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Orbital and dorsolateral frontal perfusion defect associated with behavioral response to cholinesterase inhibitor therapy in Alzheimer's disease.

The authors retrospectively explored the behavioral and functional imaging profile of Alzheimer's disease (AD) patients who respond to cholinesterase inhibitor therapy by using the Neuropsychiatric Inventory (NPI) and baseline [99mTc]HMPAO SPECT. Thirty AD patients were divided into three groups (Responders, Nonresponders, and Unchanged) based on their behavioral response to donepezil. Responders had significantly (P < or = 0.01) more pretreatment irritability, disinhibition (P < or = 0.05), and euphoria (P = 0.05) than Nonresponders and significantly lower lateral orbital frontal (P < 0.00001) and dorsolateral frontal (P < or = 0.0005) perfusion bilaterally. A pretreatment orbitofrontal syndrome may predict behavioral response to cholinesterase inhibitor therapy in AD.

Aged↗

Nucleus accumbens dopamine release is necessary and sufficient to promote the behavioral response to reward-predictive cues.

The nucleus accumbens is part of the neural circuit that controls reward-seeking in response to reward-predictive cues. Dopamine release in the accumbens is essential for the normal functioning of this circuit. Previous studies have shown that injection of dopamine receptor antagonists into the accumbens severely impairs an animal's ability to perform operant behaviors specified by predictive cues. Furthermore, excitations and inhibitions of accumbens neurons evoked by such cues are abolished by inactivation of the ventral tegmental area, the major dopaminergic input to the accumbens. These results indicate that dopamine is necessary to elicit neural activity in the accumbens that drives the behavioral response to cues. Here we show that accumbens dopamine release is causal to the rats' reward-seeking behavioral response by demonstrating that dopamine in this structure is both necessary and sufficient to promote the appropriate behavioral response to reward-predictive cues.

Animals↗

Defective corticotropin-releasing hormone mediated neuroendocrine and behavioral responses in cholestatic rats: implications for cholestatic liver disease-related sickness behaviors.

Nonspecific systemic complaints are commonly encountered in patients with cholestatic liver diseases. However, the cause of these symptoms is poorly understood. Because corticotropin-releasing hormone (CRH) has been implicated as a mediator of sickness-related systemic symptoms, we examined CRH-mediated neuroendocrine and behavioral responses in rats with cholestasis due to bile duct resection (BDR) or sham resected (sham) controls. BDR and sham rats were placed individually in an open field apparatus, and the number of inner and outer squares entered, as well as the number of fecal boli produced, counted over a 5-minute period. Fecal boli production and inner squares entered are dependent on central CRH release. BDR and sham rats entered the same number of outer squares; however, BDR rats entered significantly fewer inner squares and produced fewer fecal boli than did sham rats, suggesting defective central CRH release in BDR rats. Immediately after exposure to the open field, rats were killed and blood adrenocorticotropic hormone (ACTH) levels measured. ACTH release is dependent on central CRH release. BDR rats demonstrated significantly lower plasma ACTH levels after exposure to an open field than did sham animals. To further explore the central CRH defect in BDR rats, hypothalamic CRH contents were determined in BDR and sham rats with and without exposure to restraint stress. BDR rats had significantly lower basal hypothalamic CRH levels than sham animals, and CRH levels did not further decrease in BDR rats with restraint stress (as normally occurs). These results are consistent with defective CRH-mediated responses in cholestatic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

Gangliosides attenuate stress-induced changes on body weight, motor activity and on the behavioral response to 5-methoxy-N,N-dimethyltryptamine.

The major goal of this study was to evaluate the influence of gangliosides (GANG) treatment on the onset of adaptive changes and the sequelae induced by stress exposure. With this purpose, the behavioral response to 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 5 mg/kg, IP) and motor activity were evaluated in rats previously submitted either to a single restraint session (2 h) or to a daily restraint event for 3 consecutive days, combined or not to GANG administration (30 mg/kg IP). GANG was always injected 2 h before stress exposure. In addition, differences in body weights were recorded throughout the experiments. A similar behavioral response after 5-MeODMT was observed between saline (SAL) and GANG unstressed rats. Exposure to one or three restraint sessions did not modify the behavioral response to 5-MeODMT, whereas the association of GANG and stress during 3 consecutive days enhanced forepaw treading and hindlimb abduction. SAL-treated animals submitted to a single or to three stressful stimuli showed reduced locomotion and rearing. The combination of GANG and stress for 3 days, but not after a unique association, reversed the decrease on motor activity induced by the aversive experience. The decrease of body weights produced by one or three stress sessions was recovered only in animals treated with GANG and stress for 3 days. These findings suggest that GANG may accelerate the onset of adaptive changes on 5-HT1 sites and attenuate certain sequelae induced by previous stress experience.

Adaptation, Psychological↗

Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine.

Both clinical and rodent studies show sexually dimorphic patterns in the behavioral response to cocaine in all phases of the addiction process (induction, maintenance, and relapse). Clinical and rodent studies also indicate that hormonal fluctuations during the menstrual/estrous cycle modulate cocaine-induced subjective effects in women and locomotor activity in female rats. Evidence suggests that gonadal hormones underlie these observed differences and could be the biological basis of sex-specific differences in cocaine addiction. To study the effects of gonadal hormones on cocaine-induced activity, two approaches have been used. First, studies have examined the role of endogenous hormones through gonadectomy (GDX) and side-by-side comparisons with intact rats. Second, the individual contributions of testosterone, progesterone, and estrogen have been determined by hormone replacement in GDX rats. In this review, we discuss gonadal hormones as the biological basis for the behavioral responses to cocaine, and the clinical implications of these findings.

Animals↗

Gender differences in the behavioral responses to cocaine and amphetamine. Implications for mechanisms mediating gender differences in drug abuse.

When ovariectomized female rats receive estrogen, the response to the psychomotor stimulants amphetamine or cocaine is enhanced. Estrous cycle-dependent differences in amphetamine-stimulated behaviors and striatal dopamine release are also noted. Intact female rats exhibit a greater behavioral response to amphetamine on estrus than they do on other days of the cycle. Ovariectomy results in attenuation of amphetamine-induced behavior and the striatal dopamine response to amphetamine. Physiological doses of estrogen given to ovariectomized rats reinstate both of these responses to a level comparable to that in estrous females. Furthermore, a sex difference is noted, in that females tend to exhibit a greater behavioral response to the psychomotor stimulants, and estrogen enhances this sex difference. Repeated treatment with amphetamine or cocaine produces a progressive increase in behavioral responsiveness with subsequent drug administration, a process known as sensitization. In rodents, behavioral sensitization results in increases in both frequency and duration of psychomotor behaviors such as rotational behavior, stereotyped grooming, headbobs, and forelimb movements. Interestingly, females display greater sensitization of behaviors in response to psychomotor stimulants than do males. Previous research results are summarized, and new results are presented, demonstrating that estrogen selectively enhances components of behavior that exhibit sensitization in female rats. Results also indicate gender differences in sensitization independent of gonadal hormones, suggesting that the neural systems that undergo sensitization are sexually dimorphic.

Amphetamine↗

Behavioral responses to examination. A reappraisal of the interpretation of "nonorganic signs".

Waddell et al in 1980 developed a standardized assessment of behavioral responses to examination. The signs were associated with other clinical measures of illness behavior and distress, and are not simply a feature of medicolegal presentations. Despite clear caveats about the interpretation of the signs, they have been misinterpreted and misused both clinically and medicolegally. Behavioral responses to examination provide useful clinical information, but need to be interpreted with care and understanding. Isolated signs should not be overinterpreted. Multiple signs suggest that the patient does not have a straightforward physical problem, but that psychological factors also need to be considered. Some patients may require both physical management of their physical pathology and more careful management of the psychosocial and behavioral aspects of their illness. Behavioral signs should be understood as response affected by fear in the context of recovery from injury and the development of chronic incapacity. They offer only a psychological "yellow-flag" and not a complete psychological assessment. Behavioral signs are not on their own a test of credibility or faking.

Disability Evaluation↗

The behavioral response induced by intravesical instillation of capsaicin rats is mediated by pudendal urethral sensory fibers.

The behavioral response induced by the intravesical instillation of capsaicin has been investigated in catheter-implanted, freely moving, conscious male and female rats. Intravesical instillation of capsaicin (25 nmol/rat in 0.5 ml) evoked an intense licking directed toward the lower abdominal and perineal skin which lasted for 15 min. Capsaicin-induced licking was reduced by systemic capsaicin pretreatment at a dose of 150 mg/kg but not at 50 mg/kg, administered 4 days before the intravesical instillation. Both doses of capsaicin effectively abolished the eye-wiping response to local capsaicin application. The capsaicin-induced licking was preserved (and prolonged) in both male and female animals subjected to bilateral ablation of the pelvic ganglia, 48 h before the intravesical instillation of the irritant. The capsaicin-induced licking was almost abolished by placing a ligature around the proximal urethra (24 h before), in order to avoid the contact of the irritant with the urethra or by previous section of the pudendal nerves (48 h before). One hour intravesical infusion with tetrodotoxin (1 and 10 microM) reduced the amplitude of micturition contractions but did not prevent the licking response evoked by capsaicin. On the contrary, the intravesical infusion of lidocaine (100 mM) abolished both micturition contractions and the capsaicin-induced licking. We conclude that the behavioral response induced by the intravesical instillation of capsaicin is mainly due to the stimulation of urethral afferents travelling within pudendal nerves.

Animals↗

Aging-dependent changes in the effect of daily melatonin supplementation on rat metabolic and behavioral responses.

Pineal melatonin secretion has been reported to commonly decrease with aging, whereas intra-abdominal adiposity, plasma insulin and plasma leptin levels tend to increase. We recently demonstrated that daily melatonin administration starting at middle age suppressed male rat intra-abdominal fat, plasma leptin and plasma insulin to youthful levels, suggesting that aging-related changes in pineal melatonin secretion and in energy regulation may be functionally related. Accordingly, we have now investigated the effects of daily melatonin treatment on energy regulation in young versus middle-aged male Sprague Dawley rats. Addition of melatonin to the drinking water (0.2 microg/mL) produced nocturnal and diurnal plasma melatonin concentrations in middle-aged rats (12 months) equivalent to those of young adult (5 months) rats. Administration of this melatonin dosage every day for 10 wk starting at 10 months of age suppressed (P < 0.01) relative intra-abdominal fat, non-fasted plasma insulin and plasma leptin by 27, 39, and 51%, respectively (vs. vehicle-treated controls). In contrast, administration of melatonin for 10 wk starting at 3 months of age did not significantly alter (P> 0.10) any of these parameters. The melatonin administration stimulated (102%, P < 0.001) behavioral responsiveness of the middle-aged rats in a test of response to novelty, restoring youthful levels, but did not significantly alter behavioral responsiveness of the young rats. These results suggest that suppression of intra-abdominal adiposity and plasma leptin and insulin levels and stimulation of behavioral responsiveness in response to daily exogenous melatonin begins at middle age, coincident with and likely dependent upon the aging-associated decline in endogenous pineal melatonin secretion. These results further suggest that appropriate melatonin supplementation may potentially provide therapy or prophylaxis not only for the insulin resistance, increased intra-abdominal fat and resulting pathologies that occur with aging, but also for some aging-associated behavioral changes.

Adipose Tissue↗

Threshold and graded response behavior in human neutrophils: effect of varying G-protein or ligand concentrations.

Observing the qualitative characteristics of response behavior as key variables in the signal transduction cascade are changed can provide insight into the fundamental roles of these interactions in producing cellular responses. Using flow cytometric assays and pertussis toxin (PT) treatment of human neutrophils, we have shown that actin polymerization stimulated with the chemoattractants N-formyl-Met-Leu-Phe, leukotriene B4, and interleukin-8 exhibits threshold behavior in terms of G-protein number. Partial PT treatment resulted in both responding and nonresponding populations of cells upon stimulation. As PT treatment was increased, the responding population of cells continued to respond maximally, while the number of cells responding decreased. We also showed that N-formyl peptide-stimulated oxidant production exhibits threshold behavior in terms of G-protein number, and the threshold for oxidant production is significantly greater than that for actin polymerization. The threshold behavior observed with PT treatment contrasted with the graded response behavior seen when cells were stimulated with different doses of ligand. For actin polymerization, only one population of cells was observed at submaximal ligand concentrations, and as ligand concentration was decreased the whole population responded submaximally. For oxidant production, as ligand concentration was decreased there were two populations of cells, but the responding cells responded submaximally. A mathematical model incorporating receptor/ligand binding and G-protein activation was developed to account for these differences in response behavior. Our results predict that an early signal transduction event in addition to, and not initiated by G-protein activation, is necessary to account for actin polymerization and oxidant production in neutrophils.

Actins↗

Enhanced muscimol-induced behavioral responses after 6-OHDA lesions: relevance to susceptibility for self-mutilation behavior in neonatally lesioned rats.

Adult rats lesioned with 6-hydroxydopamine (6-OHDA), either as neonates or as adults, demonstrated increased turning, compared to unlesioned controls, when muscimol was unilaterally microinjected into the substantia nigra reticulata (SNR). At the higher doses of muscimol, the lesioned rats were so intensely lateralized that circling was impeded. These data suggest a functional supersensitivity of receptors associated with GABA function in the SNR of 6-OHDA-lesioned rats. When 30 ng muscimol was administered bilaterally into the SNR, self-mutilation behavior (SMB) was observed in 2/11 of the control unlesioned rats, in 0/8 adult 6-OHDA-lesioned rats, and in 11/11 of the neonatally-lesioned rats tested. The ability of muscimol to produce SMB in the rats lesioned as neonates was dose related. Behavioral observations indicated that behaviors associated with SMB (self-biting and taffy pulling) were present in neonatal, but not adult lesioned rats. Behavioral responses to dopamine agonist administration were also different between rats lesioned as neonates and those lesioned as adults with 6-OHDA. These data support the view that lesions of dopaminergic neurons cause an increased functional responsiveness of receptors acted upon by muscimol in the SNR, and that the increased susceptibility for SMB in neonatally lesioned rats is determined by neurons distal to the GABA receptor complex in the SNR.

Animals↗

Effects of antidepressant drugs injected into the amygdala on behavioral responses of rats in the forced swim test.

Experiments were conducted to determine if the actions of antidepressant drugs in a pharmacological screen would be localized to specific brain regions. Rats were infused in discrete brain regions with drugs of different pharmacological properties and processed in the forced swim test. Infusion of imipramine and pargyline into the amygdala produced behavioral responses similar to i.p. injections of the drugs. The regions of the amygdala from which positive responses could be elicited were highly selective. From cannula placements and diffusion studies with autoradiography it appears that a locus of action of imipramine and pargyline is confined to the central, basolateral and/or lateral nuclear regions of the amygdala. Behavioral responses of rats in which imipramine was infused into the anterior amygdala or caudate-putamen did not differ from saline controls. When infused into regions of the amygdala in which imipramine was active, iprindole, an "atypical" antidepressant, did not produce a behavioral response in the forced swim test. Two "false positives" in the forced swim test, atropine and amphetamine, were also not active when infused into the amygdala. These results indicate that the amygdala is a critical site of action for certain antidepressant drugs in the forced swim test, and that behavioral activation in the test induced by iprindole, amphetamine and atropine involve brain regions other than the amygdala.

Amygdala↗

Dose-response effects of estrogen and tamoxifen upon methamphetamine-induced behavioral responses and neurotoxicity of the nigrostriatal dopaminergic system in female mice.

In the present experiment we evaluated the dose-response effects of estrogen (estradiol benzoate; EB) and tamoxifen (TMX) in modulating the acute behavioral and chronic effects of methamphetamine (MA) upon the nigrostriatal dopaminergic (NSDA) system in ovariectomized (OVX) mice. EB over a range of doses from 1-40 microg resulted in a neuroprotective effect upon the NSDA system as defined by both a preservation of striatal dopamine (DA) concentrations and a decrease in DOPAC/DA ratios. Interestingly, the neuroprotective effect of the 1-microg EB dose occurred in the absence of any statistically significant effect upon the bioassay parameter of uterine weight. With the exception of an increase in stereotypy time as a response to the 40-microg dose, EB at any of the doses tested failed to alter any acute behavioral responses evoked by MA. In response to TMX, a statistically significant NSDA neuroprotectant response was obtained for DOPAC/DA ratios, but not DA concentrations, to doses ranging from 12.5 to 500 microg. No statistically significant effects upon uterine weights were obtained for any of the doses of TMX tested. Behaviorally, TMX at 500 microg had the effect of increasing the amount of time spent in the center of the cage. Taken together these results demonstrate: (1) EB and TMX at relatively low doses can exert a neuroprotective effect against MA; (2) these neuroprotective effects of EB and TMX can occur in the absence of an effect upon the bioassay parameter--uterine weights; (3) the parameter of DOPAC/DA ratio may indicate a more sensitive index of NSDA neuroprotection, and (4) modulatory effects of EB and TMX upon acute behavioral responses of the NSDA system to MA can be distinguished from their neuroprotective actions.

3,4-Dihydroxyphenylacetic Acid↗

Hippocampal asymmetry in the behavioral responses to the 5-HT1A receptor agonist 8-OH-DPAT.

The present study examined the behavioral responses of rats to unilateral and bilateral injections of the selective serotonin 1A (5-HT1A)-receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) 1 microgram into the hippocampal CA1 area of male Wistar rats. 8-OH-DPAT increased locomotor activity, which was most pronounced with injections into the left hippocampus. The agonist impaired learning and memory (shuttle-box), especially when injected into the right hippocampus. The elevated plus-maze experiments showed that neither left nor right nor bilateral hippocampal injections of 8-OH-DPAT produced any anxiogenic effect. However, with Vogel's conflict test, right injections of 8-OH-DPAT produced anxiety. The present study has revealed hippocampal asymmetry in the behavioral responses to the 5-HT1A-receptor agonist 8-OH-DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Characterizing the pH-responsive behavior of thin films of diblock copolymer micelles at the silica/aqueous solution interface.

The pH-responsive behavior of cationic diblock poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-(diethylamino)ethyl methacrylate) copolymer micelles adsorbed at the silica/aqueous solution interface has been characterized. The micellar morphology of this copolymer, initially adsorbed at pH 9, can be dramatically altered by lowering the solution pH. The original micelle-like morphology of the adsorbed copolymer chains at pH 9 completely disappears as the pH is decreased to 4, and a brush-like layer structure is produced. This change results from protonation of the copolymer chains: the subsequent electrostatic repulsions within the film drive the copolymer chains to expand into the aqueous phase. Returning the solution pH from 4 to 9 causes this brush-like layer to collapse, with atomic force microscopy images suggesting degradation of the film. Hence, the pH-responsive behavior of the copolymer film exhibits irreversible morphological changes. Measurements of the adsorbed/desorbed amounts of the copolymer film were conducted using both a quartz crystal microbalance with dissipation monitoring (QCM-D) and optical reflectometry (OR). After an initial rinse at both pH values, the OR adsorbed mass becomes almost constant during subsequent pH cycling, whereas the corresponding QCM-D adsorbed mass changes significantly but reversibly in response to the solution pH. Since the QCM-D measures a bound mass that moves in tandem with the surface, the discrepancy with the OR data is due to changes in the amount of bound water in the copolymer film as a result of the pH-induced changes in surface morphology. The larger effective mass observed at pH 4 suggests that the brush-like layer contains much more entrapped water than the micellar films at pH 9. The pH dependence of the contact angle of the adsorbed film is consistent with the changes observed using the other techniques, regardless of whether the solution pH is altered in situ or the aqueous solution is completely replaced. In fact, comparison of these two approaches provides direct evidence of the exposure of adsorbed micelle core blocks to the solution during pH cycling and the concomitant impact upon all the other measurements.

Journal Article↗

The effects of sex steroids and vasotocin on behavioral responses to visual and olfactory sexual stimuli in ovariectomized female roughskin newts.

Previous studies have found that vasotocin (AVT) administration to male roughskin newts (Taricha granulosa) enhances courtship clasping as well as appetitive responses to specific sexual stimuli and that treating female newts with androgens plus AVT induces the expression of male-typical courtship clasping (the selective clasping of females). However, the unique and/or interactive effects of sex steroids and AVT on appetitive responses to specific sexual stimuli have not yet been determined. To first identify male-typical, sexually dimorphic appetitive responses to female sexual stimuli, we tested intact newts during the breeding season and found that males, but not females, are attracted to female visual and pheromonal sexual stimuli. We then used ovariectomized (ovx) females implanted with empty silastic capsules (Blk) or with capsules containing testosterone (T), dihydrotestosterone (DHT), or estradiol (E2) and then injected with either saline or AVT to determine the effects of steroids and AVT, alone or in combination with each other, on male-typical behavioral responses to those stimuli. E2 treatment depressed responses toward female visual stimuli independently of AVT. On the other hand, only T-implanted, AVT-injected females displayed male-typical behavioral responses toward female olfactory stimuli, preferring to spend more time in proximity to female-scented than unscented newt models and selectively clasping the female-scented models. Together, these results support the conclusion that sex steroids and AVT influence behavioral responses to sexual stimuli via sensory-specific mechanisms. Furthermore, they suggest that T and AVT interact within the brain to influence sensorimotor processing in the pathways that integrate olfactory sexual stimuli into male-typical courtship behaviors.

Animals↗

Effect of maternal presence on the cardiac and behavioral responses to shock in rats as a function of age.

In two experiments the effects of the presence of an anesthetized lactating dam on the developing rat's response to a series of mildly painful shocks was examined. Both cardiac and behavioral responses to the shock stimulus were recorded. In the first experiment animals were tested at either 16, 20, or 24 days of age. The presence of the anesthetized dam markedly reduced the behavioral response to shock of the 16-day-old but not the older rats. A similar pattern of results was obtained with the shock-elicited tachycardia. The second experiment replicated these results with the 16-day-old rat and also demonstrated that being shocked in the presence of a lactating dam influences the animal's reaction to a subsequent series of shocks given when it is alone. The results of these two experiments are discussed in terms of other studies that have examined the influence of maternal presence on the developing animal's response to stressful or painful stimuli.

Aging↗

Differential neuroendocrine and behavioral responses to cocaine in Lewis and Fischer rats.

Lewis (LEW) and Fischer 344 (F344) rats differ in responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis as well as in their behavioral responses to drugs of abuse. The present experiments were conducted to compare hypothalamic corticotropin-releasing factor (CRF), plasma adrenocorticotropic hormone (ACTH) and plasma corticosterone (CS) responses to cocaine (0-60 mg/kg, i.p.) in LEW and F344 rats. Acute administration of cocaine resulted in decreases in CRF and dose-related increases in CS and ACTH with significant differences observed between the strains. Cocaine also increased plasma norepinephrine concentrations. Although the CS response was increased in the F344 compared to LEW rats, the percent change in the CS response was markedly enhanced in LEW rats. Plasma ACTH concentrations as well as the percentage of the control response were dramatically increased at the 40 mg/kg cocaine dose in the LEW compared to F344 rats. Since cocaine-induced changes in HPA axis activity may contribute to behavioral responses to cocaine, another experiment was performed to compare the locomotor responses to novelty and to acute cocaine between LEW and F344 rats. Strain differences were not observed in the locomotor response to novelty or to cocaine. These data indicate that strain differences exist in the neuroendocrine response to acute cocaine exposure.

Adrenal Cortex↗