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Through incorporating both physical and psychological forms of stressors, a variety of rodent models have provided important insights into the understanding of stress physiology. Rodent models also have provided significant information with regards to the mechanistic basis of the pathophysiology of stress-related disorders such as anxiety disorders, depressive illnesses, cognitive impairment and post-traumatic stress disorder. Additionally, rodent models of stress have served as valuable tools in the area of drug screening and drug development for treatment of stress-induced conditions. Although rodent models do not accurately reproduce the biochemical or physiological parameters of stress response and cannot fully mimic the natural progression of human disorders, yet, animal research has provided answers to many important scientific questions. In this review article, important studies utilizing a variety of stress models are described in terms of their design and apparatus, with specific focus on their capabilities to generate reliable behavioral and biochemical read-out. The review focusses on the utility of rodent models by discussing examples in the literature that offer important mechanistic insights into physiologically relevant questions. The review highlights the utility of rodent models of stress as important tools for advancing the mission of scientific research and inquiry., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Long-term potentiation (LTP) is commonly considered the cellular correlate of learning and memory. In learning and memory impairments, LTP is invariably diminished in the hippocampus, the brain region responsible for memory formation. LTP is measured electrophysiologically in various areas of the hippocampus. Two mechanistically distinct phases of LTP have been identified: early phase LTP, related to short-term memory; and late-phase LTP, related to long-term memory. These two forms can be severely reduced in a variety of conditions but can be rescued by treatment with nicotine. This report reviews the literature on the beneficial effect of nicotine on LTP in conditions that compromise learning and memory., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Previously, we reported that in a rat model of sporadic Alzheimer's disease (AD) generated by exogenous administration of Aβ₁₋₄₂ (250 pmol/d for 2 wk) via mini-osmotic pump, the animals exhibited learning and memory impairment, which could be attributed to the deleterious alterations in the levels of cognition-related signalling molecules. We showed that 4 wk of treadmill exercise totally prevented these impairments. Here, we evaluated the effect of exercise on non-cognitive function and basal synaptic transmission in the Cornu Ammonis 1 (CA1) area using the same AD model. Our results indicated that the anxiety behaviour of Aβ-treated rats was prevented by 4 wk of treadmill exercise. Exercised/Aβ-infused rats spent a longer time in the centre area of the open field (OF), elevated plus maze (EPM) paradigms and the light area of the light-dark (LD) box, which were similar to those of control and exercise rats. Furthermore, under basal conditions the aberrant up-regulation of calcineurin (PP2B) and reduction of phosphorylated Ca²⁺/calmodulin dependent protein kinase II (p-CaMKII) levels induced by AD-like pathology were normalised by the exercise regimen. We conclude that regular exercise may exert beneficial effects on both cognitive and non-cognitive functions in this AD model.

Diminished estrogen influence at menopause is reported to be associated with cognitive decline, heightened anxiety and hypertension. While estrogen therapy is often prescribed to overcome these behavioral and physiological deficits, antioxidants which have been shown beneficial are gaining nutritional intervention and popularity. Therefore, in the present study, utilizing the antioxidant properties of grapes, we have examined effect of 3 weeks of grape powder (GP; 15 g/L dissolved in tap water) treatment on anxiety-like behavior, learning-memory impairment and high blood pressure in ovariectomized (OVX) rats. Four groups of female Wistar rats were used; sham control, sham-GP treated, OVX and OVX+GP treated. We observed a significant increase in systolic and diastolic blood pressure in OVX rats as compared to sham-controls. Furthermore, ovariectomy increased anxiety-like behavior and caused learning and memory impairment in rats as compared to sham-controls. Interestingly, providing grape powder treated water to OVX rats restored both systolic and diastolic blood pressure, decreased anxiety-like behavior and improved memory function. Moreover, OVX rats exhibited an impaired long term potentiation which was restored with grape powder treatment. Furthermore, ovariectomy increased oxidative stress in the brain, serum and urine, selectively decreasing antioxidant enzyme, glyoxalase-1 protein expression in the hippocampus but not in the cortex and amygdala of OVX rats, while grape powder treatment reversed these effects. Other antioxidant enzyme levels, including manganese superoxide dismutase (SOD) and Cu/Zn SOD remained unchanged. We suggest that grape powder by regulating oxidative stress mechanisms exerts its protective effect on blood pressure, learning-memory and anxiety-like behavior. Our study is the first to examine behavioral, biochemical, physiological and electrophysiological outcome of estrogen depletion in rats and to test protective role of grape powder, all in the same study.

We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of α7- and α4β2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either α7-nAChRs [methyllycaconitine (MLA)] or α4β2-nAChRs [dihydro-β-erythroidine (DHβE)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 μg/side.d and 41 μg/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DHβE infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of α7-nAChRs, but not α4β2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions.

We examined whether or not grape powder treatment ameliorates oxidative stress-induced anxiety-like behavior, memory impairment, and hypertension in rats. Oxidative stress in Sprague-Dawley rats was produced by using L-buthionine-(S,R)-sulfoximine (BSO). Four groups of rats were used: 1) control (C; injected with vehicle and provided with tap water), 2) grape powder-treated (GP; injected with vehicle and provided for 3 wk with 15 g/L grape powder dissolved in tap water), 3) BSO-treated [injected with BSO (300 mg/kg body weight), i.p. for 7 d and provided with tap water], and 4) BSO plus grape powder-treated (GP+BSO; injected with BSO and provided with grape powder-treated tap water). Anxiety-like behavior was significantly greater in BSO rats compared with C or GP rats (P < 0.05). Grape powder attenuated BSO-induced anxiety-like behavior in GP+BSO rats. BSO rats made significantly more errors in both short- and long-term memory tests compared with C or GP rats (P < 0.05), which was prevented in GP+BSO rats. Systolic and diastolic blood pressure was significantly greater in BSO rats compared with C or GP rats (P < 0.05), whereas grape powder prevented high blood pressure in GP+BSO rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK-1/2) was activated (P < 0.05), whereas levels of glyoxalase-1 (GLO-1), glutathione reductase-1 (GSR-1), calcium/calmodulin-dependent protein kinase type IV (CAMK-IV), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) were significantly less (P < 0.05) in BSO but not in GP+BSO rats compared with C or GP rats. We suggest that by regulating brain ERK-1/2, GLO-1, GSR-1, CAMK-IV, CREB, and BDNF levels, grape powder prevents oxidative stress-induced anxiety, memory impairment, and hypertension in rats.

In Alzheimer's disease (AD), progressive accumulation of β-amyloid (Aβ) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve α7 and α4β2-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic Aβ production pathway, is expressed at high levels in hippocampal and cortical regions of AD brains. We measured hippocampal area CA1 protein levels of BACE and α7- and α4β2-nAChR subunits using an Aβ rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d Aβ peptides) in the presence and absence of chronic stress and/or chronic nicotine treatment. There was a significant increase in the levels of BACE in Aβ-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in Aβ rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits α7, α4 and β2 were significantly decreased in Aβ rats, but these were also normalized in Aβ rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in Aβ-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the Aβ i.c.v.-infused rat as a model of AD.

Environmental factors including chronic stress may play a critical role in the manifestation of Alzheimer's disease (AD).This review summarizes our studies of the aggravation of the impaired cognitive ability and its cellular and molecular correlates by chronic psychosocial stress and prevention by nicotine in an Aβ rat model of AD. We utilized three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of the cellular correlates of memory, long-term potentiation (LTP) and long-term depression (LTD), in anesthetized rats, and immunoblot analysis of synaptic plasticity- and cognition-related signaling molecules. The Aβ rat model, representing the sporadic form of established AD, was induced by continuous i.c.v. infusion of a pathogenic dose of Aβ peptides via a 14- day osmotic pump. In this AD model, chronic stress intensified cognitive deficits, accentuated the disruption of signaling molecules levels and produced greater depression of LTP than what was seen with Aβ infusion alone. Chronic treatment with nicotine was highly efficient in preventing the effects of Aβ infusion and the exacerbating impact of chronic stress. Possible mechanisms for the effect of chronic stress are discussed.

The effect of chronic nicotine treatment on chronic psychosocial stress-induced impairment of short-term memory and long-term potentiation (LTP) was determined. An "intruder" stress model was used to induce psychosocial stress for 4-6 wk, during which rats were injected with saline or nicotine (1 mg/kg s.c.) twice a day. The radial arm water maze memory task was used to test hippocampus-dependent spatial memory. Chronic psychosocial stress impaired short-term memory without affecting the learning phase or long-term memory. Concurrent chronic nicotine treatment prevented stress-induced short-term memory impairment. In normal rats chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anaesthetized rats showed severe reduction of LTP magnitude in stressed rats, which was normalized in nicotine-treated stressed rats. Nicotine had no effect on LTP in control animals. These results showed that chronic nicotine treatment improved hippocampus-dependent spatial memory and LTP only when impaired by stress.

Objective: Guanosine 3`,5` monophosphate (cGMP) can be used as a marker of the epileptogenicity of proconvulsant drugs. As valproic acid (VPA), at certain concentrations, acts as a proconvulsant agent in hippocampal pyramidal neurons when tested in the veratridine model, this investigation was conducted to study the effect of proconvulsant concentrations of VPA on the basal level of cGMP in hippocampal tissue., Methods: Experiments were performed using standard radioimmuonassay techniques in hippocampal tissues from rats. This study was carried out at the Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas, United States of America between 1996-1997., Results: We found that veratridine (0.3, 1 and 2 uM, n=3) increased the level of cGMP in hippocampal tissue in a concentration dependent manner. However, VPA at proepileptic concentrations (0.1, 2, 5 uM, n=3), did not significantly affect the basal level of cGMP when added alone or with veratridine (0.3 uM)., Conclusion: Guanosine 3`,5` monophosphate is not a marker of the proepileptic activity of VPA in brain tissues.

Carbon monoxide (CO), produced in the body by the enzyme heme oxygenase (HO), has been suggested as a retrograde synaptic messenger with a prominent role in the long-term potentiation (LTP) of certain areas of the brain. LTP of sympathetic ganglia is 5-HT(3) receptor-dependent and has been shown to require nitric oxide for the maintenance, but not for the induction, phase. We investigated the possibility of CO being required for the induction of ganglionic LTP. Pretreatment of rat isolated superior cervical ganglia with oxyhemoglobin (25-100 microm) completely blocked LTP. In the same ganglia, prolonged washout of oxyhemoglobin did not uncover any potentiation of the compound action potential. Oxyhemoglobin had no significant effect on the maintenance phase in ganglia with established LTP. Pretreatment of ganglia with the HO inhibitor zinc protoporphyrin-IX (ZnPP) (10 microm) completely and irreversibly prevented the expression of tetanus-evoked LTP. However, in the same ganglia, after superfusion of CO in the presence of ZnPP, tetanic stimulation readily evoked LTP. No effect was seen on the maintenance phase when ZnPP was superfused on ganglia with established LTP. Pretreatment of ganglia with the 5-HT(3) receptor antagonist ondansetron (0.4 microm) alone completely and irreversibly blocked LTP. However, in the presence of CO, ondansetron did not block LTP. These results suggest that activation of 5-HT(3) receptors may be involved in the production of CO. The results also suggest that CO, probably originating outside the presynaptic nerve terminal, is involved in the induction of LTP.

1. An extracellular recording technique was used to study the effects of 5-hydroxytryptamine (5-HT, serotonin) on the tetanus-induced long-term potentiation (LTP) of the nicotinic pathway of transmission in the superior cervical ganglion (SCG) of the rat. The postganglionic compound action potential (CAP), made submaximal by treatment with hexamethonium (O.4 mM), was used as an index of transmission in the ganglion. 2. Serotonin (10 microM) markedly enhanced the magnitude of LTP without affecting the post-tetanic potentiation (PTP). The serotonin (2-30 microM) concentration-response curve for LTP was bell shaped as no enhancement was seen with 30 microM serotonin. This may largely be due to activation of a 5-HT1 receptor subtype and not to desensitization. 3. When superfused before tetanus, the 5-HT1A receptor agonist 8-hydroxydipropylamino-tetralin (8-OH-DPAT, 5 microM) prevented the expression of LTP without affecting PTP. 4. Pretreatment of ganglia with the 5-HT2 receptor agonist R-(+)-dimethoxy-4-iodoamphetamine (R-(+)-DOI, 1 microM) enhanced the tetanus-induced LTP. Similar treatment with the 5-HT2 receptor antagonist ketanserin (3 microM) had no significant effect on LTP. 5. Pretreatment of ganglia with the 5-HT3 receptor agonist 1-m-(chlorophenyl) biguanide (m-CPGB, 1 microM), markedly increased (300%) the tetanus-induced LTP. Similar pretreatment with the 5-HT3 receptor antagonist 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, 0.5 microM) completely prevented the expression of LTP. Fully expressed LTP was reversibly blocked by MDL 72222 when applied during the maintenance phase of LTP. 6. Tetanic stimulation of monoamine-depleted ganglia (from reserpine-pretreated rats, 3 mg kg-1 for 24 h) failed to induced LTP. 7. In monoamine-depleted ganglia, tetanus preceded by superfusion with m-CPBG readily induced LTP. MDL 72222 completely blocked this LTP. However in these ganglia tetanus failed to induced LTP when m-CPBG was given 2 min (during PTP) or 1 h after tetanus. 8. Tetanic stimulation of monoamine-depleted ganglia in the presence of R-(+)-DOI failed to induced LTP. 9. We conclude that tetanus-induced LTP of the SCG of the rat requires activation of 5-HT3 receptors both for induction and maintenance.

1. Intracellular recordings from the cutaneous pectoris muscle fibres of the frog showed that giant miniature end-plate potentials (gMEPPs) occurred in untreated preparations. Emetine (10 microM), after a 15-20 min delay, increased the frequency of gMEPPs. In both cases gMEPPs disappeared in the presence of (+)-tubocurarine. 2. There was no correlation between the frequency of gMEPPs and the frequency of normal MEPPs (nMEPPs) in untreated or emetine-treated fibres. 3. Tetraphenylborate (TPB, 50 microM) applied to muscles pre-treated with emetine caused the frequency and amplitude of both nMEPPs and gMEPPs to decrease gradually. All MEPPs disappeared in about 10 min. 4. Chloride permeability was modified by changing the pH of the Ringer solution. Changing the pH from 7.2 to 8.2 or 6.2, which in both cases caused marked increases in nMEPP frequency, had no significant effect on gMEPP frequency in untreated muscles. 5. Decreasing the pH from 7.2 to 6.2 blocked the ability of emetine to increase gMEPP frequency. Increasing the pH from 7.2 to 8.2 had no significant effect on emetine ability to increase gMEPP frequency. 6. Treatment with the Cl- channel blocker SITS (0.5 mM) had no effect on gMEPPs in untreated muscle or on the ability of emetine to increase the frequency of these potentials. 7. The Ca2+ sensitivity of gMEPPs in untreated or emetine-treated muscles was tested by treatments which are known to alter intracellular Ca2+. Raising extracellular Ca2+ (10 mM), treatment with Mn2+ (10 mM), Mg2+ (10 mM), K+ (7.5 mM), hypotonic solution, ouabain (0.2 mM) or ethanol (0.5 M), although causing profound changes in nMEPP frequency had no significant effect on gMEPP frequency in untreated fibres or on the ability of emetine to increase gMEPP frequency. 8. It is concluded that at the frog neuromuscular junction generation of the normally occurring or emetine-induced gMEPPs is independent of Ca2+ and does not seem to be influenced by changing membrane C1- permeability.

1 Periodic stimulation (every 10 min) of the cervical sympathetic nerve increased the ganglionic block by low concentrations of chlorisondamine (CHL) in the superior cervical ganglion of the cat when compared to the contralateral unstimulated side.2 Periodic stimulation of the postganglionic nerve was ineffective in increasing the block.3 Ganglionic block by low concentrations of mecamylamine had the same stimulus dependency, but ganglionic block by any dose of hexamethonium was not influenced by nerve stimulation.4 Physostigmine infused together with CHL increased the rate of onset of block produced by CHL. Atropine had no apparent effect on the development of ganglionic block by CHL.5 Repeated intra-arterial injections of 1,1-dimethyl-4-phenylpiperazinium into the circulation of the superior cervical ganglion increased the magnitude of block produced by CHL. Similar injections of methacholine had no effect on ganglionic block produced by CHL.6 The results are interpreted to indicate that activation of ganglionic nicotinic receptors increased the affinity of receptors for CHL and mecamylamine.