RESUMO

Despite being one of the main components of anxiety and playing a pivotal role in how an individual perceives and copes with anxiogenic situations or responds to a given treatment, trait anxiety is paradoxically omitted in most animal models of anxiety. This is problematic and particularly more concerning in models that are used to screen drugs and other treatments for specific anxiety disorders and to investigate their neurobiological mechanisms. Our group has been engaged in the search for specific anxiety-related traits in animal models of anxiety. We developed two new lines of rats with strong phenotypic divergence for high (Carioca High-conditioned Freezing [CHF]) and low (Carioca Low-conditioned Freezing [CLF]) trait anxiety as expressed in the contextual fear conditioning paradigm. Here, we summarize key behavioral, pharmacological, physiological, and neurobiological differences in one these lines, the CHF rat line, relative to randomized-cross controls and discuss how far they represent a valid and reliable animal model of generalized anxiety disorder and so high trait anxiety.

RESUMO

The participation of the hippocampal formation in consolidation and reconsolidation of contextual fear memories has been widely recognized and known to be dependent on the activation of the cAMP response element (CRE) binding protein (CREB) pathway. Recent findings have challenged the prevailing view that over time contextual fear memories migrate to neocortical circuits and no longer require the hippocampus for retrieval of remote fearful memories. It has also recently been found that this brain structure is important for the maintenance and recall of remote fear memories associated with aversive events, a common trait in stress-related disorders such as generalized anxiety disorder (GAD), major depression, and post-traumatic stress disorder. In view of these findings, here we examined the putative role of CREB in the hippocampus of an animal model of GAD during the retrieval of remote contextual fear memories. Specifically, we evaluated CREB phosphorylation in the hippocampus of male Carioca High- and Low-conditioned Freezing rats (CHF and CLF, respectively) upon re-exposure of animals to contextual cues associated to footshocks weeks after fear conditioning. Age-matched male rats from a randomized crossbreeding population served as controls (CTL). Adrenal catecholamine levels were also measured as a biological marker of stress response. Seven weeks after contextual fear conditioning, half of the sample of CHF (n = 9), CLF (n = 10) and CTL (n = 10) rats were randomly assigned to return to the same context chamber where footshocks were previously administrated (Context condition), while the remaining animals were individually placed in standard housing cages (Control condition). Western blot results indicated that pCREB levels were significantly increased in the hippocampus of CHF rats for both Context and Control conditions when compared to the other experimental groups. CHF rats in the Context condition also exhibited significant more freezing than that observed for both CLF and CTL rats. Lastly, CHF animals in the Context condition displayed significantly higher adrenal catecholamine levels than those in the Control condition, whereas no differences in catecholamine levels were observed between Context and Control conditions for CLF and CTL rats. These findings are discussed from a perspective in which the hippocampus plays a role in the maintenance and recall of remote contextual fear memories via the CREB pathway.

Assuntos

Encéfalo , Medo , Ratos , Masculino , Animais , Fosforilação , Medo/fisiologia , Encéfalo/metabolismo , Hipocampo/fisiologia , Catecolaminas/metabolismo

RESUMO

Animal models are important tools for studying neuropsychological disorders. Considering their limitations, a more extensive translational research must encompass data that are generated from several models. Therefore, a comprehensive characterization of these models is needed in terms of behavior and neurophysiology. The present study evaluated the behavioral responses of Carioca Low-conditioned Freezing (CLF) rats to haloperidol and methylphenidate. The CLF breeding line is characterized by low freezing defensive responses to contextual cues that are associated with aversive stimuli. CLF rats exhibited a delayed response to haloperidol at lower doses, needing higher doses to reach similar levels of catatonia as control randomly bred animals. Methylphenidate increased freezing responses to conditioned fear and induced motor effects in the open field. Thus, CLF rats differ from controls in their responses to both haloperidol and methylphenidate. Because of the dopamine-related molecular targets of these drugs, we hypothesize that dopaminergic alterations related to those of animal models of hyperactivity and attention disorders might underlie the observed phenotypes of the CLF line of rats.

Assuntos

Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Haloperidol/farmacologia , Metilfenidato/farmacologia , Animais , Ansiedade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Hipercinese/tratamento farmacológico , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar

RESUMO

Anxiety disorders (AD) comprise a broad range of psychiatric conditions, including general anxiety (GAD) and specific phobias. For the last decades, the use of animal models of anxiety has offered important insights into the understanding of the association between these psychopathologies. Here, we investigate whether Carioca high- and low-conditioned freezing rats (CHF and CLF, respectively), a GAD animal model of anxiety, show similar high- and low-freezing behavioral phenotypes for cued auditory fear conditioning. Adult CHF (n = 16), CLF (n = 16) and normal age-matched Wistar rats (control, CTL, n = 16) were tested in a classical auditory-cued fear conditioning paradigm over 3 days (Tone + Shock and Tone only groups, n = 8 per treatment). Freezing responses were measured and used as evidence of fear conditioning. Overall, both CHF and CLF rats, as well as CTL animals displayed fear conditioning to the auditory CS. However, CLF animals showed a rapid extinction to the auditory conditioned stimulus compared to CHF and CTL rats. We discuss these findings in the context of the behavioral and neuronal differences observed in rodent lines of high and low anxiety traits.