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.

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.

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.

An automated method for studying stereotyped gnawing.

Stereotyped behavior in rats, consisting of compulsive, repetitive sniffing and gnawing, caused by high doses of amphetamine-like psychostimulants, may serve as an animal model for psychosis. Previous methods for measuring behavioral stereotypies of this kind have required continuous observation and rating of the behaviors or semiquantitative techniques that fail to produce a continuous record of the behaviors. The present paper describes a simple automated method that provides a continuous quantitative record of the specific gnawing behavior induced in rats by methylphenidate, an amphetamine-like psychostimulant. The apparatus described and the test procedures developed are compatible with a wide variety of common counters and recorders.

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.

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.

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.

Tonic analgesic effects of delta 9-tetrahydrocannabinol as measured with the formalin test.

The analgesic effects of delta 9-tetrahydrocannabinol (THC), the psychoactive component of marihuana, were tested using the formalin test. Rats were treated with either THC (5 mg/kg or 10 mg/kg) or a placebo by gavage 4 h before the formalin test for analgesia was initiated. THC produced a highly significant analgesic effect against both phasic pain and tonic pain. THC is discussed as a model for the development of new analgesics or as a suitable analgesic if used with another potentiating drug.

Nicotine and cannabinoids as adjuncts to neuroleptics in the treatment of Tourette syndrome and other motor disorders.

Animal studies suggest nicotine and cannabinoids may significantly enhance the therapeutic value of neuroleptics in motor disorders. This was recently demonstrated in humans by the finding that chewing nicotine gum produced striking relief from tics and other symptoms of Tourette syndrome not controlled by neuroleptic treatment alone. It appears that the use of nicotine or cannabinoids may greatly improve the clinical response to neuroleptics in motor disorders.

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.

Effect of cobra neurotoxin on retention of a brightness discrimination in rats.

In view of some recent evidence that blockade of nicotinic acetylcholine receptors might interfere with memory recall, the possibility that intracranial injections of purified corbra neurotoxin, an irreversible nicotinic receptor blocker, would produce long-lasting amnesia was explored with a brightness discrimination habit in rats. The results indicate that even the highest tolerable dose of neurotoxin had no detectable effect on memory recall.

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.

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.

Tetrahydrocannabinol potentiates reserpine-induced hypokinesia.

Delta-9-tetrahydrocannabinol (THC), a substance in marihuana, was found to produce a profound potentiation of reserpine-induced hypokinesia in rats as measured with a bar test. In these experiments, THC had no hypokinetic effect by itself but produced a more than 20-fold increase in the hypokinesia produced by reserpine. Reserpine-induced hypokinesia has been viewed as animal model of Parkinson's Disease. THC potentiation of reserpine-induced hypokinesia was observed to be both time- and dose-dependent (1 to 10 mg/kg THC). When administered by gavage to reserpine-pretreated subjects (7.5 mg/kg IP, 24 hours before), THC produced a potentiation of hypokinesia that developed fully within 1 hour, lasted at least 5 hours, and was absent by 12 hours after THC administration. This THC effect was slightly increased by physostigmine, a cholinesterase inhibitor, relatively unaffected by scopolamine, a muscarinic antagonist, and almost completely blocked by ethopropazine, an anticholinergic antiparkinson drug. The effect was completely unaffected by naloxone. Insofar as reserpine has been used with some clinical efficacy in hyperkinetic movement disorders such as Huntington's disease and tardive dyskinesia, it may be that potentiation of reserpine's hypokinetic effect by a drug such as THC could greatly increase the clinical value of reserpine or related drugs in the treatment of these disorders.

Tetrahydrocannabinol and acetylcholinesterase.

Recent evidence suggests that the psychoactive effect of delta-9-tetrahydrocannabinol (delta9-THC), the major psychoactive constituent of marihuana, may be mediated through an alteration of cholinergic neurotransmission. One possible mechanism by which delta9-THC could have its effect is by affecting acetylcholinesterase (AChE) and there is evidence that has suggested that this may be an important mechanism. The results reported in the present study have shown that there is no physiologically important interaction between AChE and delta9-THC or its metabolites that could explain its psychoactive effects or the profound clinical depression observed when human marihuana users are administered the cholinesterase inhibitor physostigmine.

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.

Comparative behavioral effects of CNS cholinesterase inhibitors.

Phenylmethanesulfonyl fluoride, methanesulfonyl fluoride, and physostigmine were compared on the efficacy with which each could suppress methylphenidate-induced stereotyped gnawing, an extrapyramidal motor behavior. Whereas physostigmine produced powerful suppression of the stereotypy, the sulfonyl fluorides did not produce any clear behavioral effect. Biochemical experiments conducted with the behavioral tests demonstrated that the sulfonyl fluorides produced inhibition of whole brain, caudate, cortex, cerebellum, hippocampus and brain stem cholinesterate equal to that produced by physostigmine. The reason for the marked discrepancy between the behavioral effect of physostigmine and the sulfonyl fluorides is unknown. It is, however, clear that the effect of the various drugs on extrapyramidal motor behaviors is not a simple function of the degree to which each inhibited CNS cholinesterase.

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.

Perioral behaviors induced by cholinesterase inhibitors: a controversial animal model.

Perioral behaviors induced by neuroleptic drugs have been interpreted as an animal model of tardive dyskinesia. However, these behaviors have also been induced or enhanced by physostigmine, a cholinesterase inhibitor. The latter result is contradictory to the clinical effect of physostigmine in human tardive dyskinesia. In view of this contradiction and other considerations, perioral behaviors have also been interpreted as a model of acute dystonia. The present experiments replicated an earlier failure to observe spontaneous perioral behaviors after long-term neuroleptic treatment in rats as well as the paradoxical effect of physostigmine. The effect of physostigmine was also compared to phenylmethanesulfonyl fluoride and methanesulfonyl fluoride, irreversible CNS active cholinesterase inhibitors. There were significant differences between the effects of the various cholinesterase inhibitors and their interactions with perioral behaviors and neuroleptic treatment. It is concluded that the effects of cholinesterase inhibitors on perioral behaviors in rodents may not be accounted for entirely by cholinesterase inhibition. Further experiments using additional agonists and antagonists will be required to clarify the behavioral effects of these cholinesterase inhibitors.