared to control animals. Conclusion: Aqueous extract of CA leaves significantly reverted the changes due to immobilization induced stress which may be due to the anti-stress activities of CA leaves.

Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model

Pathophysiological evidences of AD have indicated that aggregation of Aβ is one of the principal causes of neuronal dysfunction, largely by way of inducing oxidative stresses such as free radical formation. We hypothesized that the known antioxidative attribute of SFN could be harnessed in Alzheimer’s treatment. SFN is an indirect, potent antioxidant derived from broccoli that has previously been found to stimulate the Nrf2-ARE pathway and facilitate several other cytoprotective mechanisms. In this study, administration of SFN ameliorated cognitive function of Aβ-induced AD acute mouse models in Y-maze and passive avoidance behavior tests. Interestingly, we found that the therapeutic effect of SFN did not involve inhibition of Aβ aggregation. While the exact mechanism of interaction of SFN in AD has not yet been ascertained, our results suggest that SFN can aid in cognitive impairment and may protect the brain from amyloidogenic damages.Abbreviations: Aβ, amyloid-β; AD, Alzheimer’s disease; PBS, phosphate buffered saline; DMSO, dimethyl sulfoxide; ROS, reactive oxygen species; SFN, sulforaphane; DMEM, Dulbecco’s modified eagle medium; FBS, fetal bovine serum; ICR, imprinting control region; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DW, deionized water; ThT, thioflavin T; PA, passive avoidance; ARE, antioxidant response element.

Interaction between the mGlu receptors 5 antagonist, MPEP, and amphetamine on memory and motor functions in mice

Metabotropic glutamate mGlu receptors 5 (mGluR5) receptors are abundant in corticolimbic circuitry where they modulate glutamate and dopamine signal transduction. In this study, we explored the hypothesis that mGluR5 antagonist, (2-methyl-6-(phenylethynyl)pyridine hydrochloride) (MPEP), facilitates dopamine-dependent effects on memory and motor functions. To this aim, we examined the effects of different doses (from 0 to 24 mg/kg) of the mGluR5 antagonist, MPEP, on the modulation of amphetamine-dependent behaviors, namely passive avoidance, locomotor activity, and rotation behavior in intact and dopamine-depleted CD1 male mice. We demonstrated that a low dose (3 mg/kg) of MPEP, which is void of behavioral effects on its own, facilitates amphetamine-induced effects independently on the behavior measured both in naïve and in dopamine-lesioned mice; this synergistic effect is lost when higher doses of MPEP are used. The results are discussed in terms of possible balance between dopamine and glutamate activity in regulating the proper fine tuning of information processing.

Foster Carer-Foster Child Intervention (FFI): An Intervention Designed to Reduce Stress in Young Children Placed in a Foster Family

The Foster carer-Foster child Intervention (FFI) was developed to help foster carers recognise and cope with the stress that foster children under the age of five might experience when placed in a new family. Children who have been neglected or abused may have difficulty coping with stress and develop behavioural problems, and young children in particular can develop passive avoidance behaviour as a way of adapting to their new situation. The FFI aims to improve the interaction between foster carer and foster child by optimising the emotional availability, parenting skills and confidence of carers in a way that makes the child feel more secure. This article by Hans WH van Andel, Hans Grietens and Erik J Knorth explains the aims and principles underlying FFI and discusses its theoretical background, which includes attachment theory, psycho-education, mindfulness therapy and video interaction training. It then details the intervention and describes how it is being implemented in Dutch foster care practice. The article ends by outlining an ongoing randomised control study to determine the effectiveness of the intervention.

Involvement of neurotransmitters in the action of growth hormone-releasing hormone antagonist on passive avoidance learning

The antagonist MZ-4-71 of growth hormone-releasing hormone (GH-RH) has been shown to suppress the secretion of GH and insulin-like growth factor-1 (IGF-1), suggesting that this class of analogs could be used for the therapy of disorders characterized by excessive GH secretion. Numerous GH-RH antagonists has been synthetized and shown to suppress the growth of various tumors. MZ-4-71 facilitates the consolidation of passive avoidance learning. Beta-amyloid 25–35 impairs the consolidation of passive avoidance learning and MZ-4-71 fully blocks this impairment. However, little is known about the possible mechanism of action of GR-RH antagonists on these actions. In the present work, the possible effects of different neurotransmitters on the action of MZ-4-71 were studied in the memory consolidation of passive avoidance behavior. The involvement of cholinergic, serotonergic, dopaminergic, GABA-ergic, adrenergic and opiate receptors was tested. Mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a nonselective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic acetylcholine receptor antagonist, atropine, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, or a nonselective opioid receptor antagonist, naloxone. Atropine, methysergide, cyproheptadine and naloxone prevented the effects of MZ-4-71 on passive avoidance learning, whereas haloperidol, phenoxybenzamine, propranolol and bicuculline did not change the effects of MZ-4-71. The results demonstrate that the muscarinic acetylcholine receptor, the 5-HT1/5-HT2 serotonergic receptor and opioid receptors are involved as mediators in the action of MZ-4-71 on the consolidation of passive avoidance learning.

Avoidance of harm and anxiety: A role for the nucleus accumbens

Active and passive avoidance behaviors involve either emitting or omitting a response to avoid potential harm. Both are key components in the etiology and maintenance of anxiety disorders, yet the neural circuitry that mediates avoidance is underexplored. Using functional magnetic resonance imaging greater hemodynamic activation of the nucleus accumbens was found during active avoidance, whereas greater deactivation of the nucleus accumbens was observed during passive avoidance. These findings extend the role of the NAcc from purely reward-based action-contingencies, to one that also involves either emitting or withholding a response to avoid harm. Critically, the degree of activation and deactivation of the NAcc during avoidance was associated with individual levels of anxiety, which supports the idea that the NAcc may play a key role in the etiology and maintenance of aberrant avoidance behaviors in disorders of anxiety.

Effects of exposure to amphetamine derivatives on passive avoidance performance and the central levels of monoamines and their metabolites in mice: Correlations between behavior and neurochemistry

Considerable evidence indicates that amphetamine derivatives can deplete brain monoaminergic neurotransmitters. However, the behavioral and cognitive consequences of neurochemical depletions induced by amphetamines are not well established. In this study, mice were exposed to dosing regimens of 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH), or parachloroamphetamine (PCA) known to deplete the monoamine neurotransmitters dopamine and serotonin, and the effects of these dosing regimens on learning and memory were assessed. In the same animals, we determined deficits in learning and memory via passive avoidance (PA) behavior and changes in tissue content of monoamine neurotransmitters and their primary metabolites in the striatum, frontal cortex, cingulate, hippocampus, and amygdala via ex vivo high-pressure liquid chromatography. Exposure to METH and PCA impaired PA performance and resulted in significant depletions of dopamine, serotonin, and their metabolites in several brain regions. Multiple linear regression analysis revealed that the tissue concentration of dopamine in the anterior striatum was the strongest predictor of PA performance, with an additional significant contribution by the tissue concentration of the serotonin metabolite 5-hydroxyindoleacetic acid in the cingulate. In contrast to the effects of METH and PCA, exposure to MDMA did not deplete anterior striatal dopamine levels or cingulate levels of 5-hydroxyindoleacetic acid, and it did not impair PA performance. These studies demonstrate that certain amphetamines impair PA performance in mice and that these impairments may be attributable to specific neurochemical depletions.

Functional brain activation during retrieval of visceral pain-conditioned passive avoidance in the rat

This study assessed functional brain activation in rats during expectation of visceral pain. Male rats were trained in step-down passive avoidance (PA) for 2 days. Upon stepping down from a platform, conditioned animals received noxious colorectal distension delivered through a colorectal balloon, whereas the balloon in control rats remained uninflated. On day 3, PA behavior was assessed while [ 14C]-iodoantipyrine was infused intravenously, followed by immediate euthanasia. Regional cerebral blood flow-related tissue radioactivity (rCBF) was analyzed by statistical parametric mapping using 3-dimensional brains reconstructed from autoradiographic brain slice images. Associated with retrieved PA behavior, conditioned rats compared with control subjects showed increases in rCBF in sensory (anterior insula, somatosensory cortex), limbic/paralimbic regions (anterior cingulate, prelimbic cortex, amygdala), all regions previously reported to show activation during acute visceral pain. Increases in rCBF were also noted in the dorsal hippocampus, nucleus accumbens, and caudate putamen, regions associated with retrieval of PA. Organization of the underlying brain network was further delineated by functional connectivity analysis. This revealed in conditioned rats a strongly and positively connected corticostriatal cluster (cingulate, prelimbic cortex, caudate putamen). The amygdala and cerebellar hemispheres formed another positively connected cluster, which was negatively connected with the corticostriatal cluster, suggesting corticolimbic modulation. Prelimbic cortex, nucleus accumbens, and anterior insula emerged in conditioned animals as hubs. Our results show that during retrieval of PA, brain areas implicated in PA expression as well as those implicated in acute visceral pain processing were recruited, in line with findings from human brain imaging studies on pain expectation.