Frontofrontal and frontoparietal EEG power densities (0.5-20 Hz) in waking, light and deep slow-wave sleep, transition-type sleep, and rapid-eye-movement (REM) sleep were investigated for 8 h during the light period in 16 male Wistar rats. The data indicate that as delta activity (0.5-4.5 Hz) increased from light to deep slow-wave sleep, the number of epochs per scoring epoch with high sigma activity (11-16 Hz) as well as power densities in the rest of the spectrum (5-20 Hz) including sigma frequencies also increased. This is in parallel with other rat studies but contrasts findings in humans, where EEG sigma activity is reported to decrease as sleep deepens. During the 8-h recording period, delta activity decreased whereas sigma activity increased.
The P3(00) event-related brain potential (ERP) was elicited with auditory and visual stimuli using an oddball task in which the subject indicated with a button-press response the occurrence of a target stimulus that occurred randomly on 20% of the trials and refrained from responding to a standard stimulus. A total of four trial blocks were collected for each stimulus modality condition. P3 amplitude from the target stimuli decreased reliably across trial blocks for both the auditory and visual stimulus condition, with no interaction obtained between stimulus modality and trial block. P3 latency was shorter for the auditory compared to visual stimulus conditions, but did not vary with trial block. No changes in amplitude or latency independent of the P3 effects were obtained for the other ERP components with trial block, although the usual modality differences were observed. The results suggest that P3 components elicited by auditory and visual stimuli both habituate for actively discriminated target stimuli. The theoretical implications are discussed in the context of previous findings.
Dopamine D(1) receptor blockade does not appear to be a prerequisite for antipsychotic activity since many clinically effective antipsychotics have little or no affinity for this receptor subtype. Clozapine, however, which has minimal liability for extrapyramidal symptoms, possesses affinities of similar order for D(1) and D(2) receptors. In earlier animal models used to predict antipsychotic effect, selective D(1) antagonists have shown effects similar to standard antipsychotics with preferential D(2) or mixed D(1)/D(2) antagonism. We investigated the effects of haloperidol (0.1 mg/kg) and two selective D(1) antagonists, NNC 01-0112 (0.05, 0.1 and 0.2 mg/kg) and SCH 39166 (0.02, 0.2 and 2.0 mg/kg), on latent inhibition (LI) in rats. LI is a behavioural paradigm in which repeated nonreinforced preexposure to a stimulus retards subsequent associations to that stimulus. Disrupted LI has been suggested as a model for the attentional deficits in schizophrenia. Using preexposure to a flashing light stimulus, which subsequently served as a conditioned stimulus for suppression of water licking, we demonstrated a clear LI effect with haloperidol but with neither of the two D(1) antagonists. Since selective D(1) antagonists are not clinically effective, these results add further credibility for the relevance of LI as an animal model of psychosis.
N-0437 is a potent and highly selective dopamine D-2 receptor agonist, which has been used in the present series of experiments to investigate its potential anorectic properties. In doses of 0.3-3.0 mg/kg (IP), N-0437 significantly reduced consumption of a sweetened palatable mash in nondeprived mice (minimal effective dose, 0.3 mg/kg) and rats (minimal effective dose, 0.56 mg/kg). Reduction in food intake were also produced in rats by the less potent, but selective, D-2 agonist RU 24213 (effective at 10.0 mg/kg), and by d-amphetamine (1.0 and 3.0 mg/kg). The anorectic effect of N-0437 (1.0 mg/kg) was completely antagonized by the selective D-2 antagonist, YM-09151-2 (0.01 mg/kg). Over a series of 10 injections, N-0437 (1.0 mg/kg) maintained its effect to reduce palatable food intake. In food-deprived rats, N-0437 (0.3-3.0 mg/kg, IP) also reduced consumption of standard laboratory food, and dose-dependently reduced operant responding for food under a FR8 schedule of reinforcement. The results of the experiments are discussed in terms of a possible direct effect to reduce feeding responses resulting from stimulation of postsynaptic dopamine D-2 receptors.
Yawning and stretching responses were elicited in rats by a small dose (0.3 mg/kg) of the highly selective dopamine D2 agonist, N-0437. The responses were blocked by the highly selective dopamine autoreceptor antagonist, (+)-UH 232 (3.0 mg/kg), but not by raclopride at a dose which selectively blocks postsynaptic D2 receptors. The results strongly confirm the view that yawning and stretching are behavioral responses elicited by stimulation of presynaptic D2 receptors.
The effect of ATD on olfactory investigation in intact and in castrated, testosterone-treated male hamsters was studied using subcutaneous silastic implants. In intact males, there was a dose-dependent action of ATD in reducing sniffing towards novel females and in eliminating the discrimination between females after pre-exposure to vaginal odour. Both sniffing and olfactory discrimination reappeared after removal of ATD implants. Neither the weight nor the general behavioural activity of treated males was affected, indicating a specific behavioural affect. Testosterone (T) maintained olfactory behaviour in castrated males. Untreated castrates and castrates with ATD + T implants showed reduced sniffing and showed no discrimination between females after exposure to female odour. We conclude that conversion of T to oestrogen plays an essential role in the control of male olfactory behaviour.
1,5-Anhydroglucitol (1-DG) has been known as an antimetabolic glucose analogue. Using gas chromatography, 1-DG was found to be physiologically present in rat serum. In order to investigate its direct and long-term effects on feeding, 1-DG was infused during the light period into the rat third ventricle in doses of 3.0, 6.0 and 12.0 mumol/rat. Its effects were then compared to those of similarly applied 2-deoxy-D-glucose (2-DG). Following initial hyperphagia, both of these glucose-analogues produced suppressive effects on feeding during the subsequent day throughout the light and dark periods. On the third day after 2-DG injection reduction of feeding did not recover completely to the pretreatment baseline levels, but it did recover after 1-DG. Both 1-DG and 2-DG caused linear dose-related hypophagia, with the slope for 1-DG being about half of that for 2-DG. It is suggested that the delayed hypophagia which followed the initial hyperphagia produced by deoxyglucose was a result of sustained inactivation of the Na-pump due to intracellular ATP deficiency caused by accumulation of deoxy-glucose-6-phosphate.
Pups from gestating rats exposed to hypergravity (1.8 G) or to normal gravity at the perinatal period were evaluated for motor activity, exploration and social interactions during juvenile and adult stages. By comparison to controls, the hypergravity group had shorter latencies before choosing a maze arm in a T-maze and a lower number of exploratory pokes in a hole board. During dyadic encounters, the hypergravity group had a lower number of self-grooming episodes and shorter latencies before crossing under the opposing rat. In contrast, no intergroup differences were observed during exploration of an elevated plus-maze and a light-dark box. These results indicate that exposure to 1.8 G during development appears to decrease exploratory tendencies in the hole board and fear-related responses in T-maze and social interaction tests.
Environmental conditions promote weight gain in children and adults, with early nutritional states and the availability of energy condensed/high-fat palatable diets appearing to facilitate the development of obesity. Little is known about the extent to which prenatal and postnatal dietary manipulations alter the response of the adult offspring to high-fat, highly palatable diets. Here we exposed rat dams to highly palatable diet (supplemental diet, SD), rich in fat and sugars, during pregnancy and lactation, and assessed the potential interactions with the effects of a similar diet offered post-weaning on a range of physiological and behavioral parameters in the adult male offspring. Post-weaning exposure to SD increased body weight, body fat, and plasma leptin levels, as well as the plasma glucose response to glucose challenge, compared to chow-fed rats. Combining perinatal SD with post-weaning exposure (SD/SD group) elevated fasting plasma glucose levels, and induced leptin resistance in the adult rats. The same treatment also resulted in sensitized locomotor response to an acute injection of amphetamine. The glucocorticoid response to stress was not affected by the dietary treatments. We conclude that exposure of mother and young to a highly palatable diet with high-fat and high sugar content during the critical perinatal period, increases the risk of developing an obesity-like condition in rats exposed to the same palatable diet post-weaning, and this effect may be accompanied by adaptations in the reward-related mesostriatal dopaminergic system.
This article is based on proceedings of a symposium presented at the 2002 meeting of the Society for the Study of Ingestive Behavior and provides a brief overview of recent research suggesting a role for neuropeptide Y (NPY) in the modulation of ethanol drinking. The discussion focuses mainly on recent studies with genetic animal models including mutant mice lacking specific NPY receptor and selectively bred rodents, namely the Indiana alcohol-preferring (P) and alcohol-nonpreferring (NP) rats and the Indiana high alcohol drinking (HAD) and low alcohol drinking (LAD) rats. It is concluded that abnormal or low central NPY activity can promote high alcohol drinking and that NPY modulates alcohol consumption via the NPY Y1 and Y2 receptors.
The effects on anxiety and risk assessment of exposure to a cat were tested in hooded rats. Anxiety and risk assessment were measured in an elevated plus maze and hole board in a room different from the cat-exposure room. Behavior was tested either 1, 2, 7, 14, or 21 days after cat exposure in different groups of rats. A single exposure to a cat increased anxiety over controls in the plus maze from 1 to 21 days after exposure to a cat. The effects on anxiety were independent of activity or exploratory tendency. Severity of anxiety produced was predicted by the approach, but not the attack, behavior of the cat. Analogous correlations between traumatic stimuli and anxiety are seen in humans suffering from posttraumatic stress disorder (PTSD). Risk assessment in the plus maze was reduced over the same period in rats exposed to cats. Risk assessment was weakly correlated with anxiety. The findings are discussed with respect to the potential of this phenomenon as a model of generalized anxiety disorder found in PTSD.
Stress-related psychiatric disorders, such as depression and anxiety, affect a disproportionate number of women. We previously demonstrated that the major brain norepinephrine (NE)-containing nucleus, locus coeruleus (LC) is more sensitive to stressors and to the stress-related neuropeptide, corticotropin-releasing factor (CRF) in female compared to male rats. Because the LC-NE system is a stress-responsive system that is thought to be dysregulated in affective disorders, sex differences in LC structure or function could play a role in female vulnerability to these diseases. The present study used different approaches to compare LC dendritic characteristics between male and female rats. Immunofluorescence labeling of tyrosine hydroxylase, the norepinephrine synthetic enzyme, revealed that LC dendrites of female rats extend further into the peri-LC region, covering a significantly greater area than those of males. Optical density measurements of dendrites in the peri-LC revealed increased dendritic density in females compared to their male counterparts. Additionally, immunoreactivity for synaptophysin, a synaptic vesicle protein, was significantly greater in the LC in female rats, suggesting an increased number of synaptic contacts onto LC processes. Individual LC neurons were juxtacellularly labeled with neurobiotin in vivo for morphological analysis. LC dendritic trees of females were longer and had more branch points and ends. Consistent with this, Sholl analysis determined that, compared to males, LC dendrites of females had a more complex pattern of branching. The greater dendritic extension and complexity seen in females predicts a higher probability of communication with diverse afferents that terminate in the peri-LC. This may be a structural basis for heightened arousal in females, an effect which may, in part, account for the sex bias in incidence of stress-related psychiatric disorders.
Research has focused on understanding how overeating can affect brain reward mechanisms and subsequent behaviors, both preclinically and in clinical research settings. This work is partly driven by the need to uncover the etiology and possible treatments for the ongoing obesity epidemic. However, overeating, or non-homeostatic feeding behavior, can occur independent of obesity. Isolating the variable of overeating from the consequence of increased body weight is of great utility, as it is well known that increased body weight or obesity can impart its own deleterious effects on physiology, neural processes, and behavior. In this review, we present data from three selected animal models of normal-weight non-homeostatic feeding behavior that have been significantly influenced by Bart Hoebel's 40+-yr career studying motivation, feeding, reinforcement, and the neural mechanisms that participate in the regulation of these processes. First, a model of sugar bingeing is described (Avena/Hoebel), in which animals with repeated, intermittent access to a sugar solution develop behaviors and brain changes that are similar to the effects of some drugs of abuse, serving as the first animal model of food addiction. Second, another model is described (Boggiano) in which a history of dieting and stress can perpetuate further binge eating of palatable and non-palatable food. In addition, a model (Boggiano) is described that allows animals to be classified as having a binge-prone vs. binge-resistant behavioral profile. Lastly, a limited access model is described (Corwin) in which non-food deprived rats with sporadic limited access to a high-fat food develop binge-type behaviors. These models are considered within the context of their effects on brain reward systems, including dopamine, the opioids, cholinergic systems, serotonin, and GABA. Collectively, the data derived from the use of these models clearly show that behavioral and neuronal consequences of bingeing on a palatable food, even when at a normal body weight, are different from those that result from simply consuming the palatable food in a non-binge manner. These findings may be important in understanding how overeating can influence behavior and brain chemistry.
Significant sex differences have been demonstrated in clinical and preclinical studies of cocaine addiction, with some of the most consistent differences noted in regard to the role of stress and craving. The current study examined stress-induced reinstatement of cocaine seeking in male and female rats in an animal model of relapse using corticotropin-releasing factor (CRF) administration. Both male and female rats demonstrated increased cocaine seeking in response to CRF. CRF-induced reinstatement was highly variable across both male and female rats, and further analysis revealed a subpopulation that was particularly sensitive to CRF (high responders). Female high responders displayed significantly increased responding to CRF compared to males. Individual differences in stress responsivity could thus contribute to the likelihood of relapse, with females showing greater heterogeneity to stress-induced relapse.
The amygdala is involved in the emotional responses to fear including anxiety and heightened pain reporting. In a rodent model, bilateral activation of the central amygdala (CeA) with corticosterone (CORT) produces anxiety-like behavior, somatic allodynia and visceral hypersensitivity. Although hemisphere-specific processing differences between the left and right amygdala have been reported, it remains unclear whether the right or left CeA is involved in the production of anxiety-like behavior, and abnormal somatic and visceral perception. The goal of the present study was to investigate the hypothesis that lateralized corticoid-mediated mechanisms in the CeA produce anxiety as well as abnormal pain perception.
Anesthetized rats received stereotaxic implants of cholesterol (Chol; 30 μg) or CORT (30 μg) micropellets onto the left, right or both dorsal margins of the CeA. Following implantation (5-7 days), anxiety-like behavior was assessed on the elevated plus-maze (EPM), somatic allodynia was measured using Von Frey filaments, and visceral sensitivity was quantified as a visceromotor response (VMR) to colorectal distention (CRD) at 0-60 mmHg.
Unilateral implants of CORT onto either the left or right CeA produced anxiety-like behavior and somatic allodynia. However, our data illustrated that the bilateral placement of CORT onto the CeA was required to increase visceral sensitivity.
These results provide evidence that there is no hemispheric lateralization of the CeA involved in corticoid-mediated anxiety-like behavior and heightened pain reporting.
The adrenocortical and gonadal responses of 14 male monkeys were evaluated during four experimental conditions in order to evaluate the influence of social interactions on endocrine responsiveness. Plasma hormone levels were determined during the establishment of social relations, after 60-min exposures to a novel environment, after 60-min exposures to a snake, and 60 min after ACTH administration. Both adrenal and gonadal secretion changed significantly during the first day after social relations were established, although only dominant males showed increases in testosterone, whereas cortisol levels rose in all subjects. Increases in cortisol, but not testosterone, were also observed following exposure to novelty or a snake. The presence of a social partner reduced signs of behavioral disturbance during these test conditions, although the adrenal responses were equivalent or greater than when tested alone. This finding qualifies earlier research which indicated that social support was beneficial for reducing stress when squirrel monkeys were tested in larger groups in their home environment.
The leopard gecko has temperature-dependent sex determination (TSD); females are predominantly produced when incubated at 26 degrees C (100%), 30 degrees C (70%), and 34 degrees C (95%), whereas males are predominantly produced at 32.5 degrees C (75%). Exogenous estradiol can override the effect of temperature on sex determination. To compare temperature-determined females with hormone-determined females, eggs from the male-biased temperature were treated with estradiol benzoate during incubation. As adults, animals from a male-biased incubation temperature were more likely to exhibit aggression than animals from female-biased incubation temperatures. Furthermore, females from a male-biased incubation temperature tended to be less attractive than females from female-biased temperatures. Hormone-determined females were both attractive and aggressive. This suggests that incubation temperature is an important development determinant of adult aggressiveness and attractiveness. The 26 degrees C animals ovariectomized on the day of hatch exhibited more frequent aggression and were unreceptive to males, indicating that postnatal ovarian hormones also play a role in adult sociosexual behaviors. The parallel between incubation temperature and intrauterine position in laboratory mammals is discussed.
We compared the effects of CGS 10686B (a new drug that blocks serotonin reuptake), on nutrient selection and total food consumption with those of two other serotoninergic drugs, dl-fenfluramine and fluoxetine. The animals were given simultaneous free access to two isocaloric 40%-carbohydrate diets in separate food pans; one of these diets (5% protein) was shown to enhance brain serotonin synthesis by raising brain tryptophan levels; the other (45% protein) did not. CGS 10686B (4-7.5 mg/kg) markedly decreased (60-70%) consumption of the 5% protein diet, with a smaller effect (20-30%) on consumption of the 45% protein diet. Hence, it increased the ratio of protein to carbohydrate in the total food consumed. Higher doses (12.5-15 mg/kg) were no longer nutritionally-specific. Fluoxetine, which also blocks serotonin reuptake, and dl-fenfluramine, which both releases serotonin and suppresses its reuptake, had similar effects on nutrient intake; dl-fenfluramine was most potent and fluoxetine least. None of the drugs selectively affected carbohydrate or protein intake if the composition of the test diets provided was such that neither diet, eaten alone, would increase brain serotonin. These observations affirm that drugs which enhance serotoninergic neurotransmission selectively suppress the intake of high-carbohydrate, low-protein meals which increase brain serotonin synthesis.
Any odor-guided behavior might require generalization and/or discrimination over a wide range of odorant intensities. Proboscis extension conditioning (PEC) and electroantennogram (EAG) assays were used to investigate stimulus-intensity dynamics during olfactory processing in the honey bee. Experiments that tested generalization involved conditioning to one odorant concentration and either testing with a different odorant or with different concentrations of the same odorant. At low training concentrations, responses to either a novel odorant or to higher concentrations of the same odorant resulted in strong generalization. At higher training concentrations, significantly less generalization was observed to a novel odorant or to lower concentrations of the same odor. EAG analyses indicate that asymmetric generalization could arise due to long-term adaptation of peripheral receptor neurons. Discrimination experiments showed that relatively higher odorant concentrations associated with an appetitive reinforcer could usually be discriminated from a lower concentration that was associated with punishment, but not vice versa. Although sensory modulation in peripheral (sensory) processes might be sufficient to account for discrimination of a high from a low concentration, discrimination of low from high concentrations point to the involvement of central processes.
A combination of cannabis with even a small amount of ethanol can alter the brain function, more than either drug alone. To investigate the interacting effects of the co-administration of a low dose of ethanol and a cannabinoid CB1 receptor agonist, arachidonylcyclopropylamide (ACPA) on the conditioned place preference (CPP) test in male Wistar rats, ACPA was injected into the ventral tegmental area (VTA), basolateral amygdala (BLA) or ventral hippocampus (VH) in combination with ethanol during the conditioning or testing phase. Using a 3-day schedule of conditioning, low doses of ethanol (0.25, 0.5 and 1g/kg, i.p.) did not induce CPP or conditioned place aversion (CPA). In the second experiment, bilateral intra-VTA injection of the cannabinoid CB1 receptor agonist, arachidonylcyclopropylamide (ACPA; 0.5 and 1ng/rat) alone or with ethanol (0.5g/kg) induced a significant CPA. Bilateral intra-BLA injection of ACPA induced significant CPP, while co-administration of the same doses of ACPA with ethanol (0.5g/kg) induced CPA. Bilateral intra-VH injection of ACPA by itself produced both CPP and CPA in a dose-dependent manner. Co-administration of an ineffective dose of ACPA (9ng/rat, intra-VH) with ethanol also induced significant CPA. In the animals that had received ethanol during the conditioning phase, intra-VTA or -VH injection of ACPA, 5min before the testing phase, produced CPP while intra-BLA injection of the agonist produced CPA. None of the treatments, except intra-VH injection of ACPA, had an effect on locomotor activity. In conclusion, there may be a functional interaction between endocannabinoid system and ethanol in mediating reward or aversion.
Progesterone treatments have been shown to increase nesting levels of isolated female mice. Here we compared the effect of exogenous progesterone on the nesting behavior of C57BL/10Sn female Mus domesticus housed individually to nesting levels of the same mice housed in pairs. Progesterone increased nesting by isolated females but had no significant effect on the nesting scores of the same mice when they were grouped into pairs. The effect of exogenous progesterone on nesting levels in C57BL/10Sn females appears to depend on social circumstances.
Ten Hooded Lister rats were divided from weaning into two groups of five. One group was fed exclusively on a liquid diet in the home cage (Complan-fed subjects), the other group was given normal laboratory chow (Chow-fed subjects). At approximately 60 days of age both groups were reduced to 80% of their ad lib body-weight and given pairings of a retractable lever (conditioned stimulus, CS) and response-independent food (unconditioned stimulus, UCS). In the first experimental condition a liquid UCS was used (condensed milk solution) and in later conditions this was substituted with a solid UCS (45 mg food pellet). Analysis of CS-directed behavior in the two groups suggested that (1) only very early in autoshaping training did feeding experience in the home cage influence the topography of signal-directed behavior, and subsequently (2) both Complan-fed and chow-fed subjects bit rather than licked the CS paired with a solid UCS and licked rather than bit the CS when it was paired with a liquid UCS. These results suggest that, in the long-term, the topography of signal-centered behavior in rats is more likely to be influenced by the nature of the reinforcer signalled by the CS than by the subject's feeding experiences during early development.
The family of the endocannabinoid system comprises endogenous lipids (such as anandamide, [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and the putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-(4-hydroxy-2-methylphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (VDM-11; 10, 20 or 30μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation.
