D.E. Moss

Hippocampal theta activity and the attention component of discrimination learning

To assess the possibility that the occurrence of hippocampal theta during learning reflects the role of this structure in mediating attention or orienting responses, hippocampal electrical activity was monitored while chronically implanted cats learned and were shifted from a CRF to a cued DRL schedule in an operant conditioning apparatus. The end of the DRL was signaled by the onset of a panel of lights, and it was hypothesized that if theta is a correlate of attention to environmental responses, then as learning progressed and the animals attended to this relevant environmental cue, the incidence of theta between bar-presses should increase. Bennett and Gottfried (1970) previously reported that learning and performance of a noncued DRL are accompanied by hippocampal desynchronization. The results supported the hypothesis, and in conjunction with results previously reported by Bennett and Gottfried the present findings support the notion that the critical difference between those tasks in which learning and performance are correlated with theta versus those accompanied by hippocampal desynchronization is whether the animal can master the problem by attending to environmental cues. Some broader implications of these results for theories of hippocampal functioning are discussed.

Age-impaired impulse flow from nucleus basalis to cortex

Recent studies have renewed interest in the role of acetylcholine (ACh) in the cognitive changes associated with ageing and dementia1–4. Deficits in cortical choline acetyltransferase (ChAT) in Alzheimers disease have been consistently demonstrated5–9, while other research has suggested a connection between deterioration of cortical ACh fibres and dementia4. However, despite clear biochemical and anatomical evidence f or a fall in ACh in dementia1–9, results of therapeutic trials with cholinergic agonists, precursors and cholinesterase inhibitors have been inconsistent6–9. Such findings suggest that cortical cholinergic disorders are not wholly a function of simple biochemical change; alterations of impulse flow along cholinergic fibres could well be as debilitating. An important extrinsic source of cortical ACh innervation derives from neurones diffusely located in rat basal forebrain10–16, denoted the nucleus basalis (NB)15,17. We have now investigated the impulse conduction properties of cortically projecting, putatively cholinergic NB axons in adult and aged rats and have found that conduction latencies from NB to frontal cortex are significantly longer (by 51%) in aged animals. In addition, systematic analysis varying cortical stimulation depth revealed that these longer latencies are due entirely to decreased conduction velocities in the subcortical fibre projections. Indeed, intracortical velocities were virtually identical in the two groups. Our results indicate that ageing occasions a decrease in the temporal fidelity of impulse flow in the cholinergic input to the cortex from the NB, a previously overlooked but potentially important element in cognitive deficits that occur with age.

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 Parkinsons 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 Huntingtons disease and tardive dyskinesia, it may be that potentiation of reserpines 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.

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.

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.

Tonic analgesic effects of Δ9-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.

Kinetic analysis of differences in brain acetylcholinesterase from fish or mammalian sources

Abstract A kinetic analysis of the interactions of gold fish and rat brain AChE (acetylcholine acetylhydrolase, EC 3.1.1.7) with acetylthiocholine substrate and sulfonyl fluoride inhibitors revealed several differences between these enzymes. The fish brain AChE had a K m of 250 μM while the mammalian brain AChE had a K m of 55 μM under the same assay conditions. In addition, the mammalian brain enzyme reacted with methanesulfonyl fluoride at more than three times the rate at which the fish enzyme reacted, and fish AChE did not react with phenylmethanesulfonyl fluoride at a measurable rate while mammalian AChE was found to react rapidly. Leptocurares were found to accelerate methanesulfonylation of both enzymes; however, they inhibited phenylmethanesulfonylation. These results suggest that fish and mammalian AChE may have topographic differences in the vicinity of the anionic portion of the active site.

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.

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.