George T. Taylor

Low Doses of Memantine Disrupt Memory in Adult Rats

Memantine, a drug recently approved for treatment of Alzheimer’s disease, has been characterized as a unique NMDA antagonist that confers protection against excitotoxic neurodegeneration without the serious side effects that other NMDA antagonists are known to cause. In the present study, we determined what dose of memantine is required to protect the adult rat brain against an NMDA receptor-mediated excitotoxic process and then tested that dose and a range of lower doses to determine whether the drug in this dose range is associated with significant side effects. Consistent with previous research, we found that memantine confers a neuroprotective effect beginning at an intraperitoneal dose of 20 mg/kg, a dose that we found, contrary to previous reports, produces locomotor disturbances severe enough to preclude testing for learning and memory effects. We then determined that, at intraperitoneal doses of 10 and 5 mg/kg, memantine disrupts both memory and locomotor behaviors. Rats treated with these doses performed at control-like levels in learning a hole-board task but were significantly impaired in demonstrating what they had learned when tested 24 h later. This impairment of memory retention was not state dependent in that it was demonstrable regardless of whether the rats were or were not exposed to memantine on the day of retention testing. We conclude that, in the adult rat, memantine behaves like other NMDA antagonists in that it is neuroprotective only at doses that produce intolerable side effects, including memory impairment.

Effect of ovarian steroids on footshock avoidance learning and retention in female mice

Mice were trained to avoid footshock in a T-maze, with retention tested one week later. Adult male CD-1 mice made their first avoidance during acquisition after fewer trials than random cycling females and with less variability. Female mice in diestrus, when plasma levels of progesterone are low, learned to avoid footshock faster than females in estrus. Ovariectomized (OVX) mice learned in fewer trials than intact random cycling mice. Similar differences, though of a smaller magnitude, were found on the retention tests (i.e. males had better retention than females, mice in diestrus showed better retention 8 days later when in the same part of the estrous cycle than those in estrus, and OVX mice had better retention than cycling females). OVX mice with estrogen implants learned faster than those with progesterone implants or progesterone plus estrogen implants. Hormonal status did not affect sensitivity to acoustic or footshock stimuli as measured by a startle reflex, nor did it affect activity. Pretraining administration of amphetamine, picrotoxin and strychnine attenuated the impairing effect of progesterone on acquisition. The possibility that progesterone may impair learning and to some extent, retention by facilitating the GABAergic activity and thereby reducing arousal level is discussed.

Male rat behavior, endocrinology and reproductive physiology in a mixed-sex, socially stressful colony

Previous research suggests that social stress in the absence of females disrupts male reproductive functioning. The presence of females often increases intermale aggression and, presumably, the probability that fighting----social stress----hyperadrenalism----reproductive disruption. Colony membership of male rats was manipulated in the present research to provoke high or low aggression and the consequent environments that were characterized as high or low socially stressful. The principle comparisons were between all-male and mixed-sex colonies. Results were that the presence of females predictably increased aggressive behavior in both high and low stress environments, yet the adrenal response was different in the two environments. When females were present, adrenal weights and circulating corticosterone levels of males increased in the low stress setting but decreased in the high stress setting. Males cohabitating with females in both environments, on the other hand, experienced elevated titers of circulating testosterone, increased activity of various androgen-sensitive tissues and greater epididymal sperm reserves. The conclusion is that the profound changes in males with sexual contact can attenuate the stress----reproductive disruption relationship.

Individual odours and mating success in the golden hamster, Mesocricetus auratus

Abstract Abstract. This study tested (1) whether female golden hamsters can detect individual differences in the odours of conspecific males, and (2) whether a females exposure to individually distinctive male odours can facilitate mating success. In experiment 1, a habituation-discrimination paradigm showed that females can distinguish individual differences in the odours of flank gland secretions, urine, faeces, and soiled bedding from males. In experiment 2, four groups of females were exposed to male odours (soiled bedding) or to no odours (clean bedding) for 30 min per day for 10 days. Females then were tested in dyadic encounters with males, and aggressive and sexual behaviour patterns were recorded. Group 1 females were exposed to the odours of one male, then tested with the same male. Group 2 females were exposed to the odours of one male but tested with a different male. Group 3 females were exposed to the odours of 10 different males then tested with another unfamiliar male. Group 4 females were not exposed to any male odours and were tested with an unfamiliar male. Group 1 females showed lower levels of aggression and higher levels of sexual behaviour than did females in the other groups. Pregnancy rates were similar among the groups, but group 1 females produced significantly larger litters than did females in the other groups. These results suggest that mammalian scent marking may have important sexual functions, and that a females familiarity with the individual odours of a conspecific male may facilitate mating and affect reproductive success.

Norepinephrine modulation of social memory: evidence for a time-dependent functional recovery of behavior.

We tested the hypothesis that central nervous system (CNS) norepinephrine (NE) modulates the ability of an adult male rat to remember significant novel stimuli. Behavioral tests evaluated NE effects on general exploration and social memory. Results were that neither depletion nor elevation of NE impaired general exploration. Findings from the social memory setting suggested that animals tested 2 weeks after NE depletion were unable to discriminate novel from familiar juveniles in situations where untreated controls had no difficulty. Elevation of CNS NE, conversely, produced improved discrimination performance compared with control animals. Results suggest that activation of the CNS NE system is involved in the memory for novel stimuli. Performance of the NE-depleted group tested 3 months after treatment indicates a time-dependent functional recovery can occur in the presence of virtually total CNS NE depletion.

Testosterone in a Cyclodextrin-Containing Formulation: Behavioral and Physiological Effects of Episode-like Pulses in Rats

Testosterone, administered in the form of an inclusion complex with 2-hydroxypropyl-β-cyclodextrin by subcutaneous injection, enters the circulation in a manner markedly similar to the natural episodic release by the testes. The effects of a regimen of once-a-day administration of complexed testosterone to adult (castrated or intact) rats and to senescent (intact) rats were investigated. Although this procedure left the castrated animals with concentrations of circulatory hormone far below physiological levels for much of the day, a significant improvement in androgen-sensitive behavior and physiology was obtained. Furthermore, the testosterone effects were more pronounced when high doses were used periodically rather than when the same total amount of testosterone was equally divided among doses. The same supplementation to intact rats intensified androgen-sensitive behavior and physiology over normal levels. In senescent rats uniform pulses of the testosterone complex also improved behavior and physiology. Specifically, spermatogenesis was stimulated and, notably, the treatment increased muscle weight without substantial enlargement of the prostate. Since the testosterone–cyclodextrin complex also can be effectively administered as a sublingual tablet, the data suggest that similar regimens may be recommended for elderly men suffering from decreases in muscle mass.

Chronic fluoxetine suppresses circulating estrogen and the enhanced spatial learning of estrogen-treated ovariectomized rats.

We are interested in developing animal models to evaluate cognitive processes as influenced by the interplay of steroidal hormones and drugs commonly used in psychotherapy. Two experiments with female rats were conducted to evaluate the interaction of estrogen with the serotonin specific reuptake inhibitor (SSRI) fluoxetine on spatial learning and memory and on the endocrine system. In experiment 1, estrogen (50 microg estradiol benzoate/kg body weight) was administered SC to young adult, ovariectomized (OVX) rats either alone or in combination with fluoxetine (2 mg/kg SC). After a month, the groups were compared with appropriate OVX and gonadally intact controls on trials to criterion in a hole board spatial memory task using massed training trials. Experiment 2 was a dose-response study of the influence of fluoxetine (0.5-5 mg/kg) on circulating estrogen in OVX, estrogen treated females. Results were that the OVX females administered estrogen only reached the learning criterion significantly faster than the other groups. All other groups, including the estrogen + fluoxetine animals, performed no better than the controls. Combining fluoxetine with estrogen also lowered circulating estrogen titers, with the least estrogen reductions being in the group receiving the highest dosage of fluoxetine. No differences among groups were found on measures of activity in an open field or for anxiety in a plus maze. Conclusions were that administration of estrogen improved spatial learning and memory in OVX rats, whereas concurrent fluoxetine exposure suppressed the levels of estrogen in circulation and eliminated the gains in spatial performance obtained from chronic estrogen exposure.

The effects of chronic corticosterone on memory performance in the platform maze task

Acquisition and reversal of a memory task dependent on hippocampal integrity were assessed in rats following chronic corticosterone treatment. Young adult male rats were injected daily with corticosterone (10 mg/kg, SC) for 8 weeks. Memory was assessed during the last week of treatment with an elevated platform maze. During acquisition trials, corticosterone-treated rats did not differ from vehicle-treated controls in either the location of first hole chosen nor in the latency to locate the escape hole. In the reversal trials, when the position of the escape hole was rotated 135 degrees, both groups successfully reversed their responses without persevering towards the previously rewarded escape hole location. These findings suggest that, despite the probability of corticosterone-induced changes in hippocampal physiology, chronic corticosterone treatment does not adversely affect performance in a memory task dependent on hippocampal integrity.

Affiliation and aggression in rats

The relationship between affiliation and aggression was examined in two experiments. In the first study, each of 12 male albino rats was allowed to choose in a T-maze between two alternatives. One alternative housed a more aggressive target male and the other housed a less aggressive target male. The subjects preferred the less aggressive target animal. A second investigation allowed each of 36 male albino rats to choose between a target animal and an empty compartment. The results were that all the subjects preferred to affiliate with the target animal. However, as the level of aggressiveness by the target animal increased, the level of gregariousness decreased. The data suggest that an important determinant of affiliation is the behavior, and specifically the aggressiveness, of the target animal.

Antidepressive effects of the κ-opioid receptor agonist salvinorin A in a rat model of anhedonia.

Salvinorin A (SalvA), the hallucinogenic derivative of the plant Salvia divinorum, is a selective &kgr;-opioid receptor agonist that may also have antidepressant properties. Chronic mild stress (CMS) was applied to male and female Long–Evans rats to model anhedonia common in depression. The progressive loss in preference for a sucrose solution over plain water, a measure of anhedonia, and locomotor activity were monitored for 7 weeks. Because antidepressant medications often modify reproductive functions, endocrine glands and hormone-sensitive tissues were assessed at necropsy after the conclusion of the behavioral protocol. Three weeks of CMS exposure led to a decrease in sucrose preference. CMS was continued for 3 additional weeks and animals were randomly assigned to treatment with 1 mg SalvA/kg body weight or to a vehicle control group. The results indicate that SalvA reversed anhedonia whereas control animals continued to show a suppressed preference for the sucrose solution. In addition, no change in sucrose preference was observed in nonstressed rats that were exposed to the same dosage of SalvA. The results indicate that SalvA is an effective antidepressant agent when administered chronically to rats showing symptoms of depression similar to those observed in humans.