Social disruption-induced stress pre-exposure aggravates, while the presence of conspecifics diminishes, acetic acid-induced writhing.

RATIONALE AND OBJECTIVE: This study was undertaken to assess the modulating effects of (1) pre-exposure to repeated social disruption and (2) group testing on writhing associated with visceral pain induced by intraperitoneal administration of acetic acid. MATERIALS AND METHODS: Six consecutive days of social disruption were used to prime for stress, while group testing referred to 3 mouse cage-mates receiving the acetic acid-induced writhing test as a group. RESULTS: Social disruption-induced stress-pre-exposed mice displayed a greater number acid-induced writhes compared to mice not receiving the pre-exposure. However, mice displayed fewer acid-induced writhes in a triad group vs. individually, suggesting group-mediated writhing-reducing effects. Likewise, group testing prevented the stress pre-exposure escalation in acid-induced writhes. Additional studies revealed that the stress-pre-exposed mice had increased expression in accumbal TRPV1 receptors. Systemic (0.25 mg/kg) and bilateral intra-accumbal (0.2 ng/0.2 µl/side) administration of SB366791, a TRPV1 receptor antagonist, reliably prevented the stress pre-exposure escalation in acid-induced writhing; SB366791 treatment alone did not affect acid-induced writhing, stress pre-exposure anxiety-like behavior, or the group testing effects. Furthermore, lower neuronal activation was found in the medial septal nucleus in group vs. individual tested mice. Intra-medial septum (0.2 µg/0.5 µl) infusion with bicuculline, a GABAA receptor antagonist, effectively prevented group-mediated writhing-reducing effects, but not individual acid-induced writhing effects. CONCLUSIONS: These findings suggest that social disruption-induced stress pre-exposure may upregulate accumbal TRPV1 receptor expression and consequently aggravate acid-induced writhing. Group testing prevents such stress pre-exposure escalation of acid-induced writhing most likely by strengthening the GABAergic inhibition on local neural activity in the medial septum.

Sex differences and the modulating effects of gonad intactness on behavioral conformity in a mouse model.

Although gender differences in conformity are noticed in human studies, cultural norms and psychosocial factors inevitably affect such differences. Biological factors, especially the gonadal hormones and the brain regions involved, contributing to the sex differences in behavioral conformity remained scarcely explored. To prevent psychosocial and cultural norm confounds, intact and gonadectomized male and female mice were used to assess the modulating effects of gonadal hormones on behavioral conformity and such conformity-related brain regions using an approach of choice paradigm. Intact and gonadectomized mice' choices for the nonrewarded runway were assessed when these experimental mice were alone versus with a group, consisting of three same-sex noncagemates choosing the respective experimental mice' nonrewarded runway, in a double-J-shaped maze test. Although male and female mice exhibited comparable rewarded runway choices at the conclusion of the operant training procedures and in the test individually, male mice demonstrated greater conformity index as compared to female mice when group tested. Gonadectomy, done at their 4 or 9 weeks of age, decreased males' conformity index but did not affect females' when both sexes were group tested. Such gonadectomy did not affect the conditioning or conformity index when tested individually in either sex. Female mice had higher serum corticosterone (CORT) levels when group tested as compared to the female mice tested individually and male mice. Finally, the number of FOS-staining cells in high conformity-displaying mice was found less than it in the low conformity-performing mice in the nucleus accumbens. Taken together, we conclude that testis-derived hormones, at least, play a role in enhancing behavioral conformity in male mice. CORT and nucleus accumbal neuronal activity deserve further investigation for their involvement in behavioral conformity.

Relevance of number and physiological status of conspecifics in preventing stress-induced decreases in newly proliferated cells and neuroblasts.

RATIONALE AND OBJECTIVE: The presence of three conspecifics prevents stress-induced decreases in newly proliferated cells and neuroblasts in mouse dentate gyrus (DG). In this study, we sought to determine how many conspecifics are required to exert these protective effects against stress. In addition, we manipulated the physiological status of those conspecifics in the context of their stress-buffering effects and used airborne oxytocin exposure as a substitute for the presence of conspecifics. MATERIALS AND METHODS: Bromodeoxyuridine staining was used to indicate the newly proliferated cells and co-staining with doublecortin to reveal the proliferative neuroblasts. RESULTS: Presentation of three intact and lipopolysaccharide-treated conspecifics prevented the stress-induced decreases in the number of newly proliferated cells and neuroblasts in DG. Presentation of one saline- or oxytocin (OT)-treated conspecific did not exert observable stress-buffering effects. In contrast, airborne oxytocin prevented the stress-induced decreases in DG cell proliferation and early neurogenesis, while pretreatment with L-371,257, a selective OT receptor antagonist, abolished the buffering effects of OT. CONCLUSIONS: Physical interaction with the conspecifics and conspecifics' sickness, at best, play a minor role in mediating the buffering effects against stress-induced decreases in DG cell proliferation or early neurogenesis. Moreover, stress-buffering effects are negligible with the presence of only one conspecific. Finally, airborne OT produced stress-buffering effects possibly via its stimulation of OT receptors. Oxytocin merits further study as a substitute for the stress-buffering effects of companions.

Synergistic Effects of Psychosocial Stress and Mild Peripheral Infection on Inducing Microglial Activation in the Hippocampal Dentate Gyrus and Long-Lasting Deficits in Hippocampus-Related Memory.

Lipopolysaccharide (LPS) treatment and stress may cause immune activation in the brain, an event which has been thought to play a role in mediating stress-induced cognitive dysfunction. However, the enduring impact of psychosocial stress on brain immune activation or cognitive deficits has not been well investigated. Likewise, it remains unexplored whether there exist synergistic effects of psychosocial stress and a weak systemic LPS treatment on brain immune activation and/or cognitive function. In this work, a 10-day social defeat regimen was used to model psychosocial stress and the number and density of ionized calcium-binding adaptor molecule 1 (Iba1)-stained microglia was used to reveal brain immune activation in male Balb/C mice. The social defeat regimen did not cause observable microglial activation in dentate gyrus (DG) 24 h after the conclusion of the regimen. Microglial activation peaked in DG 24 h following a single 1 mg/kg intra-peritoneal LPS injection. At this time point, DG microglial activation was not evident providing 0.125 mg/kg or lower of LPS was used, this dose of LPS was, thus, regarded as the "sub-threshold" in this study. Twenty-four h after the conclusion of the defeat regimen, mice received a social interaction test to determine their defeat stress susceptibility and a "sub-threshold" LPS injection. DG microglial activation was observed in the defeat-stress susceptible, but not in the resilient, mice. Furthermore, the stress-susceptible mice showed impairment in object location and Y maze tasks 24 and 72 h after the "sub-threshold" LPS injection. These results suggest that psychosocial stress, when combined with a negligible peripheral infection, may induce long-lasting hippocampus-related memory deficits exclusively in subjects susceptible to psychosocial stresses.

Rottlerin impairs the formation and maintenance of psychostimulant-supported memory.

RATIONALE AND OBJECTIVE: Since brain proteins such as protein kinase C (PKC), brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) are involved in the establishment and maintenance of psychostimulant memory, we sought to determine if systemic treatment with rottlerin, a natural compound affecting all these proteins, may modulate stimulant-supported memory. MATERIALS AND METHODS: Stimulant-induced conditioned place preference (CPP) was used in modeling stimulant-supported memory. RESULTS: Three cocaine (10 mg/kg; COC) or three methamphetamine (1 mg/kg; MA) conditioning trials reliably established the drug-induced CPP in male C57BL/6 mice. An intra-peritoneal rottlerin injection (5 mg/kg) at least 24 h prior to the first COC or first MA conditioning trial prevented the establishment of CPP. Following the establishment of the COC- or MA-induced CPP, saline conditioning trial was used to extinguish the CPP. Rottlerin (5 mg/kg, intra-peritoneal (i.p.)) administered 20 h prior to the first saline conditioning trial diminished subsequent drug- and stressor-primed reinstatement of the extinguished CPP. Rottlerin (5 mg/kg, i.p.) produced a fast-onset and long-lasting increase in hippocampal BDNF levels. However, treatment with a BDNF tropomyosin receptor kinase B (TrkB) receptor antagonist, K252a (5 µg/kg), did not affect rottlerin's suppressing effect on COC-induced CPP and treatment with 7,8-dihydroxyflavone (10 mg/kg x 6, 7,8-DHF), a selective TrkB agonist, prior to each conditioning trial did not affect COC-induced CPP. CONCLUSION: These results suggest that systemic rottlerin treatment may impair the formation of COC- and MA-supported memory. Importantly, such a treatment may advance our understanding of the underlying mechanism through which extinction training resulted in the "forgetting" of the COC- and MA-supported memory.

Effects of Sodium Benzoate Treatment in Combination with An Extinction Training on the Maintenance of Cocaine-Supported Memory.

Activation of N-methyl-D-aspartate (NMDA) receptor can facilitate the extinction of various maladaptive memories. Sodium benzoate (NaB) has been known to enhance a naturally occurring full agonist on the glycine binding site of the NMDA receptor. This study aimed to test whether systemic NaB treatment can affect the extinction of a cocaine-supported memory, the cocaine-induced conditioned place preference (CPP). Following the establishment of the cocaine (10 mg/kg/conditioning × 3)-induced CPP, an extinction protocol, consisting of two consecutive extinction training bouts at an 8-h interval, was used. NaB (500 mg/kg) or an equivalent volume of saline was given immediately following each extinction training bout to test the modulating effect of NaB on the maintenance of cocaine-induced CPP. Moreover, NaB was bilaterally micro-infused into the medial prefrontal cortex (mPFC) to validate the involvement of this brain region in mediating systemic NaB treatment-produced effect on cocaine-induced CPP. Systemic (500 mg/kg) and intra-mPFC (10 µg/side) NaB treatment significantly decreased subsequent cocaine-induced CPP magnitude, although the NaB treatment or the extinction training alone did not affect such CPP magnitude. It was of importance to note that systemic or intra-mPFC NaB delivery did not affect mouse locomotor activity in the retests. These results, taken together, suggest that NaB treatment in combination with the extinction training may facilitate the extinction of the cocaine-supported memory. Moreover, systemic NaB treatment exerts such effects, at least in part, via its effect in the mPFC.

Sex Differences in Stress and Group Housing Effects on the Number of Newly Proliferated Cells and Neuroblasts in Middle-Aged Dentate Gyrus.

Sex differences in stress and coping responses have been frequently documented in aged people, while whether such differences in aged people may appear at the middle age are unknown. This study was undertaken to study the impact of acute stress and social interaction on early neurogenesis in the dentate gyrus (DG) and hippocampus-related memory in two sexes of middle-aged mice. The number of newly proliferated cells, neuroblasts in DG, the object recognition and location memory in 9-month-old male and female C57BL/6N mice were assessed under baseline conditions as well as following an acute stressor regimen and group housing. Three conspecific companions, serving as "the housing group," were used to model the social interaction throughout the stressor regimen. Males had lower numbers of newly proliferated cells and neuroblasts under baseline conditions as compared to females. The stressor regimen caused rapid decreases in the number of newly proliferated cells and neuroblasts in female DG but no obvious changes were observed in male DG. Group housing, regardless of companions' age, prevented the stress-induced decreases in the number of newly proliferated cells and neuroblasts in female DG. In contrast, the presence of young or age-matched companions potentiated the stress effect in males by decreasing the number of newly proliferated cells and neuroblasts. Finally, neither the stressor regimen nor group housing affected mouse performances in the object recognition and location memory in either sex. These findings, taken together, provide evidence to support a notion that middle-aged females appear to demonstrate more stress susceptibility on early neurogenesis in DG as compared to middle-aged males, although the hippocampus-related memory performances are comparable and not affected by stress in these males and females. Experiencing stress, middle-aged females are more prone to benefit from social interaction as compared to middle-aged males in this regard. We suggest, accordingly, that involving social interaction may afford a therapeutic advance in preventing stress-produced decreases in early neurogenesis in middle-aged females' DG.

Roles of testosterone and amygdaloid LTP induction in determining sex differences in fear memory magnitude.

Women are thought to form fear memory more robust than men do and testosterone is suspected to play a role in determining such a sex difference. Mouse cued fear freezing was used to study the sex-related susceptibility and the role of testosterone in fear memory in humans. A 75-dB tone was found to provoke weak freezing, while 0.15-mA and 0.20-mA footshock caused strong freezing responses. No sex differences were noticed in the tone- or footshock-induced (naïve fear) freezing. Following the conditionings, female mice exhibited greater tone (cued fear)-induced freezing than did male mice. Nonetheless, female mice demonstrated indistinctive cued fear freezing across the estrous phases and ovariectomy did not affect such freezing in female mice. Orchidectomy enhanced the cued fear freezing in male mice. Systemic testosterone administrations and an intra-lateral nucleus of amygdala (LA) testosterone infusion diminished the cued fear freezing in orchidectomized male mice, while pretreatment with flutamide (Flu) eradicated these effects. Long-term potentiation (LTP) magnitude in LA has been known to correlate with the strength of the cued fear conditioning. We found that LA LTP magnitude was indeed greater in female than male mice. Orchidectomy enhanced LTP magnitude in males' LA, while ovariectomy decreased LTP magnitude in females' LA. Testosterone decreased LTP magnitude in orchidectomized males' LA and estradiol enhanced LTP magnitude in ovariectomized females' LA. Finally, male mice had lower LA GluR1 expression than female mice and orchidectomy enhanced the GluR1 expression in male mice. These findings, taken together, suggest that testosterone plays a critical role in rendering the sex differences in the cued fear freezing and LA LTP. Testosterone is negatively associated with LA LTP and the cued fear memory in male mice. However, ovarian hormones and LA LTP are loosely associated with the cued fear memory in female mice.

Sex differences and the modulating effects of gonadal hormones on basal and the stressor-decreased newly proliferative cells and neuroblasts in dentate gyrus.

This study was undertaken to assess sex differences and the modulating effects of gonad intactness and the estrous phase on basal and the stressor-decreased cell proliferation and early differentiation in Balb/C mouse dentate gyrus (DG). Besides, we compared the stress-reversing effects exerted by the presence of male and female Balb/C mouse odors in stressed male and female mouse DG in this regard. Female mice had lower baselines in the number of newly proliferated cells and neuroblasts than male mice. Although the stressor induced decreases in the number of newly proliferative cells and neuroblasts in both male and female DG, an obvious decrease in neuronal lineage commitment was observed in female DG. Moreover, ovariectomy induced decreases in baselines in the number of proliferative cells and neuroblasts but did not affect the stressor-induced decrease in neuronal lineage commitment in female DG. Interestingly, pro-estrous mice exhibited the stressor-decreased neuronal lineage commitment, while estrous and diestrous mice did not display such a decrease. Furthermore, orchidectomy did not affect basal or the stressor-decreased newly proliferative cells or neuroblasts in male DG. Finally, male odors were less effective than female odors in abolishing the stressor-decreased neuronal lineage commitment in female mice, while male and female odors were comparable in reversing the stressor-decreased newly proliferated cells and neuroblasts in male mice. The protective effects of mouse odors' company in the stressed male mouse DG were associated with local BDNF and NGF replenishment. Taken together, sexual differences in baselines in the number of newly proliferative cells, neuroblasts, and the sensitivity to stress-altered neuronal lineage commitment in the DG could be, in part, due to gonadal hormone differences between the two sexes. Mouse odors may reverse stressor-decreased newly proliferative cells and neuroblasts in male, but not in female, mouse DG by restoring BDNF and NGF levels.

D-cycloserine, sarcosine and D-serine diminish the expression of cocaine-induced conditioned place preference.

Reactivation of cocaine-associated memories plays a critical role in reinstating the cocaine-seeking behavior and causing relapse. Cocaine-induced conditioned place preference (CPP) was used as a behavioral paradigm indicative of cocaine-associated memory and repeated cocaine-free preference tests served as a behavioral procedure to retrieve such a memory in this study. Since D-cycloserine was reported to eradicate drug-associated memories, two other N-methyl-D-aspartate (NMDA) receptor agonists were assessed for their efficacy on facilitating the extinction of cocaine-induced CPP. Although D-cycloserine (30 mg/kg) abolished cocaine (10 mg/kg)-induced CPP, sarcosine (300 and 600 mg/kg) and D-serine (600 mg/kg) diminished the expression of such a cocaine memory. Sarcosine (600 mg/kg) and D-serine (600 mg/kg) did not affect the storage of this cocaine memory. It was of interest to note that D-cycloserine facilitated the extinction of cocaine-induced CPP in a fast and early-onset manner, while sarcosine and D-serine decreased cocaine-induced CPP expression in a delay-onset manner. D-cycloserine (30 mg/kg), D-serine (600 mg/kg) and sarcosine (600 mg/kg) did not affect the consolidation of cocaine (5 mg/kg)-induced CPP. Finally, sarcosine (at 600 mg/kg/day for 3 consecutive days) and D-serine (at 600 mg/kg/day for 3 consecutive days) did not produce observable aversive effect associated with their administration in a conditioned place aversion paradigm. Likewise, a similar dosing regimen of sarcosine or D-serine did not cause evident activity-impairing effect. In addition to D-cycloserine treatment, our results indicate that long-term treatment with D-serine and sarcosine may afford a therapeutic advance in suppressing the expression of cocaine-associated memory.

Companions reverse stressor-induced decreases in neurogenesis and cocaine conditioning possibly by restoring BDNF and NGF levels in dentate gyrus.

The presence of companions can reverse the stressor-induced decrease in neurogenesis in mouse dentate gyrus (DG). In this study, we decided to study the underlying mechanisms of the companions' protective effect and to assess whether two DG neurogenesis-related memories, cocaine-induced conditioned place preference (CPP) and spatial memory, can be affected by our stressor and companions. Neurotrophin levels in DG were measured, in this regard, to reveal their roles in mediating the stressors' and companions' effect. We found that the stressor did not affect NT-3 but acutely decreased NGF and BDNF levels in DG. The presence of companions abolished these stressor-decreased NGF and BDNF levels. Neither the stressor nor the presence of companions affected TrkA, TrkB or TrkC expression in DG. Pre-exposure to the stressor rendered deficits in cocaine-induced CPP and spatial memory, while companions reversed the stressor-decreased cocaine-induced CPP. Intra-ventricular infusion with K252a, a mixed TrkA and TrkB antagonist, did not affect the protective effects of companions on local NGF, BDNF levels in DG, but abolished the companions' protective effects against the stressor-decreased DG neurogenesis and cocaine-induced CPP. Systemic pretreatment with 7,8-dihydroxyflavone (DHF), a selective TrkB agonist, did not affect baseline, the stressor-stimulated corticosterone (CORT) secretion or local NGF, BDNF levels in DG, but in part mimicked companions' protective effects. These results, taken together, indicate that stressor-decreased NGF and BDNF levels in DG could be involved in the stressor-decreased DG neurogenesis and cocaine conditioning. The presence of companions reverses the stressor-decreased DG neurogenesis and cocaine conditioning possibly by restoring BDNF and NGF levels in DG.

Disruption of memory reconsolidation impairs storage of other, non-reactivated memory.

Two hypotheses were tested in this study. First, blockade of neural activity by lidocaine immediately following the retrieval of a memory may impair the reconsolidation and subsequent expression of that memory. Second, a non-retrieved memory would not be affected by this lidocaine treatment. Since the basolateral nucleus of the amygdala (BLA) is involved in emotion-related memory, an intra-BLA lidocaine infusion was used immediately after the retrieval of two emotion-related memories, the step-through passive avoidance response (PA) and cocaine-induced conditioned place preference (CPP). Intra-BLA lidocaine infusion immediately after cocaine-induced CPP retrieval diminished CPP magnitude in retests. However, intra-BLA lidocaine infusion alone did not affect cocaine-induced CPP performance. Intra-BLA lidocaine infusion immediately after PA retrieval decreased PA performance in retests. Omission of PA retrieval procedure, intra-BLA lidocaine infusion did not affect subsequent PA performance. Surprisingly, intra-BLA lidocaine infusion immediately following the retrieval of PA or cocaine-induced CPP diminished both PA and cocaine-induced CPP performance in the retests. Finally, Fos-staining results revealed that a number of BLA neurons were activated by the retrieval of both cocaine-induced CPP and PA. We conclude that inactivation of neural activity in BLA immediately following retrieval of a fear or cocaine-conditioned memory can impair subsequent expression of both memories. More importantly, retrieval of a memory does not seem to be an absolute condition for rapidly changing the memory.

Involvement of amygdaloid protein synthesis in early- and late-phase reconsolidation of emotion-related memories.

This study was undertaken to test whether de novo protein synthesis in the basolateral (BLA) and central (CeA) nucleus of amygdala was required for reconsolidation of emotion-related memories. Mice were trained to sequentially acquire both cocaine-induced conditioned place preference (CPP) and step through passive avoidance (PA) memories. Immediately following PA retrieval, intra-BLA anisomycin infusion was found to decrease subsequent PA performance in retests. Immediately following PA retrieval, intra-CeA anisomycin infusion did not acutely affect PA performance but decreased such a PA memory 5 days later. Given PA retrieval procedure was omitted, intra-BLA and intra-CeA anisomycin infusion did not affect PA memory. Likewise, intra-BLA anisomycin infusion immediately following cocaine-induced CPP retrieval was found to decrease cocaine-induced CPP magnitude in early and late retests. Immediately after cocaine-induced CPP retrieval, intra-CeA anisomycin infusion did not acutely affect cocaine-induced CPP but decreased this memory 5 days later. Given the cocaine-induced CPP retrieval procedure was omitted, intra-BLA and intra-CeA anisomycin infusion did not affect cocaine-induced CPP in subsequent retests. These results, taken together, imply that de novo protein synthesis in amygdala plays an important role in modulating reconsolidation of emotion-related memory. More importantly, de novo protein synthesis in the BLA is essential for early phase reconsolidation of retrieved emotion-related memories. Protein synthesis in the CeA is required for late phase reconsolidation of retrieved emotion-related memories.

Repeated co-administrations of alcohol- and methamphetamine-produced anxiogenic effect could be associated with the neurotoxicity in the dentate gyrus.

To date, joint use of alcohol (EtOH) and methamphetamine (MA) represents a specific combination of polydrug abuse. Repeated administrations of EtOH, MA, and combined EtOH and MA were assessed for their effects on brain cell toxicity, cell mitosis and anxiety/depression-like behavior. We found that repeated co-administrations of EtOH and MA produced profound anxiogenic effects. Specifically, combined EtOH and MA decreased open arm exploratory responses in the elevated plus maze test. Moreover, combined EtOH and MA significantly decreased immobile responses in the tail suspension test. MA, EtOH, and their combination all reduced the number of NeuN-positive cells in amygdala (Amg), while neither of them altered the number of NeuN-positive cells in striatum (St) or prefrontal cortex (PFC). Combined EtOH and MA decreased the number of NeuN-positive cells in dentate gyrus (DG). EtOH, MA, and combined EtOH and MA all diminished comparable number of GFAP-positive cells in Amg, DG, and St. Neither of these treatment affected the number of GFAP-positive cells in PFC. EtOH, MA, and combined EtOH and MA generated comparable inhibiting effects on cell proliferation in the subventricular zone (SVZ) and DG. These results, taken together, suggest that repeated co-administrations of MA and EtOH may produce an observable anxiogenic effect. This combination-produced anxiogenic effect could be associated with neuronal loss in the dentate gurus. In contrast, such an anxiogenic effect is less likely related to this combination-caused glial toxicity in limbic regions or cell proliferation-inhibiting effect in the SVZ or DG.

Memantine abolishes the formation of cocaine-induced conditioned place preference possibly via its IL-6-modulating effect in medial prefrontal cortex.

In this study, we decided to use low doses of memantine pretreatment to examine the roles of the immune function in cocaine-supported conditioning. Cocaine-induced conditioned place preference (CPP) was used to assess the hedonic value and/or reinforcing efficacy of cocaine and cocaine-supported conditioning. Systemic pretreatment with memantine (20, 2.0, 0.2, and 0.02 mg/kg/injection) 30 min before each cocaine and saline conditioning trial abolished the acquisition of cocaine-induced CPP in mice. Even a total of 0.12 mg/kg memantine pretreatment in three days was effective in diminishing cocaine-induced CPP. Three consecutive days of cocaine conditioning increased interleukin-6 (IL-6) but decreased tumor necrosis factor (TNF-α) levels in medial prefrontal cortex (mPFC) and nucleus accumbens (Acb). Interestingly, pretreatment with memantine at the lowest effective dose (0.02 mg/kg/injection) reversed cocaine conditioning-enhanced IL-6 and -decreased TNF-α levels in these brain regions. Nevertheless, such a memantine dosing regimen did not affect dopamine metabolism in mPFC and Acb. Single memantine (0.02 mg/kg) injection did not acutely affect mouse locomotor activity or cocaine-increased locomotor activity. Similar memantine dosing regimen was ineffective to affect the maintenance of cocaine-induced CPP. Finally, intra-mPFC infusion of recombinant IL-6, but not thalidomide, reversed memantine (0.02 mg/kg/injection × 6)-decreased cocaine-induced CPP. These results, taken together, suggest that cocaine conditioning-enhanced IL-6 in mPFC may be, in part, involved in the acquisition of cocaine-induced CPP. Moreover, an extremely low dose of memantine may decrease the acquisition of cocaine-induced CPP by reversing cocaine conditioning-increased IL-6 levels in mPFC.

Systemic treatment with protein synthesis inhibitors attenuates the expression of cocaine memory.

It has been proposed that a memory trace enters a labile phase each time it is retrieved. A reactivated memory relies on de novo protein synthesis to be faithfully reconsolidated and restored. Thus, in theory, a long-lasting and pathological memory associated with drug use may be disrupted by inhibiting its reconsolidation through use of protein synthesis inhibitors administered immediately following the memory retrieval. However, effective and efficient strategies to reactivate drug memory remained elusive. This study was undertaken to examine the effects of systemic cycloheximide and anisomycin treatment on the reconsolidation and maintenance of a reactivated cocaine-conditioned place preference (CPP) in mice using several strategies designed to reactivate the previously acquired memory. We found that anisomycin (50 mg/kg/injection) and cycloheximide (15 mg/kg/injection) administered immediately after the reactivation of cocaine-CPP ameliorated subsequent expression and maintenance of this memory. Likewise, when anisomycin and cycloheximide were administered immediately after additional cocaine and saline conditioning trials, the reactivated memory engendered by those extra training trials was also diminished. However, a similar anisomycin dosing regimen failed to affect subsequent expression of cocaine-CPP when additional cocaine conditioning trial was used in the absence of additional saline trial. Finally, cocaine and saline administration to mice in their home cages with or without anisomycin treatment had no effect on later cocaine-CPP expression. Taken together, these findings suggest that systemic treatment with protein synthesis inhibitors immediately after the reactivation of cocaine-CPP effectively diminished the reconsolidation and maintenance of such a cocaine memory. More importantly, reactivation of cocaine-CPP could be achieved by presentation of cocaine-conditioned cues as well as by administering additional cocaine and saline conditioning trials in a balanced fashion.

Presence of conspecifics and their odor-impregnated objects reverse stress-decreased neurogenesis in mouse dentate gyrus.

Stress and corticosterone level are thought to negatively associate with neurogenesis in mammalian brains. Social support can diminish many adverse effects of stress. The present study examined the modulating effect of social support on stress-decreased cell proliferation and neuronal differentiation in a mouse model. A randomly-scheduled foot shock followed by restraint in water was used as a profound stress-provoking regimen. Bromodeoxyuridine (BrdU) staining was used to indicate newly mitotic cells and doublecortin (DCx) staining was used to reveal immature neurons. This stress-provoking regimen rapidly decreased BrdU- and BrdU/DCx-labeled cells in the dentate gyrus. However, such a stress-provoking regimen did not affect the number of these labeled cells in the subventricular zone. Familiar and unfamiliar mice' company throughout the stress regimen completely reversed the stress-decreased cell proliferation and neuronal genesis in the dentate gyrus. Likewise, both odor-familiar (from their home cages) and -unfamiliar (from cages other than their home cages) wooden blocks completely reversed the stress-decreased BrdU/DCx-labeled cells in the dentate gyrus. In contrast, wooden blocks free of any odor and camphor odor alone failed to affect the stress-decreased BrdU- or BrdU/DCx-labeled cells. Finally, we showed that conspecifics or their odors during the stress regimen reversed the stress-decreased cell proliferation and neuronal differentiation in the dentate gyrus via a corticosterone-independent mechanism. We conclude that stress and familiarity distinctively affect neurogenesis in the dentate gyrus and subventricular zone. Conspecific companions or presence of their odors reverse stress-decreased neurogenesis in the dentate gyrus, suggesting that social support during stress exposure may improve neurogenesis-related psychological functions.

Chronic treatment with monoamine oxidase-B inhibitors decreases cocaine reward in mice.

RATIONALE AND OBJECTIVE: Whether monoamine oxidase inhibitors (MAOIs) can be used to suppress the reinforcing effect of cocaine remains unknown. This study was undertaken to examine effects of a long-term dosing regimen with selective MAOIs on cocaine and food reward. MATERIALS AND METHODS: Since single dose of clorgyline (2 mg/kg), deprenyl (1 mg/kg), and pargyline (10 mg/kg) did not acutely affect mouse locomotor activity, these doses were chosen to treat the male C57BL/6j mice on a daily basis. RESULTS: Fourteen consecutive days of pretreatments with clorgyline, deprenyl, or pargyline (one injection per day) did not affect natural reward-supported operant behavior, since acquisition of the lever pressing responses for food pellets under an FR-1 protocol did not differ among these drug- and saline-treated mice. Likewise, 24 consecutive days of pretreatments with clorgyline did not alter acquisition of the cocaine (0.3 mg/kg per infusion)-supported operant responses under an FR-1 protocol. In contrast, 24 days of pretreatments with deprenyl and pargyline abolished the cocaine-supported operant responses under a similar protocol. Twenty-four days of clorgyline treatment enhanced serotonin contents in striatum, nucleus accumbens, and frontal cortex. Frontal cortical 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacidic acid concentrations were decreased following 24 days of pretreatments with deprenyl and pargyline. These changes were not evident in mice pretreated with clorgyline. CONCLUSIONS: We suggest that long-term treatments with MAO-B inhibitors may decrease cocaine-supported operant responses in cocaine-naïve mice by selectively decreasing frontal cortical metabolism of dopamine and serotonin.

Lipopolysaccharide mitagates methamphetamine-induced striatal dopamine depletion via modulating local TNF-alpha and dopamine transporter expression.

Systemic lipopolysaccharide (LPS) treatment may affect methamphetamine (MA)-induced nigrostriatal dopamine (DA) depletion. This study was undertaken to determine the critical time window for the protective effects of LPS treatment and the underlying mechanisms. An LPS injection (1 mg/kg) 72 h before or 2 h after MA treatment [three consecutive, subcutaneous injections of MA (10 mg/kg each) at 2-h intervals] diminished the MA-induced DA depletion in mouse striatum. Such an LPS-associated effect was independent of MA-produced hyperthermia. TNF-alpha, IL-1beta, IL-6 expressions were all elevated in striatal tissues following a systemic injection with LPS, indicating that peripheral LPS treatment affected striatal pro-inflammatory cytokine expression. Striatal TNF-alpha expression was dramatically increased at 72 and 96 h after the MA treatment, while such TNF-alpha elevation was abolished by the LPS pretreatment protocol. Moreover, MA-produced activation of nuclear NFkappaB, a transcription factor following TNF-alpha activation, in striatum was abolished by the LPS (1 mg/kg) pretreatment. Furthermore, thalidomide, a TNF-alpha antagonist, treatment abolished the LPS pretreatment-associated protective effects. Pretreatment with mouse recombinant TNF-alpha in striatum diminished the MA-produced DA depletion. Finally, single LPS treatment caused a rapid down-regulation of dopamine transporter (DAT) in striatum. Taken together, we conclude that peripheral LPS treatment protects nigrostriatal DA neurons against MA-induced toxicity, in part, by reversing elevated TNF-alpha expression and subsequent signaling cascade and causing a rapid DAT down-regulation in striatum.

Medial prefrontal cortex and nucleus accumbens core are involved in retrieval of the methamphetamine-associated memory.

Immunohistochemical Fos staining has proven to be a method to identify the neurons that are activated by stimulation. Although methamphetamine (MA)-conditioned place preference (CPP) memory was long-lasting, how this memory was established and retrieved remained unknown. We used the vehicle- and MA-conditioned environment (including cues and context) to reactivate the MA-CPP memory in mice. In the limbic system, Fos-positive neurons were examined following retrieval of the MA-CPP memory. We demonstrated that the current conditioning procedure produced reliable MA-CPP performance. Moreover, enhanced Fos expressions were found in the medial prefrontal cortex and the core of the nucleus accumbens after reactivation of the MA-CPP memory. Furthermore, familiarity with the environmental cues/context was found to significantly enhance Fos expressions in dorsal striatum and dentate gyrus. Nucleus accumbens shell, basolateral or lateral amygdala, in this regard, did not seem to be involved in retrieval of the MA-CPP memory. These results, taken together, suggest that the medial prefrontal cortex and the core of the nucleus accumbens are anatomical substrates responsible for reactivation of the MA-CPP memory.