Effects of scopolamine,pilocarpine, and oxotremorine on the exploratory behavior of two psychogenetically selected lines of rats in a complex maze

Rats of two psychogenetically selected lines received pretest IP injections of scopolamine hydrobromide (0.25, 1.0, or 4.0 mg/kg), pilocarpine hydrochloride (3.0, 6.0, or 12.0 mg/kg) or oxotremorine sesquifumarate (0.2, 0.4, or 0.8 mg/kg) and were subseqently placed in a complex enclosed maze of the Dashiell type that included a small, central, illuminated arena. Animals receiving pilocarpine or oxotremorine injections were pretreated with methscopolamine to counter the peripheral actions of these muscarinic cholinergic agonists. Following vehicle injections, Roman High-Avoidance rats (RHA/Verh) were significantly more active, explored more maze sectors, and required less time to activate the initial 24 different photocell units uniformly distributed throughout the maze than Roman Low-Avoidance rats (RLA/Verh). Scopolamine, pilocarpine, and oxotremorine depressed locomotor activity, reduced the explored area, and increased the time required to activate the initial 24 different photocell units within this complex maze for both RHA/Verh and RLA/Verh rats. Although the doses of scopolamine injected were approximately equally effective in both rat lines (except for total maze activity), the RHA/Verh rats exhibited significant alterations in several measures of maze patrolling after treatment with the lowest dose of pilocarpine, whereas the RLA/Verh rats did not. In contrast, most of the RLA/Verh rats exhibited very pronounced tremors following treatment with the highest dose of oxotremorine, but none of the RHA/Verh rats did. These results demonstrate that manipulation of the central cholinergic system with scopolamine, pilocarpine, or oxotremorine, despite their different pharmacological mechanisms, impair maze patrolling. Furthermore, the results suggest that the two psychogenetically bred lines of rats investigated are differentially sensitive to central cholinergic manipulation with the muscarinic receptor agonists pilocarpine and oxotremorine.     

Permissive influence of stress in the expression of a U-shaped relationship between serum corticosterone levels and spatial memory errors in rats

The relationship between glucocorticoids (GCs) and memory is complex, in that memory impairments can occur in response to manipulations that either increase or decrease GC levels. We investigated this issue by assessing the relationship between serum corticosterone (the primary rodent GC) and memory in rats trained in the radial arm water maze, a hippocampus-dependent spatial memory task. Each day, rats learned a new location of the hidden escape platform and then 30 min later their memory of the location of the platform was tested. Under control conditions, well-trained rats had excellent spatial memory and moderately elevated corticosterone levels (approximately 26 microg/dl versus a baseline of approximately 2 microg/dl). Their memory was impaired when corticosterone levels were either reduced by metyrapone (a corticosterone synthesis inhibitor) or increased by acute stress (predator exposure), forming an overall U-shaped relationship between corticosterone levels and memory. We then addressed whether there was a causal relationship between elevated corticosterone levels and impaired memory. If elevated corticosterone levels were a sufficient condition to impair memory, then exogenously administered corticosterone, alone, should have impaired performance. However, we found that spatial memory was not impaired in corticosterone-injected rats that were not exposed to the cat. This work demonstrates that an intermediate level of corticosterone correlated with optimal memory, and either a decrease or an increase in corticosterone levels, in conjunction with strong emotionality, impaired spatial memory. These findings indicate that fear-provoking conditions, which are known to engage the amygdala, interact with stress levels of corticosterone to influence hippocampal functioning.     

The effect of pre-natal Cannabis Sativa on maze learning ability in the rat

Pregnant Wistar MW-3 derived rats were treated with 250 mg/kg suboutaneously of an extract of Cannabis Sativa in 2.5 ml/kg of polyethylene glycol 300 or 2.5 ml/kg of polyethylene glycol 300 alone. A third group was left untreated. Treatments were made on days 8–11 of pregnancy. At term, the offspring were delivered normally by the mothers.Twenty-five offspring (15 males and 10 females) from each group were tested at 65 days of age in a Lashley III maze and were evaluated according to the following criteria: 3 out of 4 consecutive errorless trials; the number of errors committed and the time spent in the maze.The Cannabis Sativa treated group was significantly inferior to the polyethylene glycol group in all three parameters, although this difference was not demonstrated when evaluating females alone.     

Early Social Isolation in Male Long-Evans Rats Alters Both Appetitive and Consummatory Behaviors Expressed During Operant Ethanol Self-Administration

Background: Postweaning social isolation in rats produces profound and long‐lasting cognitive and behavioral deficits in adult animals. Importantly, this housing manipulation alters sensitivity to a number of drugs of abuse including ethanol. However, most studies with ethanol have utilized continuous or limited home‐cage access to examine interactions between juvenile social experience and drinking. More recently, social isolation was shown to increased ethanol responding in a “dipper” model of self‐administration ( Deehan et al., 2007 ). In the current study, we utilize a “sipper” operant self‐administration model to distinguish the effects of isolation rearing on ethanol seeking‐ and drinking‐related behaviors. Methods: Postweaning juvenile male Long‐Evans rats were placed into 2 housing groups for 6 weeks: one group consisted of individually housed animals; the second group was housed 4 animals per cage. Following the isolation period, anxiety‐like behavior was assessed to confirm the efficacy of the isolation procedure. In some animals, ethanol drinking in the home cage was assessed using a continuous access, 2‐bottle choice paradigm. All animals were then individually housed and trained to lever‐press for a sipper tube containing either an ethanol solution or a sucrose solution. Results: Postweaning social isolation increased the expression of anxiety‐like behavior in the elevated plus maze but not the light‐dark box. Ethanol consumption was also increased during continuous home‐cage access with the 2‐bottle choice paradigm. During operant self‐administration, isolation housing increased the response rate and increased ethanol consumption but did not alter responding for or consumption of sucrose. The housing manipulation did not change the total number of lever responses during extinction sessions. Paired‐pulse inhibition deficits that are characteristic of juvenile isolation remained intact after prolonged experience with sucrose self‐administration. Discussion: The effects of postweaning social isolation on ethanol drinking in the home cage are also manifest during operant self‐administration. Importantly, these alterations in adult operant self‐administration are ethanol‐specific.     

The stamp of ancestry: roots of behavioral and neuronal impairment in adulthood

Exposure of pregnant animals to noxious conditions affects neuronal function in the offspring. However, exposure or treatment of the maternal animal during pregnancy affects both ancestor and offspring. In the present study, female CD-1 mice were repetitively treated with 3-nitropropionate (3-np), a selective inhibitor of succinic dehydrogenase, exclusively prior to mating. Clinically, mice appeared normal during treatment. Five days after cessation of treatment animals were mated with control male animals. At 4 months of age spatial learning, LTP, NADH autofluorescence, and hypoxic tolerance were alike in controls and the offspring of treated female ancestors. However, an additional metabolic challenge in the offspring unmasks impairment of spatial learning, diminution of long-term potentiation (LTP), an altered protein microenvironment of mitochondrial enzymes, and reduced hypoxic tolerance. We conclude that the exposure of maternal ancestors to subclinical repetitive impairment of oxidative phosphorylation fosters impairment of behavior and neuronal function in the adult offspring, becoming apparent only on additional challenge. This finding may ultimately help to understand the causes of neuronal impairment or even neuropsychiatric disease in old age.     

Effects of intrahippocampal l-NAME treatment on the behavioral long-term potentiation in dentate gyrus

Using a combination of electrophysiological recordings, behavioral tests and local pharmacological administration in hippocampus, we investigated in the present study the effects of nitric oxide (NO) synthase inhibitor N-nitro-l-arginine methyl ester (l-NAME) on the behavioral long-term potentiation (LTP) and maze learning performance in freely moving rats. The results showed as follows: (1) intrahippocampal l-NAME administration led to a defect in maze learning performance of the animals; (2) l-NAME treatment also substantially impaired the induction of the behavioral LTP in perforant pathway to dentate gyrus (PP-DG) pathway induced by maze learning task, while it had no significant effects on basic synaptic transmission in PP-DG pathway; Collectively, these results indicate that NO synthesis may be critical for the behavioral LTP in PP-DG pathway and maze learning performance.     

Differential effects of osmotic and SSR149415 challenges in maternally separated and control rats: The role of vasopressin on spatial learning

Maternal separation (MS) has been demonstrated to up-regulate the hypothalamic vasopressin (VP) system. Intracerebrally released VP has been demonstrated to affect several types of animal behaviour, such as active/passive avoidance, social recognition, and learning and memory. However, the role of VP in spatial learning remains unclear. In the present study, we investigated the effects of an osmotic challenge and a V1b receptor-specific (V1bR) antagonist, SSR149415, on spatial learning of maternally separated and animal facility reared (AFR) adult male Wistar rats. The osmotic challenge was applied by injecting a hypertonic saline solution, 1 h before the Morris water maze test (MWM). V1bR antagonist SSR149415 (5 mg/kg) was injected i.p. twice (1 h and 30 min) previous to the MWM. A combined treatment with both osmotic challenge and the SSR149415 was applied to the third group whereas rats for basal condition were injected with isotonic saline. Under basal condition no differences between AFR and MS groups were observed. MS rats showed severe impairment during the MWM after the osmotic challenge, but not after the administration of SSR149415. For AFR rats, the opposite phenomenon was observed. The joint application of SSR149415 and osmotic challenge restored the spatial learning ability for both groups. The differential impairment produced by osmotic stress-induced up-regulation and SSR149415 induced V1bR blockage in MS and control rats suggested that VP involvement in spatial learning depends on the individual intrinsic ligand-receptor functional state.     

Prophylactic lithium alleviates postoperative cognition impairment by phosphorylating hippocampal glycogen synthase kinase-3β (Ser9) in aged rats

Postoperative cognition impairment is a perishing complication in elderly patients undergone surgeries. Lithium is widely used in psychiatric patients for its role in neuronal protection, whereas whether or not it could attenuate surgery-associated postoperative cognition dysfunction used prophylactically is not well defined. After approval by the Institutional Animal Care and Use Committee, 48 male Sprague-Dawley rats aged 18months old were randomly divided into three groups with 16 each: i, no surgeries and drugs were given; ii, surgical procedures were performed only without drug delivery; iii, prophylactic 2mM/kg lithium chloride was given intraperitoneally once a day for seven days before surgeries. The change in spatial memory was assessed with Morris Water Maze (MWM), and the activation of PI3K/AKT/mTOR pathway was detected, and the levels of hippocampal glycogen synthase kinase-3β (p-GSK-3β) phosphorylation at serine 9 and interleukin-1β (IL-1β) were measured. The MWM detection showed that both swimming latency and distance were considerably prolonged by the surgeries, but these changes could be markedly shortened by prophylactic lithium administration. Meanwhile, the changes in the hippocampal PI3K cascades and p-GSK-3β and IL-1β expression displayed corresponding changes that were parallel to the alterations of spatial memory, and inhibition of PI3K and GSK-3β suggested upstream PI3K activation leads to downstream change in p-GSK-3β and IL-1β. These results indicate, at least in part, that prophylactic lithium can alleviate surgery-associated impairment of the spatial memory in aged rats which is strongly associated with the reduced levels of hippocampal p-GSK-3β and IL-1β resulted from the activation of PI3K/AKT/mTORC2 pathway.