Circadian-dependent effect of melatonin on dopaminergic D2 antagonist-induced hypokinesia and agonist-induced stereotypies in rats.

Although a melatonin/dopamine relationship has been well established in nonmotor systems wherein dopamine and melatonin share an antagonist relationship, less clear is the role melatonin may play in extrapyramidal dopaminergic function. Therefore, the purpose of the present experiments was to examine the relationship between melatonin and the dopaminergic D2 receptor system and behavior. Hypokinesia was induced in male Sprague-Dawley rats with fluphenazine (D2 antagonist, 0.4 mg/kg ip) and stereotypies with apomorphine (D2 agonist, 0.6 mg/kg sc) during the light (1200 h) and dark (2200 h) phases. As expected, fluphenazine induced severe hypokinesia during the light phase (482 +/- 176 s); however, unexpectedly, fluphenazine-induced hypokinesia during the dark was almost nonexistent (25 +/- 6 s). Furthermore, melatonin treatment (30 mg/kg ip) produced a strong interaction with fluphenazine in that it reduced fluphenazine-induced hypokinesia by nearly 80% in the light (112 +/- 45 s) but paradoxically increased the minimal fluphenazine-induced hypokinesia in the dark by more than 60% (70 +/- 17 s). Melatonin also reduced apomorphine-induced stereotypies by nearly 40% in the light but had no effect in the dark. Taken together, these data show (1) a strong and unexpected nocturnal effect of fluphenazine on hypokinesia and (2) provide support for an antagonistic melatonin/dopaminergic interaction in the context of motor behavior and D2 receptor function which appears to be critically dependent on the light/dark status of the dopaminergic system.

Bright light treatment decreases depression in institutionalized older adults: a placebo-controlled crossover study.

BACKGROUND: An important parallel exists between patients with seasonal affective disorder and institutionalized older adults. Many older patients, as a result of global physical decline and immobility, are confined to their rooms, experiencing little natural sunlight. Thus, institutionalized older adults are at risk for chronic light deprivation. Testing the hypothesis that chronic light deprivation might be responsible, at least in part, for some depression among institutionalized older adults, the aim of this study was to investigate the efficacy of morning bright light treatment on depression among older adults residing in a long-term care facility. METHODS: In a placebo controlled, crossover design, participants (N = 10, six women and four men; M age = 83.8) received each of the following: (i) 1 week (5 days) of 10,000 lux (therapeutic dose); (ii) 1 week (5 days) of 300 lux (placebo); or 1 week of no treatment (control). Each week of light treatment was 5 consecutive days, 30 minutes daily, with a wash-out period consisting of 1 week between conditions. RESULTS: Geriatric Depression Scale (GDS) scores at baseline during all treatment conditions were positively correlated (r = .81, p < .01) with months of institutionalization, where participants with higher GDS scores experienced more time institutionalized. Scores on the GDS remained unchanged during the placebo and control conditions, but depression scores decreased significantly during the 10,000 lux treatment (pretest GDS M = 15 vs posttest GDS M = 11, p < .01). After the 10,000 lux treatment, 50% of the participants no longer scored in the depressed range. Improvement during the 10,000 lux condition was positively correlated (r = .62, p < .05) to baseline GDS scores, where participants with higher GDS scores experienced greater improvement following the 10,000 lux treatment. CONCLUSIONS: The results of the present study suggest that bright light treatment may be effective among institutionalized older adults, providing nonpharmacological intervention in the treatment of depression. Furthermore, the length of institutionalization may play an important role in determining the efficacy of bright light treatment for older adults in the nursing-home setting.

Relation of Dieting in College and High School Students to Symptoms Associated with Semi-starvation.

Dieting and concern with weight were found to be associated with psychological and neurological symptoms observed in cases of severe semi-starvation. College students of both sexes (n 292) and high school females (n121) rated themselves on dietary restraint and psychological and physical symptoms that were prevalent in men after 24 weeks in the Minnesota semi-starvation experiment of 1944-5. Apprehension, irritability, and moodiness were associated with a high concern with restraint. Blank spells, hunger pain, concern for health, and social withdrawal were associated with a history of restraint. Depression, lower self-esteem, eating behavior patterns, apathy, and decreased motivation were associated with both restraint parameters. Our results suggest that normal dieting may be more closely related to psychological and health risks associated with chronic semi-starvation than is commonly believed.

Methanesulfonyl fluoride (MSF): a double-blind, placebo-controlled study of safety and efficacy in the treatment of senile dementia of the Alzheimer type.

The purpose of the present study was to evaluate methanesulfonyl fluoride (MSF), a very long-acting CNS-selective acetylcholinesterase (AChE) inhibitor, as a palliative treatment for senile dementia of the Alzheimer type (SDAT). In experiment I, MSF (0.03-0.18 mg/kg) was administered orally to 10 normal volunteers to measure toxicity and establish dose/response function in erythrocyte AChE. MSF produced a dose-response function of %inhibition = (40)(Log10[MSF mg/kg] + 51.7) with no toxicity at these doses. Experiment II was a 16-week double-blind, placebo-controlled study of the safety and efficacy of MSF in doses of up to 0.18 mg/kg given three times per week in 5 men and 10 women (60-82 years), with Mini-Mental State Examination (MMSE) scores of 9-24, who had SDAT. MSF produced a mean of 89.5% inhibition of erythrocyte AChE in patients and improved cognitive performance as measured by the MMSE, Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-COG), Global Deterioration Scale, and the Clinical Interview Based Impression of Change (CIBIC). Most of the improvement on the ADAS-COG was maintained 8 weeks after ending MSF. No patients left the study because of drug-related adverse events and there were no toxic effects. MSF may be a safe and effective palliative treatment for SDAT and further clinical trials in larger groups of patients are warranted.

Semistarvation-associated eating behaviors among college binge eaters: a preliminary description and assessment scale.

Binge eating is a consequence of semistarvation in victims of war and famine and in volunteers in rare semistarvation experiments. These behaviors include bizarre mixing of ingredients and adulteration of food; eating inappropriate, soiled, or discarded food; secrecy; deception; and defensiveness. Drastic measures to resist overeating persist long after the semistarvation experience, even when food is plentiful. Binge eating, a central feature of bulimia and sometimes of anorexia nervosa, is prevalent in modern society, but the occurrence and frequency of semistarvation-related behaviors have not been well identified or quantified. A Semistarvation-Associated Behaviors Scale was constructed and administered to 40 college students. Among binge eaters, reports of bizarre semistarvation-like behaviors were common and frequent and were associated with dieting.

The effect of hypothalamic peptide YY on hippocampal acetylcholine release in vivo: implications for limbic function in binge-eating behavior.

Central injection of peptide YY (PYY) in sated rats produces the most powerful stimulating effect of food intake known to date. The neural mechanisms by which PYY regulates appetite are not clear but may be important because abnormal levels of PYY have been implicated in the neurobiology of bulimia nervosa. Interactions between brain acetylcholine (ACh) and PYY had not been studied. Therefore, the present experiments were designed to explore the in vivo release of ACh from the hippocampus (HPC) of rats in response to hypothalamic infusion of PYY. Hippocampal ACh release was found to increase 400% in response to 10 microg PYY. In a separate experiment, blockade of the same area of the HPC with bilateral intracerebral injections of 3.5 microg scopolamine did not affect intake stimulated by intrahypothalamic injection of 4 microg PYY. Furthermore, a third experiment showed, for the first time, that PYY (2.5-10.0 microg) can elicit robust feeding when infused directly into the HPC. The significance of these findings to the activation of limbic functions such as memory, reinforcement, and obsessional processes that accompany human binge-eating syndromes is discussed.

Persistence of binge-eating patterns after a history of restriction with intermittent bouts of refeeding on palatable food in rats: implications for bulimia nervosa.

OBJECTIVE: To test the hypothesis that experience with food restriction produces persistent binge eating. The Minnesota semistarvation experiment and studies of prisoners-of-war show that chronic food restriction produces dramatic changes in eating behavior (including binge eating) that endure decades after restriction has ceased. Bulimia nervosa patients who restrict also binge. Restriction may be a risk factor in the etiology of binge eating and bulimia. METHOD: Animals were subjected to four different patterns of 12-week restriction-refeeding cycles. The rats were either food restricted (dieting) or not restricted and refed regular or palatable food (binging). RESULTS: Thirty days after normalization (full feeding, no restriction cycling), rats with a history of cycles of restriction and hyperphagia continued to exhibit persistent binge eating. This effect was shown particularly with palatable food, in stated conditions, and in response to acute 24-hr deprivation. DISCUSSION: Results from this animal model implicate restriction and overeating on palatable food as biological determinants of binge-eating behaviors, including bulimia nervosa.

Combined naloxone and fluoxetine on deprivation-induced binge eating of palatable foods in rats.

Opioid antagonism and serotonergic stimulation is associated with macronutrient-specific hypophagia in animals. In the present study we evaluated their systemic effect alone, and in combination, at various doses, on the intake of sweet carbohydrate-rich and sweet fat-rich foods, tastes, and nutrients that are typical of binge-food items. Low-dose (1 mg/kg) naloxone, alone, preferentially suppressed fat-rich intake while low-dose (2.5 mg/kg) fluoxetine, alone, preferentially suppressed carbohydrate-rich intake. Each drug at these doses, combined with various doses of the other (2.5-10 mg/kg fluoxetine; 0.01-1 mg/kg naloxone) additively suppressed both kinds of the sweet foods. Naloxone and fluoxetine have therapeutic potential in treating binge-eating disorders. This animal study suggests what shortcomings and benefits might be expected when combining these two agents.

Effect of peptide YY (PYY) on food-associated conflict.

Peptide YY (PYY) administered centrally in rats induces powerful overeating. PYY also occurs endogenously in humans and is elevated in abstaining bulimic patients. To examine the effect of PYY in an environment that parallels some aspects of bulimia, rats were tested in a paradigm associated with approach-avoidance behavior, choosing a preferred (sweet) food paired with shock, over regular food safe from shock. PYY-treated rats chose to sustain shock to retrieve and consume the preferred food, at a significantly greater speed and quantity. The number of approaches that were met without retrieval of food due to anxiety after PYY treatment indicates that PYY increased motivation towards feeding, rather than anxiolysis. This effect of PYY in a model of conflict associated with food choice resembles aspects of bulimic binge-eating, which is characterized by the repetitive, rapid intake of food, despite anxiety associated with this behavior.

Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase.

One consistent finding in senile dementia of the Alzheimer's type is that the brain has reduced ability to synthesize acetylcholine. This has been related, in part, to memory dysfunctions. Although a cholinergic deficit is not singularly responsible for symptoms of dementia, treatment strategies have been designed to facilitate cholinergic activity by inhibiting acetylcholinesterase (AChE). To minimize toxicity, however, a cholinesterase inhibitor selective for only AChE would be an ideal treatment. The purpose of this study was to determine the selectivity of physostigmine, metrifonate, methanesulfonyl fluoride and tetrahydroaminoacridine (tacrine) toward AChE as compared with butyrylcholinesterase (BChE) in human cortex. The results show that methanesulfonyl fluoride is selective as an inhibitor of AChE as compared with BChE. Physostigmine inhibited AChE more than BChE. Metrifonate was found to inhibit BChE more than AChE. Tetrahydroaminoacridine inhibited both enzymes in a complex way.

Differential effects of Tyr-MIF-1, MIF-1, and naloxone on peptide YY-induced hyperphagia.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and MIF-1 (Pro-Leu-Gly-NH2) act as opiate antagonists in various behavioral systems including ingestion. Central injection of peptide YY (PYY) elicits a powerful feeding response in satiated rats, and the opioid antagonist naloxone decreases eating in a variety of conditions including PYY-stimulated eating. Therefore, the aim of this study was to examine the effects of Tyr-MIF-1 and MIF-1 as opiate antagonists on a naloxone-sensitive PYY model of hyperphagia. Naloxone at doses of 1.0 and 10.0 mg/kg, SC, decreased hyperphagia induced by 2.4 micrograms PYY injected in the PVN. MIF-1 and Tyr-MIF-1 had no effect on PYY-induced eating at doses comparable to naloxone (0.1 to 10.0 mg/kg, IP). These results suggest that in this model of eating behavior, Tyr-MIF-1 and MIF-1 do not act as opiate antagonists.

Suppression of peptide YY-induced hyperphagia by terbutaline.

Central administrations of neuropeptide Y and peptide YY (PYY) produce robust increases in food intake, and this response may be contingent upon the availability of insulin. In contrast, beta 2-adrenergic agonists decrease food intake, and this effect also appears to be dependent on circulating insulin. To investigate a possible interaction between PYY and beta 2-adrenergic function, rats were given systemic injections of terbutaline, a beta 2 agonist, at doses of 0, 5, 10, and 50 mg/kg prior to injections of 0.57 nmol PYY in the paraventricular nucleus of the hypothalamus. Terbutaline pretreatment significantly decreased feeding elicited by PYY in a dose-dependent fashion. This suggests that beta 2-adrenoreceptor activity is involved in PYY-induced feeding.

Effect of naloxone and antidepressants on hyperphagia produced by peptide YY.

Central injection of peptide YY (PYY) elicits a powerful feeding response with a short latency in satiated rats. Because of this effect, PYY has been implicated as a neurochemical signal in bulimia nervosa. Serotonin agonists and opioid antagonists induce anorectic effects upon feeding behavior in humans and animals. Therefore, to investigate a possible interaction between PYY-induced eating and these anorexigenic agents rats were given injections of either naloxone (100 micrograms/3 microliters, ICV, and 10 mg/kg, SC), fluoxetine (3-30 micrograms/3 microliters and 5-10 mg/kg, IP), or clomipramine (3-30 micrograms/3 microliters and 5-10 mg/kg, IP) prior to fourth ventricular injections of PYY (15 micrograms/18 microliters). Central and peripheral naloxone and IP but not central injections of fluoxetine blocked PYY-induced intake. Clomipramine had no effect. This suggests that PYY-stimulated feeding may require the action of endogenous opioids and may be inhibited by serotonergic function.

Chronic methanesulfonyl fluoride enhances one-trial per day reward learning in aged rats.

Aged (24-month-old) rats were treated chronically with methanesulfonyl fluoride (MSF), an acetylcholinesterase (AChE) inhibitor with selectivity for central nervous system AChE, or with injection vehicle alone. Twelve 0.22 mg/kg IP injections were given over 4 weeks. MSF rats showed significantly greater speed and accuracy on a 1 trial/day discriminative reward learning task. The chronic MSF treatment resulted in a 56% decrease in brain AChE activity but no discernable locomotor side effects and no liver damage as indicated by aspartate transferase activity.

Methanesulfonyl fluoride (MSF) blocks scopolamine-induced amnesia in rats.

Cholinesterase inhibitors, such as physostigmine and tetrahydroaminoacridine, have been found to alleviate some of the memory deficits characteristic of senile dementia of the Alzheimer's type (SDAT). Many toxic side effects, however, have been associated with the use of these compounds. Recently, a cholinesterase inhibitor, methanesulfonyl fluoride (MSF), was discovered to have low toxicity, central nervous system (CNS) selectivity, and a long therapeutic duration. The purpose of this research was to determine if MSF (1.5 mg/kg) would be effective in reducing or blocking amnesia induced by various doses of scopolamine (0.2, 0.6, and 2.0 mg/kg). One hundred and twenty-two female Sprague-Dawley albino rats were trained and retention tested in a Y-maze brightness discrimination task. MSF was highly effective in reducing scopolamine-induced amnesia.

THC does not affect striatal dopamine release: microdialysis in freely moving rats.

The hypothesis that cannabinoids potentiate the motor effects of neuroleptics and produce their abuse potential by stimulating dopaminergic activity was tested by measuring the ability of THC to increase extracellular dopamine concentrations. Male Long-Evans rats were implanted with guide cannulae for the striatum or nucleus accumbens. Fifteen hours prior to testing, removable microdialysis probes were inserted through the guide cannulae. Dialysis samples were collected during resting baseline, after 1.0 mg/kg, 10 mg/kg THC, or vehicle of olive oil with 5% ETOH (by gavage) followed by amphetamine (1.5 mg/kg) or fluphenazine (0.3 mg/kg). THC produced no change in the extracellular concentrations of DA, DOPAC, and HVA, nor in 5-HIAA. THC also had no effect on the enhancement of extracellular DA produced by amphetamine nor on the transient increase in DA, DOPAC, and HVA produced by fluphenazine. There were also no behavioral differences between groups during any of these treatments.

An animal model of bulimia nervosa: opioid sensitivity to fasting episodes.

A group of female rats was deprived and maintained at 75-80% of body weight at three different times during development. Following recovery to normal weight, food intake was measured with and without butorphanol tartrate, a kappa-sigma agonist, 8 mg/kg SC. Animals with a history of deprivation (DEP) showed an increase in postrecovery feeding when they were tested at normal body weight and not food deprived. More importantly, butorphanol prolonged food intake in the 3-h eating test only in the rats with a developmental history of food restriction. A developmental history of fasting in eating disorders may trigger changes in opiate systems that result in atypical feeding behavior in the adult.

Simple spectrophotometric assay for calcium-activated neutral proteases (calpains).

A simple spectrophotometric assay for calcium-activated neutral proteases (calpains) is a simple modification of other popular spectrophotometric assays using casein substrate and precipitation by trichloroacetic acid (TCA). The assay presented here, however, uses azocasein as substrate, and activity is measured by the amount of azo chromophore that remains in solution after TCA precipitation. Because the chromophore is specific to the substrate and the azo substrate absorbs strongly, this assay provides improved spectrophotometric performance in a practical and sensitive procedure.

Methanesulfonyl fluoride enhances one-trial reward learning in mid-aged rats.

In previous studies, 18-month-old rats have shown no significant retention 24 hours after the single acquisition trial in a one-trial discriminative reward learning task. In the present study, ten 18-month-old rats pretreated with 0.5 mg/kg MSF IP showed significantly better retention in terms of speed and errors than eleven 18-month-old rats pretreated with injection vehicle alone. However, twelve two-three-month-old rats pretreated with the same dose of MSF failed to show better retention than eleven two-three-month-old rats pretreated with vehicle alone.