Effect of social housing and oxytocin on the motivation to self-administer methamphetamine in female rats.

Social housing has been shown to attenuate the motivation for cocaine in female, but not male rats. Here we investigate the potential mechanisms mediating the effect of social housing on the response to methamphetamine (METH). Female rats were individually or socially (pair) housed. The dopamine (DA) response to an acute METH infusion (0.3mg/kg, i.v.) was investigated using in vivo microdialysis in the nucleus accumbens with or without oxytocin (OT; 0.3mg/kg, i.p.) 30min prior to METH. The effects of social housing and OT on self-administered METH (0.06mg/kg/inf) was investigated. The METH-induced DA response was higher in individually housed compared to socially-housed females. On the other hand, individually housed females had a significantly higher breaking point (BP) than socially-housed females. Two weeks of OT treatment reduced BP in both groups. Reinstatement to METH was more pronounced in isolates compared to socially-housed females. More of the socially-housed females had very low BP than did the individually housed females. OT was most effective in reducing BP in females with moderate to high BP, irrespective of housing conditions. These data show that social housing attenuates escalation of METH intake and reinstatement of METH seeking in female rats, and that chronic OT treatment can reduce motivation for METH.

The Roles of Dopamine and α1-Adrenergic Receptors in Cocaine Preferences in Female and Male Rats.

Cocaine dependence is characterized by compulsive drug taking and reduced involvement in social, occupational, or recreational activities. Unraveling the diverse mechanisms contributing to the loss-of-interest in these 'non-drug' pursuits is essential for understanding the neurobiology of addiction and could provide additional targets for treating addiction. The study objectives were to examine changes in cocaine-induced dopamine (DA) overflow in the nucleus accumbens (NAc) over the course of self-administration and determine the roles of α1- and ß-adrenergic receptors (AR) in the loss-of-interest in food rewards following the development of an addicted phenotype in male and female rats. Subjects were given access to cocaine and palatable food pellets in a choice self-administration paradigm to identify 'addicted' cocaine-preferring (CP) individuals and resistant pellet-preferring (PP) individuals based on their patterns of self-administration over 7 weeks. Cocaine-induced DA overflow in the NAc was examined with microdialysis early and late during self-administration (weeks 2 and 7). Subjects were treated in counter-balanced order with propranolol (ß-AR antagonist), terazosin (α1-AR antagonist), or vehicle for an additional 3 weeks of self-administration. CP rats displayed increased motivation for cocaine and attenuated motivation for pellets following the development of cocaine preferences. In females, the estrous cycle affected pellet, but not cocaine, self-administration. CP rats displayed attenuated cocaine-induced DA overflow in the NAc. Propranolol enhanced cocaine reinforcement and reduced pellet intake, whereas terazosin enhanced motivation for pellets and reversed preferences in a subset of CP rats. The implications of these results for the treatment of addiction are discussed.

The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors.

RATIONALE: Cocaine dependence is characterized by compulsive drug taking that supercedes other recreational, occupational or social pursuits. We hypothesized that rats vulnerable to addiction could be identified within the larger population based on their preference for cocaine over palatable food rewards. OBJECTIVES: To validate the choice self-administration paradigm as a preclinical model of addiction, we examined changes in motivation for cocaine and recidivism to drug seeking in cocaine-preferring and pellet-preferring rats. We also examined behavior in males and females to identify sex differences in this "addicted" phenotype. METHODS: Preferences were identified during self-administration on a fixed-ratio schedule with cocaine-only, pellet-only and choice sessions. Motivation for each reward was probed early and late during self-administration using a progressive-ratio schedule. Reinstatement of cocaine- and pellet-seeking was examined following exposure to their cues and non-contingent delivery of each reward. RESULTS: Cocaine preferring rats increased their drug intake at the expense of pellets, displayed increased motivation for cocaine, attenuated motivation for pellets and greater cocaine and cue-induced reinstatement of drug seeking. Females were more likely to develop cocaine preferences and recidivism of cocaine- and pellet-seeking was sexually dimorphic. CONCLUSIONS: The choice self-administration paradigm is a valid preclinical model of addiction. The unbiased selection criteria also revealed sex-specific vulnerability factors that could be differentiated from generalized sex differences in behavior, which has implications for the neurobiology of addiction and effective treatments in each sex.

Impact of pubertal and adult estradiol treatments on cocaine self-administration.

Estradiol is thought to play a critical role in the increased vulnerability to psychostimulant abuse in women. Sex differences in the ability of estradiol to influence cocaine self-administration in adult rats have been hypothesized to depend upon pubertal estradiol exposure. The current study investigated whether the presence of gonadal hormones during puberty affected cocaine self-administration behavior and its sensitivity to adult estradiol treatment in male and female Sprague-Dawley rats. Subjects were gonadectomized or SHAM-operated at postnatal day (PD) 22, and received either OIL or estradiol benzoate (EB) during the approximate time of puberty (PD27 to PD37). Adult rats were subsequently treated with either EB or OIL 30 min before cocaine self-administration (0.3 mg/kg/inf) in order to examine the effects of pubertal manipulations on the estradiol sensitivity of acquisition on a fixed ratio (FR) 1 schedule, total intake on a FR5 schedule and motivation on a progressive ratio schedule. Adult EB treatment only affected cocaine self-administration in females, which is consistent with previous research. Adult EB treatment enhanced acquisition in all females irrespective of puberty manipulations. All females, except those treated with EB during puberty, displayed increased cocaine intake following adult EB treatment. Adult EB treatment only enhanced motivation in females that were intact during puberty, whereas those treated with EB during puberty showed reduced motivation. Therefore, the sensitivities of different self-administration behaviors to adult estradiol treatment are organized independently in females, with pubertal estradiol exerting a greater influence over motivational processes, and negligible effects on learning/acquisition.

Pair housing differentially affects motivation to self-administer cocaine in male and female rats.

Female rats exhibit greater intake and motivation to self-administer cocaine. In females but not males, isolation by itself is a stressor, which could lead to increased drug intake. Therefore, we hypothesized that social housing would buffer against stress and reduce the motivation to self-administer cocaine primarily in females. Male and female Sprague-Dawley rats were housed individually or in same-sex pairs. The individually housed rats and one of each pair were allowed to self-administer (SA) a low dose of cocaine (0.2 mg/kg/inf) on a fixed ratio (FR1) schedule for one week. Motivation for cocaine SA was measured for an additional 2 weeks on a progressive ratio schedule. Isolated females had greater cocaine-intake on the FR1 schedule and greater motivation to take cocaine than males. Pair-housing in females, but not males, attenuated the motivation to take cocaine. Isolated females, but not males, showed escalation of their motivation to take cocaine, which was attenuated by pair housing of females. Concluding, the motivation to take cocaine escalates in females but not males, and pair-housing of females attenuates this escalation.

Enhanced striatal ß1-adrenergic receptor expression following hormone loss in adulthood is programmed by both early sexual differentiation and puberty: a study of humans and rats.

After reproductive senescence or gonadectomy, changes occur in neural gene expression, ultimately altering brain function. The endocrine mechanisms underlying these changes in gene expression beyond immediate hormone loss are poorly understood. To investigate this, we measured changes in gene expression the dorsal striatum, where 17ß-estradiol modulates catecholamine signaling. In human caudate, quantitative PCR determined a significant elevation in ß1-adrenergic receptor (ß1AR) expression in menopausal females when compared with similarly aged males. No differences were detected in ß2-adrenergic and D1- and D2-dopamine receptor expression. Consistent with humans, adult ovariectomized female rats exhibited a similar increase in ß1AR expression when compared with gonadectomized males. No sex difference in ß1AR expression was detected between intact adults, prepubertal juveniles, or adults gonadectomized before puberty, indicating the necessity of pubertal development and adult ovariectomy. Additionally, increased ß1AR expression in adult ovariectomized females was not observed if animals were masculinized/defeminized with testosterone injections as neonates. To generate a model system for assessing functional impact, increased ß1AR expression was induced in female-derived cultured striatal neurons via exposure to and then removal of hormone-containing serum. Increased ß1AR action on cAMP formation, cAMP response element-binding protein phosphorylation and gene expression was observed. This up-regulation of ß1AR action was eliminated with 17ß-estradiol addition to the media, directly implicating this hormone as a regulator of ß1AR expression. Beyond having implications for the known sex differences in striatal function and pathologies, these data collectively demonstrate that critical periods early in life and at puberty program adult gene responsiveness to hormone loss after gonadectomy and potentially reproductive senescence.

Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis.

In this review we propose that there are sex differences in how men and women enter onto the path that can lead to addiction. Males are more likely than females to engage in risky behaviors that include experimenting with drugs of abuse, and in susceptible individuals, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression. For this reason women enter into the downward spiral further along the path to addiction, and so transition to addiction more rapidly. We propose that this sex difference is due, at least in part, to sex differences in the organization of the neural systems responsible for motivation and addiction. Additionally, we suggest that sex differences in these systems and their functioning are accentuated with addiction. In the current review we discuss historical, cultural, social and biological bases for sex differences in addiction with an emphasis on sex differences in the neurotransmitter systems that are implicated.

Effects of a selectively bred novelty-seeking phenotype on the motivation to take cocaine in male and female rats.

BACKGROUND: Gender and enhanced novelty reactivity can predispose certain individuals to drug abuse. Previous research in male and female rats selectively bred for high or low locomotor reactivity to novelty found that bred High Responders (bHRs) acquire cocaine self-administration more rapidly than bred Low Responders (bLRs) and that bHR females in particular self-administered more cocaine than the other groups. The experiments presented here aimed to determine whether an individual's sex and behavioral phenotype interact to affect motivation to take cocaine. METHODS: We examined motivation for taking cocaine in two experiments using a range of doses on a progressive ratio (PR) schedule of responding in bHR or bLR males and females. Additionally, we included a measure of continuing to respond in the absence of reinforcement, a feature of addiction that has been recently incorporated into tests of animal models on the basis of the criteria for substance use disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Statistical analyses were performed using PASW Statistics 18.0 software. Data were analyzed using repeated-measures analysis of variance followed by a Bonferroni correction post hoc test when applicable. RESULTS: We found sex differences as well as effects of novelty reactivity on the motivation to self-administer cocaine. Specifically, females demonstrated higher breaking points on the PR schedule compared with males, regardless of phenotype, and bHR males and females exhibited higher motivation than bLR animals at a number of the doses studied. CONCLUSIONS: An individual's sex continues to be a predisposing factor with respect to drug abuse liability and can be compounded by additional individual differences such as reactivity to novelty.

Sex differences in stress responses: focus on ovarian hormones.

Women in the reproductive age are more vulnerable to develop affective disorders than men. This difference may attribute to anatomical differences, hormonal influences and environmental factors such as stress. However, the higher prevalence in women normalizes once menopause is established, suggesting that ovarian hormones may play an important role in the development of depression in women. Ovarian hormones such as estrogen can pass the brain-blood barrier and bind to cytoplasmatic estrogen receptor (ER)-alpha and ER-beta in different areas of the limbic system. During stress, estrogen can modulate the behavioral and neurobiological response depending on the concentrations of estrogen. In this review we present evidence for disparate effects of chronic stress on neuroplasticity and brain activity in male and female rats. Furthermore, we will demonstrate that effects of social support on coping with stress can be mimicked by social housing of rats and that this model can be used for identification of underlying neurobiological mechanisms, including behavior, phosphorylation of CREB and ERK1/2, and brain activity changes as measured with fos expression. Using cyclic administration of estrogen in ovariectomized female rats we could specifically address effects of different plasma estrogen levels and antidepressants on stress-induced neuroplasticity and activity changes. In this model we also studied effects of estrogen on recovery after chronic stress. We conclude that the female brain has a different innate strategy to handle stress than the male brain and that female animal models are necessary for studying the underlying mechanisms and options for treatment.

Sex differences in the effects of acute and chronic stress and recovery after long-term stress on stress-related brain regions of rats.

Studies show that sex plays a role in stress-related depression, with women experiencing a higher vulnerability to its effect. Two major targets of antidepressants are brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element-binding protein (CREB). The aim of this study was to investigate the levels of CREB, phosphorylation of CREB (pCREB), and BDNF in stress-related brain regions of male and female rats after stress and recovery. CREB and pCREB levels were examined in CA1, CA2, CA3, paraventricular nucleus of the thalamus (PVT), amygdala, anterior cingulate area, dorsal part (ACAd), and infralimbic area of prefrontal cortex (PFC), whereas dentate gyrus (DG) and prelimbic area (PL) of PFC were examined for BDNF levels. Our results demonstrate that levels of CREB and pCREB in male CA1, CA2 and CA3, PVT, amygdala, and ACAd were reduced by stress, whereas the same brain regions of female rats exhibited no change. BDNF levels were decreased by chronic stress in female PL but were increased by acute stress in female DG. BDNF levels in male DG and PL were found not to undergo change in response to stress. Abnormalities in morphology occurred after chronic stress in males but not in females. In all cases, the levels of CREB, pCREB, and BDNF in recovery animals were comparable to the levels of these proteins in control animals. These findings demonstrate a sexual dimorphism in the molecular response to stress and suggest that these differences may have important implications for potential therapeutic treatment of depression.

Effects of long-term stress and recovery on the prefrontal cortex and dentate gyrus in male and female rats.

Women show a higher prevalence for depression than men. However, the biological basis of gender differences in stress response and recovery still remain poorly understood. Therefore, the aim of the study was to assess the gender differences in response to acute stress, chronic stress and recovery in rats. Our results showed that stress decreased male body weight but had no effect on female rats. Open field test demonstrated behavioral changes in grooming and velocity after chronic stress and recovery. Increased activity of hypothalamic-pituitary-adrenocortical axis was reflected by adrenal hypertrophy and increase of plasma corticosterone levels except in the socially housed female rats after stress. Gender and brain region differences in response to stress and recovery were found in the expression of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB). On the whole, expression of CREB and pCREB in male dentate gyrus (DG) and prefrontal cortex (PFC) was sensitive but in female DG and PFC it was resistant to acute and chronic stress. Interestingly, recovery restored the measured parameters to the normal level in male rats but not in female rats. In conclusion, these results suggest that male and female rats responded to stress and recovery in a different way.

Reduction in the in vitro expression of Brain-Pancreas Relative Protein by oxygen and glucose-deprivation.

Brain-Pancreas Relative Protein (BPRP) is a novel protein found in our laboratory. In previous study we observed a significant reduction in BPRP in ischemic brain of rat. Here we undertook this study to explore the possible mediating mechanism by which oxygen and glucose-deprivation culture (OGD), a model of ischemia in vitro, decreased the expression of BPRP in PC12 cells. BPRP was found to be expressed in PC12 cells and OGD caused a significant reduction in BPRP expression. The effect of OGD was primarily mediated by reactive oxygen species (ROS) because OGD upregulated the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers reduced OGD-induced ROS production, while increased the expression of BPRP in PC12 cells. These data indicate that OGD decreases the expression of BPRP via enhanced formation of intracellular ROS.

Effects of glucose, insulin, and supernatant from pancreatic beta-cells on brain-pancreas relative protein in rat hippocampus.

Brain-pancreas relative protein (BPRP) is a novel protein that mainly expresses in brain and pancreas. In our previous study, we found that various stressors significantly decreased the expression of BPRP in pancreas in vivo, accompanied by changes in insulin and glucose levels, and that expression of BPRP in pancreas also decreased significantly in diabetic rats induced by Streptozocin (STZ). All these findings suggest that BPRP may be a glucose or insulin-sensitive protein. However, how the changes in insulin or glucose levels influence the expression of BPRP in hippocampus requires further study. Here, we investigated the effects of insulin or glucose on the expression of BPRP in primary cultured hippocampal neurons. We supplied hippocampal neurons with glucose, insulin, or supernatant from pancreatic beta-cells, which secrete insulin into the supernatant. Our data showed that insulin had beneficial effect on the viability while no significant effect on the expression of BPRP in hippocampal neurons. On the contrary, 40 mM glucose or free glucose culture significantly decreased the expression of BPRP, while had no significant effect on the viability and apoptosis of hippocampal neurons. Further study showed that levels of insulin in the supernatant collected from pancreatic beta-cells medium changed over days, and that supernatant increased the viability of hippocampal neurons, while it had no obvious effect on the expression of BPRP in hippocampal neurons. These results suggest that BPRP may be a glucose-sensitive protein.

Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents Abeta(25-35)-induced reduction in BPRP in PC12 cells.

Several lines of evidence support that beta-amyloid (Abeta)-induced neurotoxicity is mediated through the generation of reactive oxygen species (ROS) and elevation of intracellular calcium. Salvianolic acid B (Sal B), the major and most active anti-oxidant from Salvia miltiorrhiza, protects diverse kinds of cells from damage caused by a variety of toxic stimuli. In the present study, we investigated the effects of Sal B against beta-amyloid peptide 25-35 (Abeta(25-35))-induced neurotoxicity, focused mainly on the neurotoxic effects of Abeta(25-35) and the neuroprotective effects of Sal B on the expression of brain-pancreas relative protein (BPRP), which is a new protein and mainly expressed in brain and pancreas. Following exposure of PC12 cells to 20 microM Abeta(25-35), a marked reduction in the expression of BPRP was observed, accompanied with decreased cell viability and increased cell apoptosis, as well as increased ROS production and calcium influx. Treatment of the PC12 cells with Sal B significantly reversed the expression of BPRP and cell viability while it decreased ROS production and intracellular calcium. These data indicate that Abeta(25-35) decreases the expression of BPRP via enhanced formation of intracellular ROS and increased intracellular calcium, and that Sal B, as an anti-oxidant, protects against Abeta(25-35)-induced reduction in expression of BPRP through its effects on suppressing the production of ROS, calcium flux, and apoptosis. However, the role(s) of BPRP in AD and the definite mechanisms by which Sal B protects against Abeta(25-35)-induced reduction in the expression of BPRP require further study.

Chronic stress and social housing differentially affect neurogenesis in male and female rats.

Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders than men. The course of a depression is thought to be positively influenced by social support. We have used a chronic stress model in which rats received foot-shocks daily for 3 weeks. Since rats are social animals we hypothesised that 'social support' might reduce the adverse effects of chronic stress. To test this hypothesis, male and female rats were housed individually or socially in unisex groups of four rats. The proliferation marker bromodeoxyuridine (BrdU) was injected 2 weeks before the sacrifice to investigate if stress and social housing influenced the survival of proliferating cells in the dentate gyrus (DG). To investigate changes in proliferation, another group of rats was sacrificed the day after the last BrdU injection. Stress significantly decreased BrdU labelling in individually housed males and not significantly in socially housed males. In individually housed females stress increased BrdU labelling, which was prevented by social housing. The increase found in females is most likely caused by differences in survival rate, since cell proliferation was not affected by stress or housing conditions. These results indicate that social support can affect neurogenesis in both female and male rats, however in a different way.

Increased stress vulnerability after a prefrontal cortex lesion in female rats.

Neuroimaging studies in patients suffering from affective disorders have shown decreased volume and reduced regional cerebral blood flow in multiple areas of the prefrontal cortex, including the medial prefrontal cortex and the orbitofrontal cortex. This aberrant brain activity is among other things attributed to chronic stress. Affective disorders occur more often in women than in men. In the current experiment, female mPFC-lesioned and non-lesioned rats were subjected to 3 weeks of chronic unpredictable stress in order to determine the role of the mPFC in dealing with chronic stress, and the consequences of mPFC damage for coping with consecutive stressful events. mPFC damage in female rats intensified the stress-induced activation of the dorsomedial nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus as measured with Fos expression changes and markedly increased plasma catecholamine levels after 3 weeks of unpredictable stress. Additionally, an mPFC lesion significantly reduced the time of appearance of stress-induced behavioral changes in the open field. Altogether, mPFC dysfunction affects the way female rats react to chronic stress, it not only increased the activation of brain regions involved in neuroendocrine and autonomic responses to stress but it also significantly reduced the time of onset of behavioral changes.

Gender-specific effects of social housing in rats after chronic mild stress exposure.

UNLABELLED: Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders than men. The course of a depression is thought to be positively influenced by social support. The authors have used a chronic mild stress model in which rats received footshocks daily for 3 weeks. Since rats are social animals we hypothesized that "social support" might reduce the adverse effects of chronic stress. To test this hypothesis, male and female rats were housed individually or socially in unisex groups of four rats. An open field test was repeated four times during the 3 weeks of treatment. Neuronal activation in the paraventricular nucleus of the hypothalamus (PVN) and dorsal raphe nucleus (DRN) in response to stress was measured the last day with c-fos. Chronic stress exposure increased locomotor activity in the open field, especially during the first minute. This was most pronounced in the individually housed females. In females, social housing prevented the stress-induced increase of locomotor activity, while in males social housing had no effect. Fos immunoreactive (FOS-ir) in the PVN was increased in all stress-exposed groups, except for the socially housed females due to a higher FOS-ir in controls. Individually housed males and socially housed females showed increased FOS-ir in the DRN and the increase was almost significant in socially housed males. IN CONCLUSION: These results show that social housing can enhance coping with stress in female rats, whereas in male rats group housing did not have a positive influence on stress-sensitivity.