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•Swiss mice showed stable behavior on the free-exploratory paradigm.•High trait anxiety mice had increased freezing time during fear extinction.•Diazepam treatment did not decrease ...freezing time in high trait anxiety mice.
Trait anxiety is a form of chronic state anxiety that can be part of the individual’s personality and one of the individual factors that increase the risk of developing PTSD. To be able to distinguish between trait and state anxiety in animal models might be challenging, since the tests themselves are often anxiogenic. One possible approach is the use of the free exploratory paradigm (FEP), a model that consists of providing the animal the choice to explore both a familiar and a novel environment. High trait anxiety animals choose to explore more the familiar environment. Thus, the objective of this study was to evaluate if differences in trait anxiety could lead to impairments in acquisition and extinction of fear memory in a contextual fear conditioning protocol. First, Swiss mice were divided into high trait anxiety (HTA) or low trait anxiety (LTA) based on their exploration of the novel environment (%TNS) in the FEP. We observed that the %TNS was stable across three testing sessions. Also, we observed that freezing behavior was not different between HTA and LTA mice in a retrieval session 1 day after the conditioning, which indicates that acquisition was not impaired. However, HTA presented higher freezing time during extinction training and test. Also, HTA presented higher freezing in reinstatement test, but this might be related to the poor extinction learning. Moreover, diazepam (0.25 or 1.0 mg/kg, i.p.) did not prevent the differences in extinction training and test when administer 30 min before conditioning training or 30 min before extinction training, even though diazepam (1.0 mg/kg) had anxiolytic effect in the elevated plus-maze. These results demonstrate that HTA mice presented increase in freezing during extinction training and test, as well as during reinstatement. These results indicate that increased freezing time in HTA mice is not explained by high state anxiety in a specific phase of the fear conditioning, but more likely, the overall high trait anxiety throughout the entire experiment.
Disturbances in the circadian rhythms have long been associated with depression and mania. Animal models of mania and depression exhibit differential effects upon the intrinsic circadian period and ...the same occurs with antidepressants and mood stabilizers treatment. The intrinsic circadian period is expressed when there are no time clues or when the light/dark cycle length is beyond the capacity of synchronization. In summary, while there is no clear association between the circadian period and mania, depressive-like behaviour is generally associated either with lengthening of the circadian period or with arrythmicity, and the improvement of depressive-like behaviour is associated with shortening of the circadian period. Thus, this review is an attempt to summarize data regarding these correlations and find a putative role of the circadian intrinsic period in mood regulation, particularly concerning the switch from depression to mania.
► Tamoxifen, a PKC inhibitor and antiestrogenic drug, blocked methylphenidate-induced hyperlocomotion. ► Medroxyprogesterone and clomiphene, antiestrogenic drugs, did not block ...methylphenidate-induced hyperlocomotion. ► These results indicated that the antimanic-like effect of tamoxifen is related to its PKC activity.
Tamoxifen, a protein kinase C (PKC) inhibitor and antiestrogenic drug, has clinical antimanic effects and blocks psychostimulant-induced hyperlocomotion. Medroxyprogesterone (MPA), which has antiestrogenic effects, also exerts some clinical benefits in female manic patients and partially blocks amphetamine-induced hyperlocomotion, indicating that the antiestrogenic effect of tamoxifen could contribute to its antimanic effect. The present study evaluated the effect of acute and chronic (21 day) treatment of two antiestrogenic drugs, MPA and clomiphene (an estrogenic receptor antagonist), on methylphenidate (MPH, 5.0
mg/kg)-induced hyperlocomotion in mice, an animal model of mania. Acute and chronic tamoxifen administration was used as a positive control. Acute and chronic tamoxifen (1.0
mg/kg) administration blocked MPH-induced hyperlocomotion. Acute and chronic MPA (acute: 3.0 or 6.0
mg/kg; chronic: 3.0
mg/kg) and clomiphene (acute: 1.5 or 3.0
mg/kg; chronic: 1.5
mg/kg) treatment did not alter MPH-induced hyperlocomotion. These results indicate that tamoxifen exerts antimanic-like effects, and reduced estrogenic activity does not have antimanic-like effects in this psychostimulant-induced hyperlocomotion model. Therefore, the antiestrogenic effect of tamoxifen likely does not contribute to its antimanic effect, which may instead be related to its effect on PKC activity. Therefore, PKC inhibition may be associated with the antimanic effect of mood stabilizers.
•Social buffering reduces freezing behavior during extinction training.•Prosocial behavior has no correlation with freezing behavior.•Social buffering does not reduce freezing when animals are ...retested alone.
Social buffering is a phenomenon in which the stress response of an individual can be reduced by the presence of another individual. However, little is known about the effect of social buffering on aversive after memory extinction, especially when animals are tested alone afterwards. The aim of this study was to verify the social buffering effect in rats during the extinction session of the contextual fear conditioning model and the fear response when animals are tested alone in the following day. Animals were divided into subjects and associates, with the subjects undergoing the fear conditioning protocol and the associates paired with the subjects during the fear extinction session. Across five different experiments, we tested moderate and high intensity contextual fear conditioning protocols, as well four variations of pairs: (i) two conditioned subjects, (ii) a conditioned subject and a non-conditioned associate, (iii) a conditioned subject and an associate who observed the conditioning of the partner and (iv) two conditioned subjects, with one treated with diazepam. The social buffering effect was found efficient to reduce the fear memory expression during the fear extinction session. In the moderate intensity protocol, the reduction in freezing time occurred only in subjects accompanied by non-conditioned associates and observer associates. In the high intensity protocol, the social buffering effect occurred in subjects accompanied by either conditioned or non-conditioned associates, although the effect was more evident in the presence of non-conditioned subjects. Treatment of the conditioned associates with diazepam did not improve the social buffering effect. Moreover, social buffering effects were not correlated with self-grooming or prosocial behaviors, which indicates that the presence of another animal might decrease freezing by promotion of exploratory activity. Finally, the social buffering effect was not observed in the extinction test, either because the extinction was too effective in the moderate intensity protocol or because the extinction was equally ineffective in the high intensity protocol. Our results suggest that social buffering does not improve fear extinction consolidation.
Rationale
We hypothesized that the corticotropin-releasing factor (CRF) system is hyperresponsive in animals with high ethanol intake, which exhibits a reduction of ethanol intake when administered ...with a CRF
1
receptor antagonist.
Methods
Outbred Swiss mice were subjected to a long-term, three-bottle, free-choice paradigm (5 and 10 %
v
/
v
ethanol and water) that consisted of four phases: acquisition (AC; 10 weeks), withdrawal (W; 2 weeks), reexposure (RE; 2 weeks), and quinine-adulteration (AD; 2 weeks). Based on individual ethanol intake, the mice were classified into three groups: A group, preference for ethanol and persistently high consumption during AD phase; B group, preference for ethanol and a reduction of ethanol intake in the AD phase; and C group; preference for water during all phases. A control group only had access to water. CRF
1
receptor messenger RNA (mRNA) levels in the amygdala and the effect of the CRF
1
receptor antagonist CP-154,526 on ethanol and water intake in the subgroups were studied.
Results
CRF
1
transcript levels were higher in the B group than in the control group. The highest dose of CP-154,526 reduced ethanol intake and preference, with no changes in water consumption, in the A group compared with vehicle. The B group exhibited a reduction of both ethanol and water intake, with no changes in preference. The C group exhibited no changes in response to the CRF
1
antagonist.
Conclusions
CRF
1
receptors appear to be involved in ethanol consumption in mice with high ethanol consumption, and CRF system-mediated neuroadaptations depend on drinking profiles.
Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are 'direct' ...effects of light on affect, an 'indirect' pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3
mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3
) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3
mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3
nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3
phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light.
There is still insufficient data about the characteristics and clinical significance of the bimodal chronotype. We evaluated more than 1000 students with Morningness-Eveningness Questionnaire, Munich ...Chronotype Questionnaire (MCTQ), Pittsburgh Sleep Quality Index and 36-item Short Form Health Survey. Twelve percent of the sample was bimodal and they showed similar results to intermediate chronotype in MCTQ-chronotype and social jetlag, both different from morning and evening chronotypes. However, their quality of life and sleep quality were similar to evening types, both different from morning and intermediate types. We discuss if being bimodal would be a maladaptive aspect of circadian preference
Background
Although TRPA1, SP, histamine and 5-hydroxytryptamine (5-HT) have recognized contribution to nociceptive mechanisms, little is known about how they interact with each other to mediate ...inflammatory pain in vivo. In this study we evaluated whether TRPA1, SP, histamine and 5-HT interact, in an interdependent way, to induce nociception in vivo.
Methods and results
The subcutaneous injection of the TRPA1 agonist allyl isothiocyanate (AITC) into the rat’s hind paw induced a dose-dependent and short lasting behavioral nociceptive response that was blocked by the co-administration of the TRPA1 antagonist, HC030031, or by the pretreatment with antisense ODN against TRPA1. AITC-induced nociception was significantly decreased by the co-administration of selective antagonists for the NK1 receptor for substance P, the H1 receptor for histamine and the 5-HT
1A or 3
receptors for 5-HT. Histamine- or 5-HT-induced nociception was decreased by the pretreatment with antisense ODN against TRPA1. These findings suggest that AITC-induced nociception depends on substance P, histamine and 5-HT, while histamine- or 5-HT-induced nociception depends on TRPA1. Most important, AITC interact in a synergistic way with histamine, 5-HT or substance P, since their combination at non-nociceptive doses induced a nociceptive response much higher than that expected by the sum of the effect of each one alone. This synergistic effect is dependent on the H1, 5-HT
1A or 3
receptors.
Conclusion
Together, these findings suggest a self-sustainable cycle around TRPA1, no matter where the cycle is initiated each step is achieved and even subeffective activation of more than one step results in a synergistic activation of the overall cycle.
•Constant light (LL) induces depressive-like behavior in rats.•Neonatal constant light prevents LL-induced depressive-like behavior in adult rats.•Social interaction with a rat exposed to neonatal ...constant light prevents LL-induced depressive-like behavior.
Circadian rhythm disruptions are often observed in depressed patients, and changes in the light/dark cycle promote depressive-like behavior in animal models. Prolonged exposure to constant light (LL) is known to lead to arrhythmicity of circadian locomotor activity and depressive-like behavior in rats. Interestingly, neonatal exposure to LL prevents both arrhythmicity and depressive behavior in adulthood. Arrhythmic rats under LL conditions that cohabitate with a rhythmic rat exhibit improvement in circadian rhythms. We tested whether such cohabitation also protects against LL-induced depressive-like behavior. Wistar rats were assigned to conditions of either neonatal constant light (neonatal-LL) on postnatal days 10–22 or a regular light/dark cycle (neonatal-LD). On day 45, the animals were assigned to three possible pair combinations. After a baseline sucrose preference test, half of the pairs were placed under LL conditions. Weekly sucrose preference tests were conducted to evaluate depressive-like behavior. The animals were isolated by an aluminum wall on the test day. At week 2 of LL, sucrose preference was reduced in neonatal-LD/neonatal-LD pairs of animals. At week 5, neonatal-LD/neonatal-LD pairs exhibited anhedonic-like behavior, but the pairs with at least one neonatal-LL rat did not. The LL cycle was returned to an LD cycle, and the neonatal-LD/neonatal-LD pairs exhibited a restoration of sucrose preference 2 weeks later. We conclude that social interaction can prevent depressive-like behavior induced by circadian rhythm disruption as long as one of the animals is more prone to present a strong rhythm.
Glucocorticoids play a role in memory formation, and they may contribute to memory changes in stress-related mental disorders, such as posttraumatic stress disorder. Cortisol may act through ...mineralocorticoid (MR) or glucocorticoid (GR) receptors, and the objective of the present study was to evaluate the effects of the MR antagonist spironolactone, the GR antagonist mifepristone, the MR agonist fludrocortisone, and the GR agonist dexamethasone on the extinction of contextually conditioned fear in rats. Propranolol was used as a positive control. As expected, propranolol administered before the test session increased memory extinction. Pre-test administration of spironolactone and low-dose dexamethasone also increased the extinction of an aversive memory, whereas fludrocortisone impaired extinction. High-dose dexamethasone and mifepristone were found to have no effect in this model. Post-test spironolactone treatment impaired aversive memory extinction. These results indicate that MR and GR are related to extinction of aversive memories, and MR blockade may be a promising candidate for the treatment of stress-related memory disorders.
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