Effects of obesity in rats on prostate histology and expression of leptin receptor, prolactin receptor, IL-6, and NF-κB.

BACKGROUND: Hypercaloric intake can lead to obesity, which is a major risk factor associated with chronic subclinical inflammation and many types of cancer. It can increase the serum levels of leptin, prolactin, nuclear factor kappa B (NF-кB) and interleukin (IL)-6, implicated in cell proliferation, differentiation and survival. AIM: To explore the effects of obesity induced by chronic hypercaloric diet in rats on the long-term expression of leptin receptor (OB-R), prolactin receptor, NF-кB, and IL-6, and the changes of histology in rat prostate. MATERIALS AND METHODS: From postnatal day 21, experimental males were fed with normal chow or chow plus enriched hypercaloric liquid diet. On the postnatal day 90 (13 week old), the animals were euthanized for prostate histology (hematoxylin and eosin staining) and hormone receptors analysis by Western blot. RESULTS: Hypercaloric diet resulted in obesity (32% higher body weight). The prostates of the obese males showed epithelium anisocytosis and compressed interstice. There was also greater volume of lipidic content, anisokaryosis, alterations of the nucleus-cytoplasm ratio, and apparent proplasia. Measures in the ventral prostate (VP) showed that alveoli area increased, but epithelium height and nucleus area were reduced. In the dorsolateral prostate, there was only reduction of nucleus area and presence of mononuclear cells in the lumen. Hypercaloric males also expressed a trend for more OB-R 130 kD in the VP, but no changes were observed with regard to prolactin receptor, NF-кB and IL-6. CONCLUSION: The obesity due to chronic consumption of hypercaloric diet affects both prostatic regions, but VP is possibly more sensitive via OB-R. We suggest that longer periods of obesity are needed to alter other receptors or the molecular markers of inflammation.

Nature and nurture of sexual partner preference: Teachings from prenatal administration of acetaminophen in male rats.

The organizational-activational hypothesis indicates that activation of adult sexual behavior in males depends on organization of the masculine brain during the perinatal sensitive period. In the medial preoptic area such masculinization depends on a neuroendocrine cascade that includes exposure to testosterone, aromatization to estradiol, activation of estrogen receptors, synthesis of cyclooxygenase (COX), increase of prostaglandins, release of glutamate, and activation of AMPA receptors that result in the formation of more dendritic spines. Thus, in the present study we assessed the sexual partner preference (SPP) of adult male rats prenatally treated with acetaminophen (APAP), an analgesic/antipyretic drug that inhibits COX-2 and is commonly used and prescribed during pregnancy. Female rats received either saline (2 ml/kg s.c.) or APAP (50 mg/kg s.c.) every 12 h, during days 16-20 of pregnancy. At postnatal day PD60 half of the male offspring were exposed to sexual experience with receptive females during 5 trials, and the other half remained sexually naïve. At PD90 all them were tested for SPP with one sexually receptive female and one stud male. The results indicated that only APAP-naïve males failed to display SPP. However, APAP-experienced males displayed SPP for females. We discuss the effects of prenatal APAP in the disruption of unconditioned responses towards females (nature mechanisms), and the effects of sexual experience (nurture mechanisms) in the development of conditioned heterosexual preference.

Prepuberal stress and obesity: effects on serum corticosterone, prolactin, testosterone and precancerous prostate lesions in adult rats.

Stress during puberty and obesity can represent conditions that facilitate the long-term development of diseases, especially for stress-related disorders that depend on neuroendocrine and immune responses. The prostate is prone to diseases that result from neuroendocrine or immune challenges, such as cancer. AIM: In the present study, we assessed the long-term effects of an acute pubertal stressor (immune-challenge) or obesity on the development of precancerous lesions in rats. MATERIALS AND METHODS: Pubertal male rats received a single injection of lipopolysaccharide (LPS) or saline during puberty (5 weeks of age). In adulthood (8 weeks old), subgroups of males were fed with hypercaloric liquid diet to induce obesity. This resulted in a total of six subgroups: (1) intact-non obese, (2) intact-obese, (3) saline-non obese, (4) saline-obese, (5) LPS-non obese, and (6) LPS-obese. At 16 weeks of age the rats were sacrified for prostate histology (hematoxylin and eosin stain) and hormone analysis (testosterone, corticosterone and prolactin). RESULTS: As compared to intact-non obese rats, males treated with LPS and those with obesity expressed histological alterations in both the dorsolateral and ventral portions of the prostate. Only prolactin was altered in LPS-treated males, whereas corticosterone was altered in LPS-obese rats. CONCLUSIONS: These results indicate that puberal exposure to an immune challenge or obesity facilitate the development of prostatic lesions in adult male rats. We discuss the role of hormones in the development of precancerous lesions.

Stress during puberty facilitates precancerous prostate lesions in adult rats.

Puberty can be a critical period for the long-term development of diseases, especially for stress-related disorders that depend on neuroendocrine and immune responses. Some organs like the prostate are prone to diseases that result from neuroendocrine or immune challenges, such as cancer. AIM: In the present study, we assessed the long-term effects of an acute pubertal stressor (immune-challenge) on the development of precancerous lesions in adult rats, and compared them with testosterone-induced prostatic lesions. MATERIALS AND METHODS: Pubertal male rats received a single injection of lipopolysaccharide (LPS) or saline during puberty (5 weeks old). At adulthood (8 weeks old) males were subcutaneously implanted with either an empty capsule or filled with testosterone propionate (100 mg/kg). This resulted in a total of five groups: 1) intact untreated, 2) saline-treated and implanted with a blank capsule, 3) saline-treated and implanted with a testosterone capsule, 4) LPS-treated and implanted with a blank capsule, 5) LPS-treated and implanted with a testosterone capsule. Four weeks later, the rats were sacrified and their prostates processed for histology (hematoxylin and eosin stain) and blood serum processed for hormone analysis (testosterone and corticosterone). RESULTS: Males treated with LPS (stressed during puberty via immune challenge) expressed epithelium dysplasia (specially in the ventral prostate), anisocytosis, presence of mononuclear cells, anisokariosis, non-basal polarity, abnormal nucleus-cytoplasm ratio, proplastic myoepithelium, and granular content in the lumen. These histological alterations were similar, but less severe than those observed in males implanted with testosterone during adulthood. CONCLUSION: These results indicate that pubertal exposure to an immune challenge (stress) facilitates the long-term development of prostatic lesions in adult male rats.

Effect of electrolytic lesion of the dorsomedial striatum on sexual behaviour and locomotor activity in rats. / Efecto de la lesión electrolítica del estriado dorsomedial sobre la conducta sexual y actividad locomotora de la rata.

INTRODUCTION: Cortical motor areas are influenced not only by peripheral sensory afferents and prefrontal association areas, but also by the basal ganglia, specifically the striatum. The dorsomedial striatum (DMS) and dorsolateral striatum are involved in both spatial and stimulus-response learning; however, each of these areas may mediate different components of learning. The aim of the study is to determine the effect of electrolytic lesion to the DMS on the learning and performance of sexual behaviour and locomotor activity in male rats. METHOD: Once the subjects had learned to perform motor tests of balance, maze navigation, ramp ascent, and sexual behaviour, they underwent electrolytic lesion to the DMS. Five days later, the tests were repeated on 2 occasions and researchers compared performance latencies for each test. RESULTS: Average latency values for performance on the maze and balance tests were higher after the lesion. However, the average values for the ramp test and for sexual behaviour did not differ between groups. CONCLUSIONS: Electrolytic lesion of the DMS modifies the performance of locomotor activity (maze test and balance), but not of sexual behaviour.

Effect of copulation on potentially precancerous prostate lesions, serum testosterone and prolactin levels in rats.

UNLABELLED: The prostate is an exocrine reproductive gland that participates in ejaculation and it is prone to diseases, including cancer. AIM: In the pre-sent study, we assessed the long-term effects of copulation on the development of precancerous lesions in rats, and compared them with testosterone-induced prostatic lesions. MATERIALS AND METHODS: One group of Wistar males was given 10 copulatory sessions to one ejaculation with ovariectomized, hormone-primed females. Sessions occurred twice per week for a total of ten trials. A second group was exposed to females during the same trials, but physical contact was prevented. In addition, each group received a subcutaneous implant in the back either filled with testosterone propionate (T, 100 mg/kg) or empty. This resulted in four subgroups: 1) Control + No sex, 2) Control + Sex, 3) T + No sex and 4) T + Sex. Two days after the 10(th) trial all the males were sacrificed for prostate histo-logy (H&E) and hormone analysis (testosterone and prolactin). RESULTS: Males from the group Control + No sex expressed normal histo-logy. However, those in the groups Control + Sex and T + No sex expressed metaplasia and dysplasia in both the dorsolateral and ventral portions of the prostate, respectively. Interestingly, males from the group T + Sex expressed dysplasia in the dorsolateral prostate only, but not in the ventral prostate. CONCLUSIONS: These results indicate that constant copulation may facilitate the development of prostatic lesions in males with normal levels of testosterone. However, copulation induces less lesions in the ventral prostate of males treated with testosterone.

Long-term administration of prolactin or testosterone induced similar precancerous prostate lesions in rats.

UNLABELLED: Evidence indicates that prolactin plays a crucial role in the normal function and development of the prostate, but abnormal high levels of the hormone are associated with hyperplasia and cancer of the gland. AIMS: The present study was designed to describe the progressive specific histological abnormalities in the prostate of rats with chronic hyperprolactinemia. MATERIAL AND METHODS: Prolactin was administered during 4; 12 or 24 weeks, and the resulting prostatic alterations were compared with control rats, and also with those treated with testosterone, or the combination of prolactin + testosterone. RESULTS: Rats treated with prolactin, testosterone or prolactin + testosterone expressed precancerous histological abnormalities in the dorsolateral and ventral portions of the prostate as early as in 4 weeks of treatment, but in all cases the malignancy increased after 12 or 24 weeks of treatment. CONCLUSION: Our study confirms that chronic hyperprolactinemia is a cause of prostate precancerous pathologies.

Activation of the cerebellum by olfactory stimulation in sexually naive male rats.

INTRODUCTION: The cerebellum has been linked to multiple functions, such as motor control, cognition, memory, and emotional processing. As for its involvement in the sensory systems, the role of the cerebellum in the sense of smell remains unclear. We suggest that sexually naive male rats will present increased neuronal activity in the cerebellar vermis after being stimulated with almond odour or oestrous odour from receptive females. METHODS: We compared activity in the cerebellar vermis using Fos immunoreactivity after olfactory stimulation. Stimulation took place during 60 min in a cube-shaped acrylic chamber with a double bottom. Stimuli were clean woodchip bedding, bedding with almond extract, and bedding taken from a cage of receptive females. Male rats were subsequently anaesthetised with intraperitoneal sodium pentobarbital. Cerebellar tissue was fixed with paraformaldehyde for later immunohistochemical analysis. RESULTS: The number of Fos immunoreactive cells in all lobes of the cerebellar vermis was similar between groups stimulated with almond extract and with oestrous odour, and higher than in the clean woodchip group. CONCLUSIONS: Stimulation of the main olfactory system (almond) and the accessory system (oestrous odour) increases Fos protein production in the granular layer of the cortex of the cerebellar vermis in naive male rats.

Brain activation by an olfactory stimulus paired with juvenile play in female rats.

We have previously shown that reward experienced during social play at juvenile age can be paired with artificial odors, and later in adulthood facilitate olfactory conditioned partner preferences (PP) in female rats. Herein, we examined the expression of FOS immunoreactivity (FOS-IR) following exposure to the odor paired with juvenile play (CS+). Starting at day P31 females received daily 30-min periods of social play with lemon-scented (paired group) or unscented females (unpaired group). At day P42, they were tested for play-PP with two juvenile males, one bearing the CS+ (lemon) and one bearing a novel odor (almond). Females were ovariectomized, hormone-primed and at day P55 tested for sexual-PP between two adult stud males scented with lemon or almond. In both tests, females from the paired group displayed conditioned PP (play or sexual) toward males bearing the CS+. In the present experiments females were exposed at day P59 to the CS+ during 60 min and their brains processed for FOS-IR. One group of female rats (Play+Sex) underwent play-PP and sexual-PP, whereas a second group of females (Play-only) underwent exclusively play-PP but not sexual-PP. Results showed that in the Play-only experiment exposure to the CS+ induced more FOS-IR in the medial prefrontal cortex, orbitofrontal cortex, dorsal striatum, and ventral tegmental area as compared to females from the unpaired group. In the Play+Sex experiment, more FOS-IR was observed in the piriform cortex, dorsal striatum, lateral septum, nucleus accumbens shell, bed nucleus of the stria terminalis and medial amygdala as compared to females from the unpaired group. Taken together, these results indicate mesocorticolimbic brain areas direct the expectation and/or choice of conditioned partners in female rats. In addition, transferring the meaning of play to sex preference requires different brain areas.

Beyond the basal ganglia: cFOS expression in the cerebellum in response to acute and chronic dopaminergic alterations.

The suggestion of an anatomical and functional relationship between the basal ganglia and cerebellum is recent. Traditionally, these structures were considered as neuronal circuits working separately to organize and control goal-directed movements and cognitive functions. However, several studies in rodents and primates have described an anatomical interaction between cortico-basal and cortico-cerebellar networks. Most importantly, functional changes have been observed in one of these circuits when altering the other one. In this context, we aimed to accomplish an extensive description of cerebellar activation patterns using cFOS expression (cFOS-IR) after acute and chronic manipulation of dopaminergic activity. In the acute study, substantia nigra pars compacta (SNc) activity was stimulated or suppressed by intra cerebral administration of picrotoxin or lidocaine, respectively. In addition, we analyzed cerebellar activity after the induction of a parkinsonism model, the tremulous jaw movements. In this model, tremulous jaw movements were induced in male rats by IP chronic administration of the dopamine antagonist haloperidol (1.5mg/kg). Acute stimulation of SNc by picrotoxin increased cFOS-IR in the vermis and cerebellar hemispheres. However, lidocaine did not produce an effect. After 14days of haloperidol treatment, the vermis and cerebellar hemispheres showed an opposite regulation of cFOS expression. Chronic dopaminergic antagonism lessened cFOS expression in the vermis but up-regulated such expression in the cerebellar hemisphere. Overall, the present data indicate a very close functional relationship between the basal ganglia and the cerebellum and they may allow a better understanding of disorders in which there are dopamine alterations.

[Biological and neural bases of partner preferences in rodents: models to understand human pair bonds]. / Bases biológicas y neurales de las preferencias de pareja en roedores: modelos para entender los vínculos afectivos en humanos.

AIM: To analyse the biological and neural bases of partner preference formation in rodents as models to understand human pair bonding. DEVELOPMENT: Rodents are social individuals, capable of forming short- or long-lasting partner preferences that develop slowly by stimuli like cohabitation, or rapidly by stimuli like sex and stress. Dopamine, corticosteroids, oxytocin, vasopressin, and opioids form the neurochemical substrate for pair bonding in areas like the nucleus accumbens, the prefrontal cortex, the piriform cortex, the medial preoptic area, the ventral tegmental area and the medial amygdala, among others. Additional areas may participate depending on the nature of the conditioned stimuli by which and individual recognizes a preferred partner. CONCLUSIONS: Animal models help us understand that the capacity of an individual to display long-lasting and selective preferences depends on neural bases, selected throughout evolution. The challenge in neuroscience is to use this knowledge to create new solutions for mental problems associated with the incapacity of an individual to display a social bond, keep one, or cope with the disruption of a consolidated one.

[Conditioned preferences induced by sex and drugs: a comparison of the neural bases]. / Preferencias condicionadas por sexo y drogas: comparación de las bases neurales.

AIM: To compare the behavioral and neural bases of conditioned preferences induced by drugs and sex in animal models. DEVELOPMENT: Sex- and drug-induced preferences have certain commonalities. For example, sex and drug reward can induce the development of new preferences, leading to the idea that the partner preferences that develop after sexual encounters and drug consumption are, in part, consequences of classical conditioning. Both phenomena depend on the activity of mesolimbic areas, and neurotransmitters such as dopamine, opioids and oxytocin. Agonists for these neurotransmitters facilitate conditioned preferences in the absence of sex and drug reward, whereas antagonists disrupt them even after sex or drug consumption. CONCLUSIONS: This review adds evidence to the idea that conditioned preferences induced by drugs use similar neural systems as those that evolved to sense and learn about natural rewards like sex.

Neuronal activation by stimuli that predict sexual reward in female rats.

Conditioned stimuli (CSs) associated with paced copulation induce a conditioned partner preference for males bearing the CS. Here we examined the activation of Fos immunoreactivity (Fos-IR) following exposure to a CS previously paired with either paced or nonpaced copulation. Ovariectomized, hormone-primed rats received 10 sequential conditioning trials at 4-day intervals. In experiment 1, females in the odor-paired group learned to associate an almond odor on a male with paced copulation and an unscented male with nonpaced copulation. In the odor-unpaired group, females received the opposite association. In experiment 2, females associated two different strains of male, Long-Evans or Wistar, with paced or nonpaced copulation, respectively. A preference test indicated that females in both experiments developed a conditioned preference for the pacing-related males, as indicated by significantly more solicitations toward the male and a preference to copulate with the pacing-related male. Subsequently, females were exposed to the CS (odor or strain) alone for 1 h prior to kill and preparation of their brains for immunocytochemistry. In both experiments, the CS associated with paced copulation produced significantly more Fos-IR in the piriform cortex, medial preoptic area, and ventral tegmental area, relative to the same odor or strain cues associated with nonpaced copulation. These findings provide evidence that the state associated with paced copulation can be conditioned to environmental stimuli such as neutral odors or strain cues, which earn an incentive value via classical conditioning. The significance of the brain areas activated is discussed with regard to their role in sexual and other motivated behaviors.