Leslie Matuszewich

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.

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.

Sex-dependent effects of chronic unpredictable stress in the water maze

Exposure to chronic predictable stress, such as restraint, can affect performance on spatial memory tasks and these effects have been shown to be sex-specific in rats. It is not known whether unpredictable stress has similar sex-specific effects on spatial memory and whether those effects are present after the stress procedure has ended. Therefore, the current study tested male and female rats in the Morris water maze either immediately or 3 weeks following exposure to 10 days of unpredictable stress (CUS). Male and female rats were exposed to 10 days of stressors that varied by type and time of stressor application. Exposure to CUS decreased the distance swam to locate the hidden platform during acquisition training in the water maze for female but not male rats. Overall, male rats performed better than female rats during the acquisition, probe and matching to place trials. These effects were observed when assessing spatial memory performance immediately or 3 weeks following the last stressor. Plasma corticosterone levels followed the behavioral differences during the acquisition trials in that control female rats had increased basal and swim-stimulated corticosterone levels compared to CUS female rats and control male rats. These data demonstrate that unpredictable stress influences performance on the water maze in a sex-specific manner, which parallel plasma corticosterone levels. The improved performance of female rats following CUS exposure was present 3 weeks after the termination of the stress procedures, suggesting that stress may have lasting effects on underlying neural systems.

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.

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

Abstract: 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.

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 2 mg/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.

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.

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.

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.

Effects of pretraining and water temperature on female rats' performance in the Morris water maze

The water maze is a complex spatial task that requires the coordination of multiple systems to perform efficiently. Various factors have been shown to influence performance in this task, including motivational state and prior experience. Although a consistent sex difference has been observed in acquiring the water maze in rats, the contribution of the various factors in female rat performance has not been fully assessed. Therefore, the current study tested the effects of motivation as manipulated by water temperature of the maze and prior experience in the maze on the performance of female rats. It was hypothesized that females pretrained in the maze would perform better than those without exposure to the water maze, regardless of water temperature, but in naïve rats, colder water would improve performance as shown previously in male rats. For pretraining, female rats were taught to find a visible platform in cold (19 °C, 4 trials on one day) and warm (25 °C, 4 trials on one day) water before acquisition trials, with the order of the water temperature randomly assigned. Control rats were not given any training and were naïve to the water maze procedure. Pretrained and control rats were then tested to locate a hidden platform in either cold or warm water for 5 consecutive days. Overall, pretraining had a significant effect on distance, latency, and directness of path to the platform. Water temperature did not show a significant effect on any measure or a significant interaction with pretraining. Thus, while our hypothesis that pretraining would improve performance was supported, the results did not support the prediction that water temperature would also significantly influence performance. These results show that non-spatial pretraining can critically improve the performance of females in acquiring a place strategy for the hidden platform, irrespective of water temperature.