Repeated social defeat stress induces chronic hyperthermia in rats

Psychological stressors are known to increase core body temperature (T_c) in laboratory animals. Such single stress-induced hyperthermic responses are typically monophasic, as T_c returns to baseline within several hours. However, studies on the effects of repeated psychological stress on T_c are limited. Therefore, we measured T_c changes in male Wistar rats after they were subjected to 4 social defeat periods (each period consisting of 7 daily 1 h stress exposures during the light cycle followed by a stress-free day). We also assessed affective-like behavioral changes by elevated plus maze and forced swim tests.In the stressed rats, the first social defeat experience induced a robust increase in T_c (+ 1.3 °C). However, the T_c of these rats was not different from control animals during the subsequent dark period. In comparison, after 4 periods of social defeat, stressed rats showed a small but significantly higher (+ 0.2-0.3 °C) T_c versus control rats during both light and dark periods. Stressed rats did not show increased anxiety-like behavior versus control rats as assessed by the elevated plus maze test. However, in the forced swim test, the immobility time of stressed rats was significantly longer versus control rats, suggesting an increase in depression-like behavior. Furthermore, hyperthermia and depression-like behavior were still observed 8 days after cessation of the final social defeat session. These results suggest that repeated social defeat stress induces a chronic hyperthermia in rats that is associated with behavior resembling depression but not anxiety.     

The effects of dopaminergic drugs in the ventral hippocampus of rats in the nicotine-induced anxiogenic-like response

Nicotine an active alkaloid of tobacco has dopaminergic properties. The drug alters anxiety-like behavior in rodents. Ventral hippocampus (VHC) may be a site for modulation of anxiety-like behaviors. The possible involvement of ventral hippocampal dopaminergic receptor mechanism in the nicotine influence on anxiogenic-like response has been investigated in the present study. The effects of apomorphine, sulpiride and SCH23390 on nicotine response in elevated plus maze in rats have been investigated. Intraperitoneal administration of nicotine (0.6 mg/kg) decreased percentage of open arm time (%OAT) but not percentage of open arm entries (%OAE) and locomotor activity, indicating an anxiogenic-like response. Intra-hippocampal injection (intra-VHC) of apomorphine, a D₁/D₂ dopamine receptor agonist (0.1 and 0.2 μg/rat) also caused anxiogenic-like effects, but the drug blocked that of nicotine. Intra-VHC administration of the D₂ receptor antagonist, sulpiride (1, 2.5 and 5 μg/rat) or the D₁ receptor antagonist, SCH23390 (0.01, 0.1 and 1 μg/rat) did not elicit any response. However, pretreatment with sulpiride (1 μg/rat) or SCH23390 (0.1 μg/rat) decreased nicotine's effect. The results may indicate a modulatory effect for the D₁ and D₂ dopamine receptors of VHC in the anxiogenic-like response induced by nicotine.     

Sexual experience of male rats influences anxiety-like behavior and androgen levels

There is a wide body of literature to suggest that sexual experience may influence androgen secretion in various species, in turn, androgens may also influence anxiety. We hypothesized that sexual experience may alter anxiety behavior and secretion of endogenous androgens. Experiment 1: anxiety behavior of rats with a history of sexual experience was compared to that of sexually-inexperienced, na?ve male rats. Sexually-experienced rats showed less anxiety-like behavior in the open field and elevated plus maze, and exhibited increased plasma and hippocampal testosterone (T) levels. Experiment 2: the effects of recent sexual experience on anxiety behavior of sexually-experienced male rats, sexually-responsive but inexperienced male rats, and sexually-unresponsive, inexperienced male rats exposed to a receptive female immediately prior to testing was examined. Recent sexual experience significantly decreased anxiety-like behavior in the open field, elevated plus maze, and the elevated zero maze tasks, and tended to decrease anxiety-like behavior in the light-dark task. Rats with recent sexual experience exhibited increased plasma and hippocampal T levels. Experiment 3: to examine the effect of recent sexual experience, anxiety behavior of rats with a history of sexual experience that received sexual experience with a stimulus female immediately prior to testing was compared to that of rats with a history of sexual experience that did not receive sexual experience immediately prior to behavioral testing. Experienced rats that were exposed to a female prior to testing showed decreased anxiety-like behavior in the open field, elevated plus maze, and light-dark transition tasks, and showed increased plasma and hypothalamic, T and 3alpha-diol, and increased hippocampal T. Thus, sexual experience is associated with lower levels of anxiety-like behavior and higher levels of androgen secretion.     

Zinc deficiency induces depression-like symptoms in adult rats

There is mounting evidence suggesting a link between serum zinc levels and clinical depression. Not only is serum zinc negatively correlated with the severity of symptoms, but zinc levels appear to be lowest in patients who do not respond to antidepressant drug therapy. It is not known if reduced zinc levels are contributing to depression, or the result of dietary or other factors associated with major depression. Thus, we designed this study to test the hypothesis that dietary zinc deficiency would induce depression-like behaviors in rats. Two-month-old male rats were fed zinc adequate (ZA, 30 ppm), deficient (ZD, 1 ppm), or supplemented (ZS, 180 ppm) diets for 3 weeks. Consistent with the development of depression, ZD rats displayed anorexia (p < 0.001), anhedonia (reduced saccharin:water intake, p < 0.001), and increased anxiety-like behaviors in a light-dark box test (p < 0.05). Furthermore, the antidepressant drug fluoxetine (10 mg/kg body wt) reduced behavioral despair, as measured by the forced swim test, in rats fed the ZA and ZS rats (p < 0.05), but was ineffective in ZD rats. Together these studies suggest that zinc deficiency leads to the development of depression-like behaviors that may be refractory to antidepressant treatment.     

Impairment of emotional behavior and spatial learning in adult Wistar rats by ferrous sulfate

The aim of this study was to investigate the effects of FeSO₄ on the behavior of adult Wistar rats. Rats were treated with moderate doses of iron (1.5 or 3.0 mg/kg) for 5 consecutive days, and the effects of iron supplementation on emotional behavior were studied. One group of rats was tested in elevated plus-maze and in open field, and other group was tested for learning abilities in water maze and for motor skills in rotarod task. Iron level in the brain was measured in the frontal cortex, cerebellum, basal ganglia and hippocampus. The effects of the iron treatment (in particular, a dose of 3.0 mg/kg) on emotional behavior in the elevated plus maze and in the open field were significant. The effects of iron on spatial learning were less pronounced, but significant impairments due to the treatment were observed during the probe test. Motor skills and procedural learning in the rotarod task were not significantly affected by the treatment. These behavioral impairments were associated with significant iron accumulations in the hippocampus and basal ganglia of rats treated with 3.0 mg/kg iron and are discussed in terms of possible neuronal impairments of these structures. Thus, FeSO₄ administration at 3.0 mg/kg for 5 consecutive days in adult rats overcomes the mechanisms that shield the brain from iron intoxication and leads to behavioral impairments, in particular with respect to emotional behavior.     

Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites

There may be a role of age-related decline in androgen production and/or its metabolism for late-onset depression disorders of men and women. Thus, the anti-depressant-like effects of testosterone (T) and its metabolites are of interest. Given that these androgens have disparate mechanisms of action, it is important to begin to characterize and compare their effects in an aged animal model. We hypothesized that there would be sex differences in depression behavior of aged mice and that androgens would reduce depression-like behaviors in the forced swim test. To investigate this, male and female mice (~ 24 months old) were subcutaneously administered T, or one of its 5α-reduced metabolites (dihydrotesterone-DHT, 5α-androstane,17β-diol-3α-diol), or aromatized metabolite (estradiol — E₂), or oil vehicle. Mice were administered androgens (1 mg/kg) 1 h before being tested in the forced swim test, an animal model of depression. We found that males spent more time immobile, and less time swimming, than females. Administration of T, DHT, or 3α-diol similarly reduced time spent immobile, and increased time spent struggling, of male and female mice. E₂, compared to vehicle administration, decreased time spent immobile of males and females, but increased time spent swimming of females and time spent struggling of male mice. Together, these data suggest that T and its 5α-reduced and aromatized metabolites have anti-depressant-like effects in aged male and female mice.     

Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis

In vulnerable individuals, exposure to stressors can result in chronic disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). The extended amygdala is critically implicated in mediating acute and chronic stress responsivity and anxiety-like behaviors. The bed nucleus of the stria terminalis (BNST), a subregion of the extended amygdala, serves as a relay of corticolimbic information to the paraventricular nucleus of the hypothalamus (PVN) to directly influence the stress response. To investigate the influence of the corticosteroid milieu and housing conditions on BNST function, adult C57Bl/6J were either acutely or chronically administered corticosterone (CORT, 25 mg/kg in sesame oil) or vehicle (sesame oil) or were group housed or socially isolated for 1 day (acute) or 6-8 weeks (chronic). To ascertain whether these stressors could influence anxiety-like behavior, studies were performed using the novel open-field (NOF) and the elevated zero maze (EZM) tests. To investigate potential associated changes in plasticity, alterations in BNST function were assessed using ex vivo extracellular field potential recordings in the (dorsal-lateral) dlBNST and a high frequency stimulus protocol to induce long-term potentiation (LTP). Our results suggest that chronic CORT injections and chronic social isolation housing conditions lead to an increase in anxiety-like behavior on the EZM and NOF. Chronically stressed mice also displayed a parallel blunting of LTP in the dlBNST. Conversely, acute social isolation housing had no effect on anxiety-like behavior but still resulted in a blunting of LTP in the dlBNST. Collectively, our results suggest acute and chronic stressors can have a distinct profile on plasticity in the BNST that is not uniformly associated with an increase in anxiety-like behavior.     

Estradiol or diarylpropionitrile decrease anxiety-like behavior of wildtype, but not estrogen receptor beta knockout, mice

Clinical and basic studies demonstrate that estrogen (E-sub-2)-based therapies influence anxiety and mood, but the receptor targets (e.g., a or ss isoform of the estrogen receptor, ER) for these effects requires further investigation. To address the specificity of E2's anxiolytic-like effects through ERss, anxiety, motor, and nociceptive behavior of ovariectomized, wildtype (WT), and ERss knockout (ssERKO) mice was examined. Mice were administered oil vehicle or ER agonists, 17ss-E2 (E2; 0.1 mg/kg; similar affinity for ERa and ERss), and a selective ER modulator, diarylpropionitrile (DPN; 0.1 mg/kg; greater affinity for ERss than ERa). Performance of mice in anxiety (open field, elevated plus maze, elevated zero maze, social interaction), motor activity (activity monitor) and nociception (tailflick, pawlick) measures was compared. Results supported our hypothesis that ERss is important in modulation of anxiety-like behavior by E2 in some tasks. Administration of E2 or DPN to WT, but not ssERKO, mice increased open field central entries, plus maze open arm time, zero maze open quadrant time, and social interaction. This pattern was neither seen in motor activity nor pain threshold measures. Thus, actions of ERss may be important for modulating anxiety-like behavior of mice.     

Activation of brain somatostatin 2 receptors stimulates feeding in mice: Analysis of food intake microstructure

We recently reported that the oligosomatostatin receptor agonist, ODT8-SST increases food intake in rats via the somatostatin 2 receptor (sst₂). We characterized ingestive behavior following intracerebroventricular (icv) injection of a selective sst₂ agonist in freely fed mice during the light phase. The sst₂ agonist (0.01, 0.03, 0.1, 0.3 or 1 μg/mouse) injected icv under short inhalation anesthesia dose-dependently increased cumulative light phase food intake over 4 h compared to vehicle with a 3.1-times increase at 1 μg/mouse (p < 0.05). Likewise, the sst_2,3,5 agonist octreotide (0.3 or 1 μg/mouse) dose-dependently increased 4-h food intake, whereas selective sst₁ or sst₄ agonists at 1 μg/mouse did not. In vehicle-treated mice, high fat diet increased caloric intake/4 h by 2.8-times compared to regular diet (p < 0.05) and values were further increased 1.4-times/4 h by the sst₂ agonist. Automated continuous assessment of food intake established a 6.6-times higher food intake during the dark phase due to increased number of meals, meal size, meal duration and rate of ingestion compared to non-treated mice during the light phase. During the first 4 h post icv sst₂ agonist injection, mice had a 57% increase in number of meals with a 60% higher rate of ingestion, and a 61% reduction in inter-meal intervals, whereas meal sizes were not altered compared to vehicle. These data indicate that the activation of brain sst₂ receptors potently stimulates the light phase ingestive behavior under basal or high fat diet-stimulated conditions in mice. The shortened inter-meal interval suggests an inhibitory effect of the sst₂ agonist on “satiety”, whereas “satiation” is not altered as indicated by normal meal size.     

Anxiety-like effects of SR141716-precipitated delta9-tetrahydrocannabinol withdrawal in mice in the elevated plus-maze

Marijuana discontinuation has been recently reported to be anxiogenic in humans, which may predict relapse. Limited animal research has been carried out to model this withdrawal-associated negative affect. The current study sought to investigate the potential anxiety-like effects of cannabinoid withdrawal in mice. Male ICR mice were injected s.c. with delta9-tetrahydrocannabinol (THC) at 10 mg/kg or vehicle once daily for 10 days. To precipitate withdrawal, the cannabinoid CB1 antagonist SR141716 (0.3, 1.0, or 3.0 mg/kg) or vehicle was administrated i.p. 4 h following the last THC or vehicle treatment. Thirty minutes later, mice were tested on the elevated plus-maze (EPM) for 5 min. SR141716 did not significantly change EPM behaviors in vehicle-treated mice. In contrast, SR141716 precipitated a reduction in exploration of the open arms of EPM in mice repeatedly treated with THC vs vehicle. At 3.0 mg/kg, SR141716 significantly reduced % open arm entries of the total arm entries, % open arm time of total time in arms, and the absolute time spent in open arms. No significant differences in the number of closed or total arm entries were observed, indicating that the behavioral changes were not due to altered motor activity. Collectively, the present results constitute the first evidence that cannabinoid withdrawal produces anxiety-like effects in mice. This animal model may help to identify the mechanisms that contribute to adaptations in the neuronal circuitry of the brain that are expressed as emotional symptoms of cannabinoid withdrawal.     

Teneurin C-terminal associated peptide (TCAP)-1 modulates dendritic morphology in hippocampal neurons and decreases anxiety-like behaviors in rats

Teneurin C-terminal associated peptide (TCAP)-1 is a member of a novel family of neuropeptides that has been highly conserved throughout evolution. TCAP-1 is expressed in the limbic system in areas such as the hippocampus and amygdala. In vitro, TCAP-1 increases cytoskeletal proteins in immortalized neurons and modulates neurite outgrowth in cultured primary hippocampal neurons. In vivo, TCAP-1 blocks stress-induced c-Fos in the hippocampus and amygdala, and modulates stress-induced anxiety-like behaviors. This suggests that TCAP-1 plays a role in the remodeling of limbic system networks to alter stress behaviors. Dendritic spines on the apical and basilar shafts of hippocampal neurons are sensitive to stress and many receive incoming excitatory synaptic connections. In this study, repeated daily injection of TCAP-1 for 10 days increased spine density in the CA1 and CA3 regions of the hippocampus without affecting spine density in the amygdala. Further investigation of the CA3 region indicated that TCAP-1 did not affect the morphology of apical dendrites, but decreased branching in the basilar dendrites 90-130 μm away from the soma. Moreover, TCAP-1 treatment increased open arm time and decreased closed arm entries on the elevated plus maze, a test of anxiety-like behavior. These results suggest that TCAP-1 may be associated with anxiety-like behavior via regulation of dendritic morphology in the hippocampus, independent of amygdalar modification.     

Novel 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2(3H)-thione as selective adenosine A2A receptor antagonist

Adenosine A_2A receptor (A_2AR) antagonists have emerged as potential drug candidates to alleviate progression and symptoms of Parkinson's disease (PD), and reduce the dopaminergic side effects. The synthesis of novel compound 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2-(3H)-thione (BTTP) was carried out to evaluate the potential of BTTP as A_2AR antagonist using SCH58261, a standard A_2AR antagonist. The strong interaction of BTTP with A_2AR (ΔG = −12.46 kcal/mol and K_i = 0.6 nM) in silico analysis was confirmed by radioligand receptor binding studies showing high affinity (K_i = 0.004 nM) and selectivity with A_2AR (A_2A/A₁ = 1155-fold). The effect of CGS21680 (selective A_2AR agonist) induced cAMP concentration (0.1 pmol/ml) in HEK293 cells was antagonized with BTTP (0.065 pmol/ml) and SCH58261 (0.075 pmol/ml). Furthermore, BTTP pre-treated (5, 10 and 20 mg/kg) haloperidol-induced mice demonstrated significant attenuation in catalepsy and akinesia. BTTP induced elevation in the striatal dopamine concentration (2.90 μM/mg of tissue) was comparable to SCH58261 (2.92 μM/mg of tissue) at the dose of 10 mg/kg. The results firmly articulate that BTTP possesses potential A_2AR antagonist activity and can be further explored for the treatment of PD.     

Immunoglobulin-Mediated Neuro-Cognitive Impairment: New Data and a Comprehensive Review

Excessive influx of immunoglobulin (IgG) into the brain has been reported to induce central nervous system (CNS) dysfunction. Depressed patients may exhibit immune activation manifested by elevated inflammatory markers and pro-inflammatory cytokines. The brain and especially the limbic system contain high concentrations of high affinity Fc receptors. We reviewed the literature on this phenomena and present data on the behavioral effects of pooled normal IgG on the brain. Many disease states are associated with depression and we examined whether this may be linked to high IgG influx. Female Balb/C mice were injected intra-cerbroventricularly with human immunoglobulin whole molecule, or human IgG F(ab′)₂ or Fc fragments. Control mice were injected with saline. The four groups were subjected to behavioral (staircase, forced swimming test, and elevated plus maze) and cognitive tests (passive avoidance test). IgG-injected mice exhibited depression-like behavior as reflected by significantly higher immobility time in the forced swimming test (p?<?0.05) and hyperactive behavior as reflected by higher number of stairs climbed in the staircase test compared to controls (p?<?0.01). Fc-fragments-injected mice showed hyperactive behavior as reflected by both higher number of stairs climbed and rearing events in the staircase test compared to controls. The results indicate that high levels of normal IgG in the cerebrospinal fluid can cause hyperactivity and depression-like behavior. The mechanism involved in these CNS manifestations include possibly Fc receptor binding.     

Emotional behavior in heterozygous rolling mouse Nagoya Cav2.1 channel mutant mice

Although rolling mouse Nagoya, a Ca_v2.1α₁ mutant, exhibits ataxia and elevated serotonin concentrations, heterozygous mice have not been examined in detail. Patients with heterozygous mutations in this orthologous gene exhibit neurological disorders. To examine the emotional behavior of heterozygous mice, we used behavioral tasks and examined Ca_v2.1α₁ message levels, tryptophan hydroxylase expression patterns, and monoamine concentrations in 2- and 22-month-old mice. Reduced anxiety in the elevated plus maze, light-dark exploration, and marble-burying behavioral tests and reduced depression in the forced swimming and tail suspension tests were observed in 22-month-old heterozygous mice compared to aged-matched wild-type mice. The levels of mutant-type Ca_v2.1α₁ message, phosphorylation of tryptophan hydroxylase, and serotonin increased in the brainstems of 22-month-old heterozygous mice. No difference was observed between 2-month-old heterozygous and wild-type mice in these analyses. These findings suggest that heterozygous mice show age-related emotional changes due to alterations in the serotonin system associated with mutant-type Ca_v2.1α₁, and that heterozygous mice may represent a novel model to delineate the interaction between Ca_v2.1 function and synaptic transmission.     

Effect of saikosaponin A on maintenance of intravenous morphine self-administration

In this study, we investigated the effects of saikosaponin A (SSA), a major compound of Bupleurum falcatum L., on morphine self-administration behavior. Male Sprague–Dawley rats were trained to self-administer intravenous morphine (0.1 mg/kg per injection over 5 s) during daily 1-h sessions under a fixed-ratio 1 schedule. Rats were pretreated with SSA (0.25, 0.5, 1.0 mg/kg) by intraperitoneal injection 30 min prior to the start of the test session. Results demonstrated that pretreatment with SSA reduced morphine-maintained responding dose-dependently. Additionally, SSA inhibition of morphine-reinforced behavior was blocked by the selective GABA_B receptor antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), but not the selective GABA_A receptor antagonist bicuculline. Together, these results suggest that SSA may effectively suppress morphine-reinforced behavior by activating GABA_B receptors.     

Inflammatory mediators potentiate high affinity GABAA currents in rat dorsal root ganglion neurons

Following acute tissue injury action potentials may be initiated in afferent processes terminating in the dorsal horn of the spinal cord that are propagated back out to the periphery, a process referred to as a dorsal root reflex (DRR). The DRR is dependent on the activation of GABA_A receptors. The prevailing hypothesis is that DRR is due to a depolarizing shift in the chloride equilibrium potential (E_Cl) following an injury-induced activation of the Na⁺–K⁺–Cl⁻-cotransporter. Because inflammatory mediators (IM), such as prostaglandin E₂ are also released in the spinal cord following tissue injury, as well as evidence that E_Cl is already depolarized in primary afferents, an alternative hypothesis is that an IM-induced increase in GABA_A receptor mediated current (I_GABA) could underlie the injury-induced increase in DRR. To test this hypothesis, we explored the impact of IM (prostaglandin E₂ (1 μM), bradykinin (10 μM), and histamine (1 μM)) on I_GABA in dissociated rat dorsal root ganglion (DRG) neurons with standard whole cell patch clamp techniques. IM potentiated I_GABA in a subpopulation of medium to large diameter capsaicin insensitive DRG neurons. This effect was dependent on the concentration of GABA, manifest only at low concentrations (<10 μM). THIP evoked current were also potentiated by IM and GABA (1 μM) induced tonic currents enhanced by IM were resistant to gabazine (20 μM). The present data are consistent with the hypothesis that an acute increase in I_GABA contributes to the emergence of injury-induced DRR.     

Neurobehavioral deficits in db/db diabetic mice

Recent clinical studies indicate neurobehavioral disturbances in type-2 diabetics. However, there is paucity of preclinical research to support this concept. The validity of db/db mouse as an animal model to study type-2 diabetes and related complications is known. The present study was designed to investigate comprehensively the db/db mouse behavior as preclinical evidence of type-2 diabetes related major neurobehavioral complications. We tested juvenile (5-6 weeks) and adult (10-11 weeks) db/db mice for behavioral depression in forced swim test (FST), psychosis-like symptoms using pre-pulse inhibition (PPI) test, anxiety behavior employing elevated plus maze (EPM) test, locomotor behavior and thigmotaxis using open field test and working memory deficits in Y-maze test. Both juvenile and adult group db/db mice displayed behavioral despair with increased immobility time in FST. There was an age-dependent progression of psychosis-like symptoms with disrupted PPI in adult db/db mice. In the EPM test, db/db mice were less anxious as observed by increased percent open arms time and entries. They were also hypo-locomotive as evident by a decrease in their basic and fine movements. There was no impairment of working memory in the Y-maze test in db/db mice. This is the first report of depression, psychosis-like symptoms and anxiolytic behavior of db/db mouse strain. It is tempting to speculate that this mouse strain can serve as useful preclinical model to study type-2 diabetes related neurobehavioral complications.     

Effects of cholinergic system of dorsal hippocampus of rats on MK-801 induced anxiolytic-like behavior

Rationale: Some investigations have shown that the glutamate receptors play a critical role in cognitive processes such as learning and anxiety. Objectives: The possible involvement of the cholinergic system of the dorsal hippocampus in the anxiolytic-like response induced by MK-801, NMDA receptor antagonist, was investigated in the present study. Methods: Male Wistar rats were used in the elevated plus maze apparatus to test the parameters: open arm time (%OAT), open arm entries (%OAE), close arm time (%CAT), close arm entries (%CAE) and other exploratory behaviors (locomotor activity, grooming, rearing and defecation) of anxiety-like response. Results: The data indicated that intra-CA1 administration of MK-801 increased %OAT (2 μg/rat) and %OAE (1 and 2 μg/rat) while decreased %CAT and %CAE and did not alter other exploratory behaviors, indicating an anxiolytic-like effect. Moreover, intra-hippocampal injections of mecamylamine, a cholinergic receptor antagonists (2 μg/rat) and scopolamine (4 μg/rat), by themselves, 5 min before testing, increased %OAT and %OAE but decreased %CAT and %CAE and did not alter locomotor activity and other exploratory behaviors, suggesting an anxiolytic-like effect. On the other hand, intra-CA1 co-administration of an ineffective dose of scopolamine (3 μg/rat), but not mecamylamine (1 μg/rat), with an ineffective dose of MK-801 (0.5 μg/rat) increased %OAT and %OAE and decreased %CAT and %CAE. The data may indicate the possible involvement of the cholinergic system of the CA1 in the anxiolytic-like response induced by MK-801.