Neurochemical and behavioral effects of chronic unpredictable stress.

Chronic stress can influence behaviors associated with medial prefrontal cortex (mPFC) function, such as cognition and emotion regulation. Dopamine in the mPFC is responsive to stress and modulates its behavioral effects. The current study tested whether exposure to 10 days of chronic unpredictable stress (CUS) altered the effects of acute elevation stress on dopamine release in the mPFC and on spatial recognition memory. Male rats previously exposed to CUS or nonstressed controls were tested behaviorally, underwent microdialysis to assess mPFC dopamine levels or underwent blood sampling for corticosterone analysis. Dopamine in the mPFC significantly increased in both groups during acute elevation stress compared with baseline levels, but the level was attenuated in CUS rats compared with controls. Control rats exposed to elevation stress immediately before the T-maze test showed impaired performance, whereas CUS rats did not. No group differences were observed in general motor activity or plasma corticosterone levels following elevation stress. The present results indicate that prior exposure to this CUS procedure reduced dopamine release in the mPFC during acute elevation stress and prevented the impairment of performance on a spatial recognition test following an acute stressor. These findings may contribute to an understanding of the complex behavioral consequences of stress.

Sex differences in effort-related decision-making: role of dopamine D2 receptor antagonism.

RATIONALE: Depressed individuals demonstrate debilitating symptoms, including depressed mood, anhedonia, and effort-related deficits. Effort-related decision-making can be measured through providing subjects with a choice between high effort/reward and low effort/reward options, which is a dopamine (DA)-dependent behavior. While previous research has shown sex differences in depression rates, this has not been examined within operant-based effort-related decision-making tasks nor has DA been shown to underlie this behavior in female rats. OBJECTIVES: The current study investigated sex differences in an effort-related decision-making task prior to and following administration of the DA D2 receptor antagonist haloperidol (HAL). METHODS: Adult rats were food restricted or fed freely and trained in an effort-related progressive ratio choice task. After stable responding, HAL was administered acutely (0.05-0.2 mg/kg) prior to testing. RESULTS: Results indicate a significant effect of sex on training variables, with males having a greater number of lever presses, higher ratios, and longer active lever times. Pretreatment with HAL significantly reduced the same measures in both sexes for the high-valued reward, while increasing chow consumption in the food restricted males. Food restricted rats showed a greater number of total lever presses and achieved higher ratios; however, the effect in male food restricted rats was greatest. CONCLUSIONS: These data suggest that, although there are sex differences in training, HAL decreases behavior across sexes, demonstrating that the D2 mechanism is similar in both sexes. These findings provide a better understanding of motivational dysfunction in both sexes and potential treatment targets for depression.

Hormonal changes and couple bonding in consensual sadomasochistic activity.

In two studies, 58 sadomasochistic (SM) practitioners provided physiological measures of salivary cortisol and testosterone (hormones associated with stress and dominance, respectively) and psychological measures of relationship closeness before and after participating in SM activities. Observed activities included bondage, sensory deprivation, a variety of painful and pleasurable stimulation, verbal and non-verbal communication, and expressions of caring and affection. During the scenes, cortisol rose significantly for participants who were bound, receiving stimulation, and following orders, but not for participants who were providing stimulation, orders, or structure. Female participants who were bound, receiving stimulation, and following orders also showed increases in testosterone during the scenes. Thereafter, participants who reported that their SM activities went well showed reductions in physiological stress (cortisol) and increases in relationship closeness. Among participants who reported that their SM activities went poorly, some showed decreases in relationship closeness whereas others showed increases. The increases in relationship closeness combined with the displays of caring and affection observed as part of the SM activities offer support for the modern view that SM, when performed consensually, has the potential to increase intimacy between participants.

Interaction of stress and stimulants in female rats: Role of chronic stress on later reactivity to methamphetamine.

Previous research in humans and animals suggests that prior exposure to stress alters responsivity to drugs of abuse, including psychostimulants. Male rats show an augmented striatal dopamine response to methamphetamine following exposure to chronic unpredictable stress (CUS). Compared to males, female rats have been shown to be highly sensitive to the effects of stimulants and stress independently, however few studies have examined the interaction between stress and stimulants in female rats. Therefore, the current study investigated whether prior exposure to chronic stress potentiated the behavioral and neurochemical responses to an acute injection of methamphetamine in female rats. Adult female Sprague-Dawley rats were either exposed to CUS or left undisturbed (control) and then two weeks later received an injection of 1.0 or 7.5 mg/kg methamphetamine. Based on open field findings, a subsequent group of rats were exposed to CUS or left undisturbed and then two weeks later received 7.5 mg/kg methamphetamine and either dopamine efflux in the dorsal striatum or nucleus accumbens was measured or methamphetamine and amphetamine levels were measured in the brain and plasma. Female rats exposed to CUS traveled greater distances in the open field immediately following an injection of 7.5 mg/kg, but not 1.0 mg/kg, of methamphetamine and then showed high levels or stereotypy similar to control rats. Animals exposed to CUS had significantly greater increases in dorsal striatum dopamine following an acute injection of 7.5 mg/kg methamphetamine compared to control rats, but not in the nucleus accumbens. These differences were not due to group differences in levels of methamphetamine or amphetamine in the brain or plasma. The current findings demonstrate stress-augmented neurochemical responses to a dose of methamphetamine, similar to that self-administered, which increases understanding of the cross-sensitization between stress and methamphetamine in females.

Social anxiety and employment interviews: does nonverbal feedback differentially predict cortisol and performance?

BACKGROUND & OBJECTIVES: Interviewers often provide positive nonverbal feedback to reduce interviewees' anxiety. Socially anxious individuals typically harbor negative self-views discrepant with positive feedback. We examined whether nonverbal feedback and social anxiety jointly influence cortisol responses to, and performance during, interviews. DESIGN: An experimental between-subjects design randomly assigned participants to feedback condition. METHODS: Undergraduate students (N = 130) provided saliva and completed social anxiety, interview anxiety, and affective measures before a simulated interview. Following a standardized script, a confederate interviewer provided positive, ambiguous, or negative nonverbal feedback. Participants then provided saliva and completed self-focused attention and self-awareness measures. Confederate interviewers and an external rater evaluated participants' anxiety displays, assertive behavior, and performance. RESULTS: Positive feedback decreased cortisol and improved performance for low social anxiety participants. Socially anxious participants exhibited higher cortisol but did not exhibit significant differences in performance after positive compared to negative feedback. CONCLUSIONS: Consistent with previous findings, positive feedback did not benefit socially anxious interviewees. Positive feedback increased physiological arousal relative to negative feedback but did not hinder performance among people high in social anxiety. These results provide novel information about the interactive influence of social anxiety and nonverbal interviewer feedback on arousal, self-focus, and interview performance.

Social isolation alters central nervous system monoamine content in prairie voles following acute restraint.

Animal models have shown that social isolation and other forms of social stress lead to depressive- and anxiety-relevant behaviors, as well as neuroendocrine and physiological dysfunction. The goal of this study was to investigate the effects of prior social isolation on neurotransmitter content following acute restraint in prairie voles. Animals were either paired with a same-sex sibling or isolated for 4 weeks. Plasma adrenal hormones and ex vivo tissue concentrations of monoamine neurotransmitters and their metabolites were measured following an acute restraint stressor in all animals. Isolated prairie voles displayed significantly increased circulating adrenocorticotropic hormone levels, as well as elevated serotonin and dopamine levels in the hypothalamus, and potentially decreased levels of serotonin in the frontal cortex. However, no group differences in monoamine levels were observed in the hippocampus or raphe. The results suggest that social stress may bias monoamine neurotransmission and stress hormone function to subsequent acute stressors, such as restraint. These findings improve our understanding of the neurobiological mechanisms underlying the consequences of social stress.

The effects of methamphetamine exposure during preadolescence on male and female rats in the water maze.

Exposure to methamphetamine early in life can have lasting effects on cognitive processes. The maturation of neurotransmitter systems targeted by methamphetamine differs by gender during childhood and preadolescence, which could lead to differential long-term effects of early drug exposure. Therefore, the current study assessed whether preadolescent exposure to methamphetamine has gender specific long-term effects on adult spatial memory in rodents. Male and female rats were given 1 daily injection of 0 or 2mg/kg methamphetamine or not handled from PD21-35 and then tested as adults (PD95) in the Morris water maze. In general, male rats performed better than female rats in the water maze task regardless of treatment group. Female rats exposed to methamphetamine from PD21-35 had shorter latencies and took more direct paths to the hidden platform compared to control females during the 4 days of acquisition training and when the hidden platform was moved each day on matching to place trials. Male rats exposed to methamphetamine swam a shorter distance to the hidden platform on the first day of acquisition training, similar to the methamphetamine exposed females. However, the methamphetamine exposed males performed more poorly compared to control males in the matching to place trials. Overall, the current study found that methamphetamine exposure during preadolescence has long-term effects on spatial memory in a gender specific manner. These findings may contribute to our general understanding of the long-term effects of psychostimulant exposure at early developmental stages.

The delayed effects of chronic unpredictable stress on anxiety measures.

Previous research has found that exposure to unpredictable stress can augment anxiety in humans and animals. The appearance of anxiety symptoms in humans frequently develop after stress exposure has terminated, but few rodent studies have systematically examined the delayed anxiogenic effects of unpredictable stress. Therefore, the current study investigated whether anxiety-like behaviors in rats would increase at several time intervals following exposure to chronic unpredictable stress (CUS). Unconditioned and conditioned response tasks were used to assess anxiety in male rats 1, 7 or 14 days following exposure to 10 days of a variety of stressors. Rats exposed to CUS showed increased burying behaviors and immobility during the defensive burying test, a conditioned anxiety test. The effects on burying behavior were apparent 7 and 14 days after the termination of the unpredictable stress procedure, but not when tested 1 day after CUS. Total time immobile in the defensive burying test also increased 14 days after termination of the last stressor. In contrast, there were no significant effects of CUS on behavioral measures in the unconditioned response tasks, the elevated plus-maze or light-dark box, at any time point following exposure to CUS. The current findings suggest that CUS may be a useful model of human conditioned anxiety that develops subsequent to chronic stress exposure.

The effects of chronic unpredictable stress on male rats in the water maze.

Exposure to chronic stress can affect cognitive processes in a complex manner depending upon the intensity and duration of the stressors. The current study investigated the effects of chronic unpredictable stress (CUS), a procedure thought to use moderate stressors, on acquisition of and performance in the Morris Water Maze (MWM). Separate behavioral tests were also used to determine whether the stress-induced changes in MWM were due to general changes in locomotor activity or preference for a rewarding stimulus. Adult male rats were exposed to 10 days of different stressors applied at various times. Following the last stressor, stressed and non-stressed rats began training in the MWM, were tested in an open field box, or were tested for sucrose preference. In the MWM, rats exposed to stress had shorter latencies to reach the hidden platform during training. The path lengths on day 2 of training, trials 2 and 4, were shorter in CUS rats compared to controls, with the stressed rats traveling less in the outer portion of the maze. During the probe trial, CUS rats also traveled less overall and less in the outer portion of the maze, although all other measures were the same. The facilitation in learning the platform location was not due to a change in other behavioral components that could contribute to the measures, such as general activity, sensorimotor processing or the preference for a 2% sucrose solution. Thus, chronic unpredictable stress selectively appears to affect the search strategies in the water maze.

Long-lasting effects of chronic stress on DOI-induced hyperthermia in male rats.

RATIONALE: Exposure to chronic stress can affect the serotoninergic (5-HT) system and behavioral measures associated with 5-HT. Repeated stress increases 5-HT receptor subtype 2 (5-HT2) mediated behaviors in rodents, such as wet dog shakes and head twitch. OBJECTIVES: The current study investigated whether exposure to chronic unpredictable stress would augment 5-HT(2A/C) receptor-mediated hyperthermia. Furthermore, the persistence of these hyperthermic effects was investigated by testing rats up to 60 days after the stress procedure terminated. METHODS: For 2 or 10 days, rats were either not stressed (controls) or exposed to chronic unpredictable stress, i.e. two stressors per day of the following: cage rotation, cold exposure, swim, restraint, light cycle manipulations, single housing, and food and water deprivation. After the termination of stress (day 3 or 11), the 5-HT(2A/C) receptor agonist DOI (1.5 mg/kg) or saline, was injected and the rectal temperature of the rats was monitored. In a separate experiment, the 5-HT2 receptor antagonist, LY-53,587, was injected 30 min prior to the injection of DOI or saline. Finally, DOI was injected into rats 8, 30 or 60 days after the 10-day stress procedure ended. RESULTS: Rats exposed to 10 days, but not 2 days, of unpredictable stress exhibited higher rectal temperatures following DOI than non-stressed rats. The DOI-induced hyperthermia was attenuated by LY-53,587. The augmentation of DOI-induced hyperthermia in stressed rats persisted when examined 8, 30 and 60 days following the stress procedure. CONCLUSIONS: The enhancement of 5-HT receptor function by chronic stress persists even after the environmental stressor is removed. This lasting increase in 5-HT receptor function may have implications for clinical disorders associated with stress, such as depression or post-traumatic stress disorder.

Effects of chronic stress on methamphetamine-induced dopamine depletions in the striatum.

Research has shown that exposure to repeated stress alters acute behavioral and neurochemical responses to drugs of abuse. However, few studies have characterized the longer-term detrimental effects of psychostimulant drugs such as methamphetamine (METH) after exposure to chronic stress. The current study tested whether 10 days of unpredictable stress produced greater striatal dopamine depletions after neurotoxic injections of METH and whether monoamine reuptake blockers protected against stress/METH-induced DA depletion. Male rats were exposed to 10 d of unpredictable stress or weighed daily but not stressed. On day 11, all rats were given 4 injections of 0, 7.5, or 10 mg/kg METH, 1 injection every 2 h, and tissue collected 7 d later. Male rats exposed to unpredictable stress had greater depletions of striatal dopamine tissue content than nonstressed controls injected with METH. In a separate study, rats were treated with vehicle, desipramine (10 mg/kg), or fluoxetine (5 mg/kg) daily during the 10-d stress regimen. These antidepressants did not attenuate the stress-potentiated depletion of striatal dopamine. These findings suggest that chronic unpredictable stress enhances vulnerability of the brain to neurotoxic effects of psychostimulants, but this vulnerability is mediated through mechanisms other than the norepinephrine or serotonin uptake systems.

Persistent behavioral and neurochemical sensitization to an acute injection of methamphetamine following unpredictable stress.

Prior research in humans and animals suggest that exposure to chronic stress alters the response to drugs of abuse, increasing vulnerability to drug addiction. Chronic unpredictable stress (CUS) has been shown to augment the increase of dopamine in the striatum when challenged with high doses of methamphetamine immediately following stress exposure, however it is not known whether this neurochemical stress-sensitization continues after the cessation of the stressors or if behavioral sensitization is also present. Therefore, the current study examined the immediate and delayed effects of CUS on methamphetamine-induced behaviors and striatal dopamine levels. Male rats were exposed to 10 days of CUS and then tested in either an open field box to assess locomotion or underwent in vivo microdialysis to measure striatal dopamine levels immediately following CUS or after a 1-2 week delay. All rats exposed to CUS showed a potentiated locomotor response immediately following an acute injection of 7.5mg/kg methamphetamine compared to non-stressed control rats. Both groups of CUS rats also showed augmented dopamine release and rectal temperatures following methamphetamine with prolonged increases in the CUS rats tested after a delay. These results suggest that CUS increases the sensitivity of a rat to a single injection of methamphetamine and that the increased sensitivity persists for up to 2 weeks following the last stressor.

Juvenile but not adult methamphetamine exposure improves performance in the Morris Water Maze in male rats.

Early exposure to psychostimulants has been found to lead to long-lasting effects on cognitive processes. Our lab has previously reported that juvenile male rats administered methamphetamine showed improved performance in a spatial navigation task when tested in adulthood (McFadden and Matuszewich, 2007). What is not known, however, is if these effects are specific to the developing rat, or if a similar methamphetamine protocol given to adult rats would lead to an equally beneficial long-term change in spatial cognition. In the current study, male rats were given 1 daily injection of 2mg/kg methamphetamine or saline for 15 days during either preadolescence (PD20-34) or adulthood (PD70-84). Approximately 45 days after treatment, all rats then underwent 5 days of place training in the Morris water maze at a time when juvenile rats reached adulthood. Similar to previous findings, juvenile rats exposed to repeated methamphetamine displayed shorter latencies and distances to reach the platform throughout training compared to saline-treated rats. The juvenile rats treated with methamphetamine also swam shorter distances and had faster latencies to the hidden platform compared to adult methamphetamine-treated rats. There were no significant differences in rats treated in adulthood with methamphetamine compared to saline-treated rats. Likewise, there were no effects of prior methamphetamine treatment or age on matching-to-place trials or visible platform trials. Overall, the results show that repeated methamphetamine exposure can selectively improve spatial learning in adult male rats when administered during preadolescence, but does not significantly affect spatial learning when administered in adulthood. Furthermore, the current findings demonstrate the unique susceptibility of the developing brain to drugs that modulate dopaminergic activity, as well as the long-term behavioral impact of exposure at critical ages.

Juvenile exposure to methamphetamine attenuates behavioral and neurochemical responses to methamphetamine in adult rats.

Previous research has shown that children living in clandestine methamphetamine (MA) labs are passively exposed to the drug [1]. The long-term effects of this early exposure on the dopaminergic systems are unknown, but may be important for adult behaviors mediated by dopamine, such as drug addiction. The current study sought to determine if juvenile exposure to low doses of MA would lead to altered responsiveness to the stimulant in adulthood. Young male and female rats (PD20-34) were injected daily with 0 or 2 mg/kg MA or left undisturbed and then tested at PD90. In the open field, adult rats exposed to MA during preadolescence had reduced locomotor activity compared to control non-exposed rats following an acute injection of MA (2 mg/kg). Likewise, methamphetamine-induced dopamine increases in the dorsal striatum were attenuated in male and female rats that had been exposed to MA as juveniles, although there were no changes in basal in vivo or ex vivo dopamine levels. These findings suggest that exposure of juveniles to MA leads to persistent changes in the behavioral and neurochemical responses to stimulants in adulthood.

Alterations in adult behavioral responses to cocaine and dopamine transporters following juvenile exposure to methamphetamine.

The present experiment assessed whether preadolescent exposure to methamphetamine would alter adult behavioral responses to cocaine and dopamine transporter immunoreactivity in the striatum of male and female rats. Juvenile rats were injected once daily with 0 or 2 mg/kg methamphetamine from postnatal days 21 to 35 and tested in adulthood. Male rats, but not female rats, exposed to methamphetamine showed an increase in responsiveness to cocaine in the open field and an increase in dopamine transporter immunoreactivity in the striatum. These findings suggest that early exposure to methamphetamine can lead to sex specific altered responses to psychostimulants in adulthood, which may contribute to later vulnerability to drug use.