Rationale A number of tasks are used to assess working memory in rodents, but the Odor Span task (OST) is unique in studying performance as a function of the number of stimuli to remember. Objectives The purpose of the present study was to better characterize the behavioral pharmacology of the OST by exploring the effects of several amnestic agents including an NMDA antagonist (dizocilpine), a positive GABA-A modulator (chlordiazepoxide), an anticholinergic compound (scopolamine) and as a negative control, an opiate receptor agonist (morphine). Methods Rats were trained to perform on the OST which is a non-match-to-sample procedure with an incrementing number of sample odors to remember as the session progresses. Trials with a simple odor discrimination task (SD) were interspersed to provide a control for effects unrelated to memory load. Results All four drugs disrupted performances on the OST task in a dose-dependent fashion, but only the NMDA antagonist dizocilpine produced impairments that were clearly dependent on the number of stimuli to remember. Dizocilpine impaired OST performance at a dose (0.1 mg/kg) that did not affect SD and that impairment depended on memory-load. Chlordiazepoxide (3.0 mg/kg) also produced amnestic effects that were manifest by shorter memory spans and runs of correct responding. In contrast, morphine and scopolamine impaired OST accuracy only at doses that also disrupted SD (18.0 and 0.3 mg/kg, respectively). Conclusions These results provide evidence of NMDA and benzodiazepine modulation of working memory as assessed by the OST.
Men consume the most nicotine and cannabis products but impacts on sperm epigenetics are poorly characterized. Evidence suggests that preconception exposure to these drugs alters offspring neurodevelopment. Epigenetics may in part facilitate heritability. We therefore compared effects of exposure to tetrahydrocannabinol (THC) and nicotine on DNA methylation in rat sperm at genes involved in neurodevelopment. Reduced representation bisulfite sequencing data from sperm of rats exposed to THC via oral gavage showed that seven neurodevelopmentally active genes were significantly differentially methylated versus controls. Pyrosequencing data revealed majority overlap in differential methylation in sperm from rats exposed to THC via injection as well as those exposed to nicotine. Neurodevelopmental genes including autism candidates are vulnerable to environmental exposures and common features may mediate this vulnerability. We discovered that autism candidate genes are significantly enriched for bivalent chromatin structure, suggesting this configuration may increase vulnerability of genes in sperm to disrupted methylation.
As the older class of brominated flame retardants (BFRs) are phased out of commercial use because of findings of neurotoxicity with developmental exposure, a newer class of flame retardants have been introduced, the organophosphate flame retardants (OPFRs). Presently, little is known about the potential for developmental neurotoxicity or the behavioral consequences of OPFR exposure. Our aim was to characterize the life-long neurobehavioral effects of 4 widely used OPFRs using the zebrafish model. Zebrafish embryos were exposed to 0.1% DMSO (vehicle control); or one of the following treatments; isopropylated phenyl phosphate (IPP) (0.01, 0.03, 0.1, 0.3 µM); butylphenyl diphenyl phosphate (BPDP) (0.003, 0.03, 0.3, 3 µM); 2-ethylhexyl diphenyl phosphate (EHDP) (0.03, 0.3, 1 µM); isodecyl diphenyl phosphate (IDDP) (0.1, 0.3, 1, 10 µM) from 0- to 5-days postfertilization. On Day 6, the larvae were tested for motility under alternating dark and light conditions. Finally, at 5-7 months of age the exposed fish and controls were tested on a battery of behavioral tests to assess emotional function, sensorimotor response, social interaction and predator evasion. These tests showed chemical-specific short-term effects of altered motility in larvae in all of the tested compounds, and long-term impairment of anxiety-related behavior in adults following IPP, BPDP, or EHDP exposures. Our results show that OPFRs may not be a safe alternative to the phased-out BFRs and may cause behavioral impacts throughout the lifespan. Further research should evaluate the risk to mammalian experimental models and humans.
The Odor Span Task is an incrementing non-matching-to-sample procedure that permits the study of behavior under the control of multiple stimuli. Rats are exposed to a series of odor stimuli and selection of new stimuli is reinforced. Successful performance thus requires remembering which stimuli have previously been presented during a given session. This procedure has been frequently used in neurobiological studies as a rodent model of working memory; however, only a few studies have examined the effects of drugs on performance in this task. The present experiments explored the behavioral pharmacology of a modified version of the Odor Span Task by determining the effects of stimulant drugs methylphenidate and methamphetamine, NMDA antagonist ketamine, and positive GABAA modulator flunitrazepam. All four drugs produced dose-dependent impairment of performances on the Odor Span Task, but for methylphenidate and methamphetamine, these occurred only at doses that had similar effects on performance of a simple odor discrimination. Generally, these disruptions were based on omission of responding at the effective doses. The effects of ketamine and flunitrazepam were more selective in some rats. That is, some rats tested under flunitrazepam and ketamine showed decreases in accuracy on the Odor Span Task at doses that did not affect simple discrimination performance. These selective effects indicate disruption of within-session stimulus control. Overall, these findings support the potential of the Odor Span Task as a baseline for the behavioral pharmacological analysis of remembering.
Acute effects of methylenedioxymethamphetamine (MDMA), methamphetamine (MA) and methylphenidate (MPD) were studied using a within-subject, repeated acquisition/performance procedure adapted to the Morris Swim Task. To investigate place learning, the acquisition component consisted of a hidden platform that varied in location across experimental sessions. As a control for drug effects not specific to acquisition, a performance component was included in which the hidden platform was in the same pool location in every experimental session. All three drugs increased escape latencies and swim distances in dose-dependent fashion. However, impairment in the acquisition component was generally observed only at doses that also produced impairment in the performance component, suggesting that effects were not selective to place learning. None of the drugs produced enhancement of learning or performance at any dose. Taken together, the results suggest that acute exposure to these psychomotor stimulants produce global impairment of performance in the Morris task, rather than specific deficits in place learning.
The effects of acute and sub-chronic MDMA were assessed using a procedure designed to test rodent working memory capacity: the odor span task (OST). Rats were trained to select an odor that they had not previously encountered within the current session, and the number of odors to remember was incremented up to 24 during the course of each session. In order to separate drug effects on the OST from more general performance impairment, a simple olfactory discrimination was also assessed in each session. In Experiment 1, acute doses of MDMA were administered prior to select sessions. MDMA impaired memory span in a dose-dependent fashion, but impairment was seen only at doses (1.8 and 3.0 mg/kg) that also increased response omissions on both the simple discrimination and the OST. In Experiment 2, a sub-chronic regimen of MDMA (10.0 mg/kg, twice daily over four days) was administered after OST training. There was no evidence of reduced memory span following sub-chronic MDMA, but a temporary increase in omission errors on the OST was observed. In addition, rats exposed to sub-chronic MDMA showed delayed learning when the simple discrimination was reversed. Overall, the disruptive effects of both acute and sub-chronic MDMA appeared to be due to non-mnemonic processes, rather than effects on specific memory functions.
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