Pituitary-adrenal and dopaminergic modulation of schedule-induced polydipsia: behavioral and neurochemical evidence.

Five experiments investigated in rats the effects of increasing or decreasing plasma corticosterone levels on schedule-induced polydipsia and dopamine efflux in the nucleus accumbens. The results indicate that the acquisition of schedule-induced polydipsia could be decreased by adrenalectomy, blockade of corticosterone synthesis, or administration of corticosterone. Performance of established schedule-induced polydipsia was also decreased by adrenalectomy. The effects of corticosterone administration on established schedule-induced polydipsia depended on the level of performance. High levels of drinking were enhanced by a high dose of corticosterone, whereas low rates of drinking were increased by a low dose. Similar injections of corticosterone also significantly increased dopamine efflux. The relative involvement of pituitary-adrenal activity and dopamine neurotransmission in the nucleus accumbens in the acquisition and performance of SIP is discussed and related to contemporary hypotheses of schedule-induced behavior.     

The entorhinal cortex-nucleus accumbens pathway and latent inhibition: a behavioral and neurochemical study in rats

Latent inhibition (LI) refers to the decrease in conditioned response produced by the repeated nonrein-forced preexposure to the to-be-conditioned stimulus. Experiment I investigated the effects of electrolytic lesions of the entorhinal cortex on LI in a conditioned emotional response procedure. Entorhinal cortex lesions attenuated LI. Experiments 2 and 3 investigated whether this attenuation of LI could result from a modification in nucleus accumbens (NAcc) dopamine (DA) release. Rats with entorhinal cortex lesions displayed normal spontaneous and amphetamine-induced locomotor activity, as well as normal basal and amphetamine-induced release of DA within the NAcc (assessed by microdialysis). Taken together, these results show that entorhinal cortex lesions disrupt LI in a way that is unlikely to be due to an alteration of DA release within the NAcc.     

GSA: behavioral, histological, electrophysiological and neurochemical effects

Renal insufficient patients suffer from a variety of complications as direct and indirect consequence of accumulation of retention solutes. Guanidinosuccinic acid (GSA) is an important probable uremic toxin, increased in plasma, urine, cerebrospinal fluid and brain of patients with uremia and supposed to play a role in the pathogenesis of some neurological symptoms. GSA, an NMDA-receptor agonist and GABA-receptor antagonist, is suggested to act as an excitotoxin and shown to be convulsive. The effect of hippocampal (i.h.) GSA injection on behavior and hippocampal volume in mice is presented here. In addition, hippocampal cGMP concentration after systemic injection of GSA was measured. The effect of co-application of NMDA-receptor antagonist CGP37849 with GSA was tested, in vivo, after hippocampal GSA injection and, in vitro, on GSA evoked currents in spinal cord neurons. A significant dose-dependent effect of i.h. injection of GSA on cognitive performance, activity and social exploratory behavior was observed. There was a protective effect of CGP37849 on GSA induced behavioral alterations. Volume of hippocampal cornu ammonis region decreased significantly and dose-dependently after GSA injection. Systemic GSA injection increased cGMP concentration in hippocampal formation. It can be concluded that GSA is an important neurotoxin. As GSA is increased in patients with uremia, it probably contributes to their neurological symptoms. Knowledge of neurotoxic effects and mechanisms of action of GSA and other uremic retention solutes could help in the development of more efficient treatment of uremic patients. Animal models like the 'GSA mouse model' are useful tools for research in this context.     

Sex differences in behavioral and neurochemical profiles after chronic stress: role of housing conditions

This experiment sought to identify the extent housing conditions can differentially enhance or dampen the effects chronic restraint stress has on exploration and object memory in male and female rats. Subjects were either pair- or singly housed during stress (21 days of 6-h restraint) and maintained under those conditions during poststress behavior testing (7 days). Neurochemical analysis of neural tissue was accomplished by HPLC with electrochemical detection. Interactions between stress and housing conditions were found across both sexes. Stress was associated with less activity in the center of the forced open-field in both sexes. Stress also decreased the latency for males to enter the free open-field to female levels. Object recognition was greatly impaired in double-housed males but unaffected by stress or housing in females. Object location memory was impaired in stressed males if they were singly housed, and females performed as well as control males only if they were stressed. Both sexes generally showed increased in hippocampal (CA3) norepinephrine levels in their respective stress groups. Singly housed subjects had higher CA1 serotonin levels compared to double-housed subjects, whereas in the prefrontal cortex, a general sex difference was found with females having higher levels of serotonin and dopamine metabolites. These results show that stress affects limbic neurochemistry across sex, although only males exhibit stress-dependent decrements in object memory. Housing condition also has a profound effect on neurochemistry and male performance on object recognition. Thus, housing condition is a critical variable for male models of stress that can influence the extent the stress manipulation affects behavior. The differences observed across sex are further discussed in the context of behavioral inhibition.     

Perinatal undernutrition facilitates morphine sensitization and cross-sensitization to cocaine in adult rats: a behavioral and neurochemical study

The development of sensitization to the locomotor effects of morphine and cross-sensitization between morphine and cocaine were evaluated in adult rats submitted to a protein malnutrition schedule from the 14th day of gestation up to 30 days of age (D-rats), and compared with well-nourished animals (C-rats). Dose-response curves to morphine-induced locomotor activity (5, 7.5, 10 or 15 mg/kg, i.p., every other day for 5 days) revealed a shift to the left in D-rats compared to C-rats. This implies that D-rats showed behavioral sensitization to the lower dose of morphine used (5 mg/kg), which was ineffective in C-rats. Furthermore, when a cocaine challenge (10 mg/kg, i.p) was given 48 h after the last morphine administration, only D-rats exhibited cross-sensitization in morphine-pretreated animals (7.5 and 10 mg/kg). In order to correlate the differential response observed with the functioning of the mesocorticolimbic dopaminergic system, extracellular dopamine (DA) levels were measured in the nucleus accumbens (core and shell) and the dorsal caudate-putamen. A challenge with cocaine in morphine pre-exposed animals produced an increase in DA release, but only in the nucleus accumbens “core” of D-rats. Similar DA levels were found in the nucleus accumbens “shell” and in the dorsal caudate-putamen of both groups. Finally, these results demonstrate that D-rats had a lower threshold for developing both a progressive behavioral sensitization to morphine and a cross-sensitization to cocaine. In accordance with these behavioral findings, a higher responsiveness of the nucleus accumbens core, expressed by increased DA levels, both basal and after cocaine challenge, was observed in D-rats.     

Sexual behavior, neuroendocrine, and neurochemical aspects in male rats exposed prenatally to stress

The present study was designed to examine some short- and long-term effects of maternal restraint stress--during the period of sexual brain differentiation--on reproductive and endocrine systems, sexual behavior, and brain neurotransmitters in male rat descendants. Pregnant rats were exposed to restraint stress for 1 h/day from gestational days (GDs) 18 to 22. Prenatal stress did not influence the wet weight of sexual organs and the quantity of germ cells in adult male pups; however, these animals showed reduced testosterone levels, delayed latency to the first mount and first intromission, and also decreased number of ejaculations. Additionally, there was an increase in the dopamine and serotonin levels in the striatum. Our results indicate that prenatal stress had a long-term effect on neurotransmitter levels and sexual behavior. In this sense, reproductive problems caused by injuries during the fetal period can compromise the later success of mating as well as the capacity to generate descendants.     

CCK as a central satiety factor: behavioral and electrophysiological evidence

CCK and its derivatives potently inhibit feeding, even after vagotomy. This effect is thus considered to be peripheral. Recently, however, the vagal gastric branch was reported to essentially bring feeding inhibition into full play. In the present study, it was found that CCK-8, administered into the third cerebroventricle (III-cv), or into the lateral hypothalamus (LHA), significantly and dose-dependently inhibited feeding induced by electrical stimulation of the contralateral LHA (LHA-ESIF) in the chronic rat. This inhibition by CCK-8 was not affected by systemic pretreatment with proglumide (1 mg), a selective antagonist, while CCK (250 ng) simultaneously microinjected into the III-cv with 5 micrograms proglumide almost completely eliminated the CCK effect on LHA-ESIF. Neuronal activity of the ventromedial hypothalamus (VMH) was enhanced, and that of the LHA was suppressed by electrophoretic direct application of CCK on neurons in urethane-chloralose-anesthetized rats. CCK also markedly decreased the threshold of VMH glucose responding neurons. These results indicate that the satiety effect is not only peripheral, but might also be central, especially through feeding-related hypothalamic neurons, which are probably important in feeding inhibition.     

Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats

The forced swim test (FST) has been considered as a pharmacologically valid test of the depressive syndrome in rodents. However, few studies have focused on neurochemical and behavioral responses during FST in both male and female rats. Thus, we investigated certain behavioral and neuroendocrine responses as well as the serotonergic activity after the application of FST in both sexes. Our data show that the duration of immobility was increased in both male and female rats during the 2nd session of the FST. Sex differences are observed in some behavioral responses, such as head swinging that is mostly present in male rats. In female rats FST induced a decrease in serotonergic activity in hippocampus and hypothalamus while in male rats it induced an increase in serotonergic activity in hypothalamus. Corticosterone serum levels were elevated in both sexes. However, hippocampal GR mRNA levels tended to be increased in males and females respectively. Moreover, hypothalamic serotonin (5-HT)1A mRNA levels were decreased in female rats while in male rats hippocampal 5-HT1A mRNA levels were increased. These data have shown that FST induces "depressive like symptoms" in both sexes and provide evidence that sex differences characterize certain behavioral aspects in the FST. Notably, hippocampal and hypothalamic serotonergic activity has been differentially modified in male rats compared with female rats and these neurochemical findings could be relevant to the differentiated expression of 5-HT1A receptor. Hypothalamic-pituitary-adrenal axis activity was also affected by FST application in a sex specific manner. The present results support that FST induced behavioral, neurochemical and neurobiological alterations, which are sex dependent.     

Septal lesions and avoidance behavior: Genetic,neurochemical and behavioral considerations

Previous research found that the effects of septal lesions on active and passive avoidance behavior were dramatically determined by the genotype of the mouse employed. We present here a series of experiments which attempted to described how septal lesions affect these lines as reflected in behaviors known to be sensitive to such brain damage and how such changes might relate to those seen in avoidance behavior. We examined turnover rates and levels of catecholamines and changes in sensory/motor reactivity in a series of 5 experiments. Although many of our measures were markedly altered by interactions between genotype and lesion, a simple predictive relationship between such changes and avoidance behavior was not observed. Our results emphasize the critical need to establish extensive behavioral “profiles” which take into account task and genotypic considerations in the analysis and interpretation of the impact which brain damage has on behavior.     

Social stress and reproductive success in the female Syrian hamster: endocrine and behavioral correlates

In many mammal species, reproduction is not shared equally among the members of a social unit. Even though reproductive skew seems unlikely in females of solitary species, this phenomenon could result from environmental factors. Although solitary in the wild, captive Syrian hamsters (Mesocricetus auratus) are generally housed in groups. We investigated whether social stress produces some degree of reproductive skew in this solitary species and whether female reproductive success varies as a function of social rank. To assess the physiological relationship between social stress and fertility, we monitored reproductive hormones and glucocorticoids of solitary and pair-housed females during pregnancy by means of recently established non-invasive methods for measuring hormone metabolites in the feces. The patterns of fecal progesterone, estrogen and glucocorticoid metabolites were similar to those found in blood and reported in the literature for pregnant hamsters. As expected, dominant females had higher breeding success than subordinate females. However the rate of reproductive failure was also very high among the singly housed females of our control group. The number of pups per litter, the average sex-ratio in each group, and the mean weight of pups did not differ significantly among groups. Glucocorticoid concentrations were unaffected by housing and social rank and the few differences between the endocrine profiles of singly- and pair-housed females are not sufficient to explain the observed difference in breeding success. It is likely that social isolation impairs reproduction in the same manner as subordination. Our findings suggest that social isolation of animals accustomed to group living was equally as disturbing as cohabitation with an unknown conspecific.     

Use-dependent behavioral and neurochemical asymmetry in MPTP mice

Early in Parkinson's disease (PD) physical activity becomes difficult resulting in a more sedentary lifestyle. Clinical and experimental studies have found that increased activity following striatal dopamine loss leads to increased motor function. Decreased physical activity early in PD along with findings that increased physical activity results in functional improvement suggested to us that decreased physical activity during the period of nigrostriatal degeneration may not only be a symptom of the injury, but may also act to potentiate the degeneration. Using the bilateral MPTP mouse model of PD, we restricted use of one forelimb for the first 7 days post-injection. This transient behavioral manipulation during the period of dopamine degeneration resulted in a long-lasting deficit of the restricted forelimb. This was manifested as sustained asymmetrical use of the forelimbs during wall exploration, as well as a neurochemical imbalance between striatal hemispheres measured by immunoreactivity of the dopamine terminal markers, DAT, VMAT2 and TH. These results show a significant interaction between behavior and neurochemistry and suggest that a reduction in activity level may further exacerbate degeneration.     

Use-dependent behavioral and neurochemical asymmetry in MPTP mice

Folic acid is believed to play a role in protection from oxidant stress. Low levels of folic acid had been found in serum from patients with Alzheimer disease (AD). Folate concentration was evaluated in sera from 136 patients with cortical dementia [AD, n = 108; frontotemporal dementia (FTD), n = 28], 57 patients with subcortical dementia [Lewy body disease (LBD), n = 9; corticobasal degeneration (CBD), n = 5; progressive supranuclear palsy (PSP), n = 6; Parkinson disease with dementia (PD-Dem), n = 37], and 76 nondemented, healthy age-matched people. Serum folic acid levels were decreased in patients with AD and FTD as compared with either controls or patients with subcortical dementia (3.60 ± 2.22 and 5.37 ± 2.92 μg/L versus 6.87 ± 3.50 μg/L, respectively; P < 0.01). A tendency towards decreased folate concentration was found in LBD and CBD, but not to a significant extent. The highest proportion of folate-deficient patients was found in CBD, FTD and AD (respectively, 60, 48.2 and 46.3% versus 7.9% in controls; P < 0.001). Folate deficiency characterizes FTD as well as AD. These differences observed among different clinical dementing syndromes may be related to neocortical damage.     

Differential involvement of GABA system in mediating behavioral and neurochemical effect of acupuncture in ethanol-withdrawn rats

In our previous study we demonstrated that acupuncture at Shenmen (HT7) points suppressed a decrease of accumbal dopamine (DA) release in ethanol-withdrawn rats. Furthermore, here we found that it inhibited behavioral withdrawal signs of ethanol. In an effort to better understand the mechanisms underlying this inhibition, the potential role of GABA receptor system in acupuncture was investigated. Male Sprague–Dawley rats were treated with 3 g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 48 or 72 h of ethanol withdrawal, acupuncture was applied at bilateral HT7 for 1 min. The selective GABA_A antagonist bicuculline and the selective GABA_B antagonist SCH 50911 were injected intraperitoneally 20 min before acupuncture, respectively. Importantly, suppressive effects of acupuncture on DA deficiency were completely abolished by SCH 50911, but not by bicuculline, whereas ameliorating effects of acupuncture on ethanol withdrawal syndrome were completely blocked either by SCH 50911 or bicuculline. These results suggest that acupuncture at specific acupoint HT7 may normalize the DA release in the mesolimbic system and attenuate withdrawal syndrome through the GABA_B receptor system in ethanol-withdrawn rats.     

Sleep fragmentation elevates behavioral, electrographic and neurochemical measures of sleepiness

Sleep fragmentation, a feature of sleep apnea as well as other sleep and medical/psychiatric disorders, is thought to lead to excessive daytime sleepiness. A rodent model of sleep fragmentation was developed (termed sleep interruption, SI), where rats were awakened every 2 min by the movement of an automated treadmill for either 6 or 24 h of exposure. The sleep pattern of rats exposed to 24 h of SI resembled sleep of the apneic patient in the following ways: sleep was fragmented (up to 30 awakening/h), total rapid eye movement (REM) sleep time was greatly reduced, non-rapid eye movement (NREM) sleep episode duration was reduced (from 2 min, 5 s baseline to 58 s during SI), whereas the total amount of NREM sleep time per 24 h approached basal levels. Both 6 and 24 h of SI made rats more sleepy, as indicated by a reduced latency to fall asleep upon SI termination. Electrographic measures in the recovery sleep period following either 6 or 24 h of SI also indicated an elevation of homeostatic sleep drive; specifically, the average NREM episode duration increased (e.g. for 24 h SI, from 2 min, 5 s baseline to 3 min, 19 s following SI), as did the NREM delta power during recovery sleep. Basal forebrain (BF) levels of extracellular adenosine (AD) were also measured with microdialysis sample collection and high performance liquid chromatography detection, as previous work suggests that increasing concentrations of BF AD are related to sleepiness. BF AD levels were significantly elevated during SI, peaking at 220% of baseline during 30 h of SI exposure. These combined findings imply an elevation of the homeostatic sleep drive following either 6 or 24 h of SI, and BF AD levels appear to correlate more with sleepiness than with the cumulative amount of prior wakefulness, since total NREM sleep time declined only slightly. SI may be partially responsible for the symptom of daytime sleepiness observed in a number of clinical disorders, and this may be mediated by mechanisms involving BF AD.     

Ontogeny of odor discrimination: a method to assess novel odor discrimination in neonatal rats.

Recent research using molecular and functional imaging techniques has demonstrated a highly precise spatial representation of odor quality in the rodent olfactory bulb, which is enhanced by extensive lateral inhibitory circuitry. Much of this olfactory bulb circuitry develops postnatally in the rat, leading to the prediction that behavioral discrimination of odor quality may also emerge postnatally. However, currently no behavioral paradigm has been identified to test this prediction. The present report describes the expression and habituation of odor-evoked heart rate-orienting responses in neonatal rats. The results demonstrate that odor-evoked-orienting responses can be observed at least as early as postnatal day 4 (PN 4), and in those animals showing orienting responses, habituation is constant throughout the postnatal period. Furthermore, the results suggest that examination of cross-habituation using this paradigm can be used to explore odor discrimination ability in neonates. These results lay the foundation for future studies of precise mapping of the ontogeny of novel odor discrimination.