Voluntary oral methamphetamine increases memory deficits and contextual sensitization during abstinence associated with decreased PKMζ and increased κOR in the hippocampus of female mice.

BACKGROUND: Female populations exhibit vulnerabilities to psychostimulant addiction, as well as cognitive dysfunction following bouts of abuse. AIMS: The goal for this study was to advance our understanding of the mechanisms that produce sex disparities in drug addiction. METHODS: We used an animal model for voluntary oral methamphetamine administration (VOMA) and focused on male and female mice that consumed 7.6-8.2 mg/kg of methamphetamine (MA) per day during the last 18 days of the paradigm. RESULTS: The VOMA-exposed female mice displayed increased locomotor activity in the drug-administration context compared to male mice, demonstrating sex-specific changes in contextual sensitization. During 2 weeks of forced abstinence, mice underwent further behavioral testing. We show that abstinence increased open-arm entries on the elevated plus maze in both sexes. There were no differences in immobility on the tail suspension test. In a hippocampal-dependent radial arm maze task, VOMA-treated female mice, but not male mice, showed working memory deficits. Hippocampal tissue was collected and analyzed using Western blotting. VOMA-exposed female mice exhibited increased kappa opioid receptor (κOR) expression in the hippocampus compared to male mice, suggesting a vulnerability toward abstinence-induced dysphoria. Female VOMA mice also exhibited a decrease in the memory protein marker, protein kinase M zeta (PKMζ), in the hippocampus. CONCLUSIONS: Our study reveals sex-specific effects following abstinence from chronic MA consumption on hippocampal κOR and PKMζ expression, suggesting that these neural changes in female mice may underlie spatial memory deficits and identify an increased susceptibility to dysregulated neural mechanisms. These data validate VOMA as a model sensitive to sex differences in behavior and hippocampal neurochemistry following chronic MA exposure.

Estradiol rapidly increases GluA2-mushroom spines and decreases GluA2-filopodia spines in hippocampus CA1.

Hippocampal dendritic spine density rapidly increases following estradiol (E2 ) treatment, but the types of spines and trafficking of synaptic markers have received little investigation. We assessed rapid effects of E2 over time on the density of four spine types (stubby, filopodial, long thin, and mushroom) and trafficking of AMPA receptor subunit GluA2 and PSD95 on tertiary, apical dendrites in CA1. Castrated male rats received 20 µg kg-1 of E2 or vehicle and were sacrificed 30 or 120 min later. Images of Golgi-Cox impregnated and PSD95/GluA2 stained dendrites were captured under the confocal microscope and quantified with IMARIS-XT. Stubby and filopodial spine densities did not change following treatment. Long-thin spines significantly decreased at 30 min while mushroom spines significantly increased at 120 min. GluA2, PSD95, and GluA2/PSD95 colocalization levels in stubby or long thin spines did not change, but filopodial spines had significantly reduced GluA2 levels at 30 min. Mushroom spines showed significantly increased levels for GluA2, PSD95 and GluA2/PSD95 colocalization at 120 min. Because GluA2 is important for memory consolidation, current results present novel data suggesting that trafficking of GluA2 to mushroom spines provides one mechanism contributing to estradiol's ability to enhance learning and memory by the PI3 signaling pathway.

Gonadal Hormones Rapidly Enhance Spatial Memory and Increase Hippocampal Spine Density in Male Rats.

17ß-estradiol (E2) rapidly, within minutes, activates behaviors and cognition by binding to membrane estrogen receptors, activating cell signaling cascades and increasing dendritic spines. In female rodents, E2 enhances spatial memory within 2-4 hours, and spine density is increased in the CA1 area of the hippocampus within 30-60 minutes. Although chronic gonadal hormone treatments in male rats alter cognition and spines/spine synapses and acute hormone effects occur in hippocampal slices, effects of acute, in vivo hormone administration in males are unknown. Therefore, we assessed rapid effects of E2 (20 µg/kg) and testosterone (T) (750 µg/kg) on spatial memory using the object placement task and on hippocampal spine density using Golgi impregnation. Orchidectomized rats received hormones immediately after the training trial and were tested for retention 2 hours later. Vehicle-injected orchidectomized males spent equal time exploring objects in the old and new locations, but E2- or T-treated subjects spent more time exploring objects at the new location, suggesting enhanced memory. Both hormones also increased spine density in CA1, but not the dentate gyrus, by 20%-40% at 30 minutes and 2 hours after injections. This report is the first, to our knowledge, to show E2 and T enhancements of memory and spine density within such a short time frame in male rats.

Environmental Enrichment Increases Glucocorticoid Receptors and Decreases GluA2 and Protein Kinase M Zeta (PKMζ) Trafficking During Chronic Stress: A Protective Mechanism?

Environmental enrichment (EE) housing paradigms have long been shown beneficial for brain function involving neural growth and activity, learning and memory capacity, and for developing stress resiliency. The expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2, which is important for synaptic plasticity and memory, is increased with corticosterone (CORT), undermining synaptic plasticity and memory. Thus, we determined the effect of EE and stress on modulating GluA2 expression in Sprague-Dawley male rats. Several markers were evaluated which include: plasma CORT, the glucocorticoid receptor (GR), GluA2, and the atypical protein kinase M zeta (PKMζ). For 1 week standard-(ST) or EE-housed animals were treated with one of the following four conditions: (1) no stress; (2) acute stress (forced swim test, FST; on day 7); (3) chronic restraint stress (6 h/day for 7 days); and (4) chronic + acute stress (restraint stress 6 h/day for 7 days + FST on day 7). Hippocampi were collected on day 7. Our results show that EE animals had reduced time immobile on the FST across all conditions. After chronic + acute stress EE animals showed increased GR levels with no change in synaptic GluA2/PKMζ. ST-housed animals showed the reverse pattern with decreased GR levels and a significant increase in synaptic GluA2/PKMζ. These results suggest that EE produces an adaptive response to chronic stress allowing for increased GR levels, which lowers neuronal excitability reducing GluA2/PKMζ trafficking. We discuss this EE adaptive response to stress as a potential underlying mechanism that is protective for retaining synaptic plasticity and memory function.

Estradiol and cognitive function: past, present and future.

A historical perspective on estradiol's enhancement of cognitive function is presented, and research, primarily in animals, but also in humans, is reviewed. Data regarding the mechanisms underlying the enhancements are discussed. Newer studies showing rapid effects of estradiol on consolidation of memory through membrane interactions and activation of inter-cellular signaling pathways are reviewed as well as studies focused on traditional genomic mechanisms. Recent demonstrations of intra-neuronal estradiol synthesis and possible actions as a neurosteroid to promote memory are discussed. This information is applied to the critical issue of the current lack of effective hormonal (or other) treatments for cognitive decline associated with menopause and aging. Finally, the critical period hypothesis for estradiol effects is discussed along with novel strategies for hormone/drug development. Overall, the historical record documents that estradiol positively impacts some aspects of cognitive function, but effective therapeutic interventions using this hormone have yet to be realized.

Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density.

Estrogens exert sustained, genomically mediated effects on memory throughout the female life cycle, but here we review new studies documenting rapid effects of estradiol on memory, which are exerted through membrane-mediated mechanisms. Use of recognition memory tasks in rats shows that estrogens enhance memory consolidation within 1h. 17α-Estradiol is more potent than 17ß-estradiol, and the dose response relationship between estrogens and memory is an inverted U shape. Use of specific estrogen receptor (ER) agonists suggests mediation by an ERß-like membrane receptor. Enhanced memory is associated with increased spine density and altered noradrenergic activity in the medial prefrontal cortex and hippocampus within 30 min of administration. The environmental chemical, bisphenol-A, rapidly antagonizes enhancements in memory in both sexes possibly through actions on spines. Thus, estradiol and related compounds exert rapid alterations in cognition through non-genomic mechanisms, a finding which may provide a basis for better understanding and treating memory impairments.

The interaction of chronic restraint stress and voluntary alcohol intake: effects on spatial memory in male rats.

Alcohol consumption and exposure to stressful life events activate similar neural pathways and thus result in several comparable physiological and behavioral effects. Alcoholics in treatment claim that life stressors are the leading cause of continued drinking or relapse. However, few studies have investigated the interactive effects of stress and alcohol on cognitive behavior. The effects of restraint stress, alcohol, and stress in combination with alcohol were examined on a spatial memory test, the object placement (OP) task. In addition, intake levels were measured to determine if stress altered general consumption of alcohol. Male Sprague-Dawley rats were assigned to one of four conditions: no alcohol/no stress control (CON), stress alone (STR), alcohol alone (ALC), and STR+alcohol (STR+ALC). Following each restraint stress bout, the STR+ALC and the ALC groups were given access to 8% alcohol for 1h using the two-bottle choice limited access paradigm. As predicted, the STR+ALC group significantly increased alcohol consumption, while the ALC group had consistent drinking over the 10-day treatment. On the OP task, STR and ALC groups performed at chance levels, whereas the CON and STR+ALC groups significantly discriminated between objects in the new and old locations. These data show that stress increases alcohol intake and the intake of alcohol is associated with reduction of the stress-induced impairment of spatial memory. The data have important implications for the development of alcohol abuse and its treatment.

Age-related deficits in spatial memory and hippocampal spines in virgin, female Fischer 344 rats.

Effects of aging on memory and brain morphology were examined in aged, 21-month-old, and young, 4-month-old, Fischer 344 female rats. Spatial memory was assessed using the object placement task, and dendritic spine density was determined on pyramidal neurons in the hippocampus following Golgi impregnation. Consistent with previous studies, aged females showed poorer object placement performance than young subjects. Young subjects significantly discriminated the location of objects with a 1.5-hour intertrial delay while aged subjects did not. Spine density of basal dendrites on CA1 pyramidal cells was 16% lower in the aged subjects as compared to the young subjects. No differences in spine density were found between young and aged subjects in basal dendrites of CA1 or in either dendritic field of CA3 pyramidal neurons. Thus, decreased hippocampal CA1 dendritic spine density in aged rats may contribute to poorer spatial memory as compared to young rats. The possibility that the neuroplastic changes observed in this study may pertain only to female subjects having had a specific set of life experiences is discussed. Different factors, such as reproductive status, diet, and handling may contribute to neuroplasticity of the brain during aging; however, this view requires further examination.

Acute progesterone treatment impairs spatial working memory in intact male and female rats.

INTRODUCTION: The aim of this study was to determine if progesterone affects spatial and non-spatial working memory in intact male and female rats. METHODS: Rats received subcutaneous injections of progesterone (500 microg) or vehicle (sesame oil). Four hours after hormone treatments, spatial and non-spatial memories were tested using novel object recognition and spatial object recognition tasks. RESULTS: Vehicle-treated female rats had higher progesterone serum levels than males, but progesterone treatment produced equivalent progesterone serum levels in both sexes. In the object recognition task--a non-spatial memory task-females showed better performance than males, and progesterone had no effect on either sex. However, in the object replacement task--a spatial memory task-progesterone significantly impaired the retention in both male and female rats as compared with vehicle-treated groups. CONCLUSION: These results suggest that acute progesterone treatment interferes with spatial working memory consolidation, but not recognition (non-spatial) working memory. As such, the observed sexual incongruities in progesterone's effects on working memory suggest that progesterone-based hormone therapies have a negative impact on cognition.

Changes in anxiety and cognition due to reproductive experience: a review of data from rodent and human mothers.

Rodent research suggests that pregnancy, motherhood and attendant offspring care affect changes in neural function and behaviors that are not directly maternal in nature, but involve cognition, affect, and responses to stress. Thus, female rats having had one pregnancy and bout of rearing (primiparous), or multiple pregnancies and bouts of rearing (multiparous), generally show greater resilience to stress, decreased anxiety, and better memory abilities than female rats that have never experienced motherhood (virgin or nulliparous). Moreover, some studies show that these neural changes remain long after the last pregnancy, persisting even into old age. In the current review, we will begin by discussing these behavioral and neural changes in rodents and provide some information concerning their possible mechanisms. Then we will review data from studies examining anxiety and cognition in postpartum human mothers. While this data is less conclusive than that from non-human animals, it appears that reproductive experience may confer some beneficial changes to human mothers in terms of lowering the anxiety/stress response and enhancing certain aspects of memory.

Evidence for sex-specific shifting of neural processes underlying learning and memory following stress.

Recent human research has been focused upon determining whether there is evidence that stress responses cause qualitative changes in neural activity such that people change their learning strategies from a spatial/contextual memory process through the hippocampus to a procedural stimulus-response process through the caudate nucleus. Moreover, interest has shifted to determining whether males and females exhibit the same type of stress-induced change in neural processing of associations. Presented is a select review of 2 different animal models that have examined how acute or chronic stressors change learning in a sex-specific manner. This is followed by a brief review of recent human studies documenting how learning and memory functions change following stressor exposure. In both cases, it is clear that ovarian hormones have a significant influence on how stress affects learning processes in females. We then examine the evidence for a role of acetylcholine, dopamine, norepinephrine, or serotonin in modulating this shifting of processing and how that may differ across sex. Conclusions drawn suggest that there may be evidence for sex-specific changes in amygdala and hippocampus neuromodulation; however, the behavioral data are still not conclusive as to whether this represents a common or sex-specific shift in how males and females process associations after stressor exposure.

Effects of multiparity on recognition memory, monoaminergic neurotransmitters, and brain-derived neurotrophic factor (BDNF).

Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.

Changes in hippocampal function of ovariectomized rats after sequential low doses of estradiol to simulate the preovulatory estrogen surge.

In adult female rats, robust hippocampal changes occur when estradiol rises on the morning of proestrus. Whether estradiol mediates these changes, however, remains unknown. To address this issue, we used sequential injections of estradiol to simulate two key components of the preovulatory surge: the rapid rise in estradiol on proestrous morning, and the slower rise during the preceding day, diestrus 2. Animals were examined mid-morning of simulated proestrus, and compared to vehicle-treated or intact rats. In both simulated and intact rats, CA1-evoked responses were potentiated in hippocampal slices, and presynaptic mechanisms appeared to contribute. In CA3, multiple population spikes were evoked in response to mossy fiber stimuli, and expression of brain-derived neurotrophic factor was increased. Simulation of proestrous morning also improved performance on object and place recognition tests, in comparison to vehicle treatment. Surprisingly, effects on CA1-evoked responses showed a dependence on estradiol during simulated diestrus 2, as well as a dependence on proestrous morning. Increasing estradiol above the physiological range on proestrous morning paradoxically decreased evoked responses in CA1. However, CA3 pyramidal cell activity increased further, and became synchronized. Together, the results confirm that physiological estradiol levels are sufficient to profoundly affect hippocampal function. In addition: (i) changes on proestrous morning appear to depend on slow increases in estradiol during the preceding day; (ii) effects are extremely sensitive to the peak serum level on proestrous morning; and (iii) there are striking subfield differences within the hippocampus.

Aged rats: sex differences and responses to chronic stress.

Cognitive, as well as physiological, sex differences exist in young adult rats under both basal conditions and following chronic stress; however, few studies have examined whether sex differences remain in aged subjects and whether responses to stress are altered. We compared aged male and female Fischer 344 rats (21.5 months at testing) without stress and when given 21 days of restraint for 6 h/day on locomotion, anxiety-related behaviors, object recognition (non-spatial memory), object placement (spatial memory), body weight and serum steroid hormone levels. Control (unstressed) females had lower levels of estradiol and testosterone and higher corticosterone than males, and stress had no lasting effect on hormone concentrations. Females weighed less than males and showed less weight loss with stress. Locomotion measures on an open field were similar in the sexes and unaffected by stress. Anxiety-related behavior measures on the field showed that males were generally more anxious and that stress increased male, but decreased, female anxiety-related behaviors. In memory testing, exploration of objects was not different between the sexes, with or without stress, while stress increased exploration in both sexes during object recognition trials. Both males and females, regardless of treatment, discriminated between old and new objects at short, but not long, inter-trial delays. The typical advantage of young males for spatial memory performance was not observed in aged subjects on the object placement tasks. Stress-dependent enhancements in females and impairments in males for object placement are reported for young rats, but in aged rats, neither sex was altered by stress. Current data suggest that aging is associated with changes in the pattern of sex differences present in young adult rats in some behaviors and in the behavioral responses to stress.

The 17alpha and 17beta isomers of estradiol both induce rapid spine synapse formation in the CA1 hippocampal subfield of ovariectomized female rats.

Previous studies have demonstrated that estradiol-17beta and estradiol-17alpha both induce short-latency effects on spatial memory in rats, estradiol-17alpha being at least as potent as its 17beta isomer. To determine whether the mechanisms underlying these behavioral responses might include effects on hippocampal synaptic plasticity, CA1 pyramidal spine synapse density (PSSD) was measured in ovariectomized rats within the first few hours after s.c. estrogen injection. PSSD increased markedly (by 24%) 4.5 h after the administration of 45 microg/kg estradiol-17beta. The PSSD response was significantly greater (44% above control) 30 min after estradiol-17beta injection and was markedly dose dependent; a 3-fold lower estradiol-17beta dose (15 microg/kg) did not significantly affect CA1 PSSD at either 30 min or 4.5 h. Estradiol-17alpha was a more potent inducer of PSSD than estradiol-17beta. Dose-response analysis determined an ED50 for the effect of estradiol-17alpha on PSSD of 8.92 +/- 1.99 microg/kg, with a maximal response at 15 microg/kg. These results demonstrate that high doses of estradiol induce rapid changes in CA1 PSSD. CA1 spine synapse formation appears to be more sensitive to estradiol-17alpha than to estradiol-17beta, paralleling previous data on the effects of these two steroids on spatial memory. Rapid remodeling of hippocampal synaptic connections may thus contribute to the enhancement of spatial mnemonic processing observed within the first few hours after estrogen treatment. The potency of estradiol-17alpha suggests that hormone replacement therapy using this steroid might be useful clinically in ameliorating the impact of low endogenous estrogen production on the development and progression of neurodegenerative disorders involving the hippocampus.

Chronic stress alters amphetamine effects on behavior and synaptophysin levels in female rats.

Previous studies show that stress cross-sensitizes with or alters amphetamine (AMPH) effects in male rats; however, few studies include females. We investigated combining daily restraint stress (21 days for 6 h/day) with chronic AMPH (10 injections every other day) on locomotor activity, exploratory activity in an open field and object recognition, a memory task, in female rats. A synaptic protein, synaptophysin, was also quantified by radioimmunocytochemistry (RICC) in brain to determine possible mechanisms for behavioral changes. Beginning at 5 days after cessation of treatments, AMPH increased locomotion, modified exploration, impaired object recognition, and increased serum corticosterone (CORT) levels. Stress did not alter these parameters but blocked AMPH effects on exploration and object recognition, potentiated AMPH-dependent locomotor effects, and did not alter increased CORT levels. AMPH treatment decreased synatophysin expression in the hippocampus. In the caudate nucleus, the AMPH group showed increased synaptophysin expression which was reversed by stress. These results in females corroborate previously shown cross-sensitizations between stress and AMPH for locomotion in males and demonstrate that chronic stress counteracts AMPH-dependent impairments in recognition memory. Stress may counteract AMPH effects on the memory task by blocking both the induction of AMPH anxiety-like effects and neuroplastic changes in the caudate nucleus of female rats.

Sexually dimorphic effects of prenatal stress on cognition, hormonal responses, and central neurotransmitters.

Exposure to stress during gestation results in physiological and behavioral alterations that persist into adulthood. This study examined the effects of prenatal stress on the postnatal expression of sexually differentiated cognitive, hormonal, and neurochemical profiles in male and female rats. Pregnant dams were subjected to restraint stress three times daily for 45 min during d 14-21 of pregnancy. The offspring of control and prenatally stressed dams were tested for anxiety-related and cognitive behaviors, stress and gonadal steroid hormone levels, as well as monoamines and metabolite levels in selected brain regions. Postnatal testosterone levels (measured at 1 and 5 d) did not differ between controls and prenatally stressed animals. In adulthood, the serum corticosterone response to stress was attenuated in prenatally stressed females, eliminating the sex difference normally observed in this parameter. Prenatally stressed females exhibited higher anxiety levels, evidenced by longer open field entry latencies. Prenatal stress had no effect on object recognition memory, but eliminated the advantage normally seen in the male performance of a spatial memory task. Neurochemical profiles of prenatally stressed females were altered toward the masculine phenotype in the prefrontal cortex, amygdala, and hippocampus. Thus, prenatal stress altered subsequent cognitive, endocrine, and neurochemical responses in a sex-specific manner. These data reinforce the view that prenatal stress affects multiple aspects of brain development, interfering with the expression of normal behavioral, neuroendocrine, and neurochemical sex differences. These data have implications for the effects of prenatal stress on the development of sexually dimorphic endocrine and neurological disorders.

Rapid enhancement of visual and place memory by estrogens in rats.

Estrogenic effects on visual (object recognition) and place (object placement) memory were investigated. Ovariectomized (OVX) rats received acute sc injections 30 min before a sample trial (viewing objects), and 4 h later a recognition/retention trial was performed. During recognition/retention trials, discrimination between sample (old) and new objects (visual memory) or between objects in sample (old) and new locations (place memory) was tested. Subjects given 17alpha- or 17beta-estradiol or diethylstilbestrol (DES) 30 min before sample trials discriminated between objects or locations during recognition/retention trials whereas vehicle-treated, OVX rats did not. Estrogens were given a postsample trial to investigate whether enhancements were due to effects on memory processes or psychological/performance parameters. Hormones were given immediately after or 2 h after sample trials (delayed injections), and recognition/retention were tested 4 h after the sample trial. Both object and place discriminations were enhanced when estrogens were given immediately after sample trials, but not when injections were delayed. These results provide evidence that estrogen rapidly enhances visual and place memory. Moreover, posttraining injections suggest effects on mnemonic processes, consolidation, or encoding, not on performance parameters. Place memory enhancements required higher estrogen doses, both pre- and postsample trial. The rapid time course, stereospecificity of responses (alpha- and beta-estradiol are effective), and efficacy of various estrogens suggest interactions at other than classic estrogen alpha- or beta-receptors in mediating the effects. Thus, these results provide the first demonstration of rapid memory enhancements by estrogen and implicate nongenomic mechanisms, possibly an extranuclear receptor(s), in mediating the response.

Chronic D-amphetamine induces sexually dimorphic effects on locomotion, recognition memory, and brain monoamines.

While acute and chronic D-amphetamine (AMPH) treatments produce greater scores for locomotor activity in female rats in comparison with male rats, little is known about AMPH-induced gender differences on cognition. The objectives of the present study were to (1) investigate during a withdrawal period following chronic AMPH treatment whether performance of two memory tasks, object recognition (OR) and object placement (OP) are altered, and (2) determine if an AMPH challenge dose after a withdrawal period amplifies previously reported gender differences in locomotor activity and neurochemistry. Sprague-Dawley male and female adult rats were included in a chronic AMPH treatment (10 injections, 1 every other day; males: 3 mg/kg, females 2.6 mg/kg). Locomotor activity was quantified (acute, chronic, and after a 16-day withdrawal period). Neurotransmitter levels in brain areas were evaluated after an AMPH challenge dose on the 16th withdrawal day. During the withdrawal period, OR (2- and 4-h delays) was impaired in AMPH-treated males but they did not show any impairment in OP; AMPH females also showed impairments in OR (only 4-h delay). AMPH females showed more locomotion after acute and chronic treatment but AMPH-induced hyperactivity was comparable for females and males after a challenge dose. Following a challenge dose of AMPH after a withdrawal period, gender differences in dopaminergic and serotonergic neurotransmission in the striatum were found. These gender differences elicited by AMPH in monoaminergic pathways may be related to sex differences on behavioral components involved in locomotion and OR memory.