Aromatized testosterone attenuates contextual generalization of fear in male rats

Lynch, Joseph F.; Vanderhoof, Tyler; Winiecki, Patrick; Latsko, Maeson S.; Riccio, David C.; Jasnow, Aaron M.

doi:10.1016/j.yhbeh.2016.06.007

Cited by 15 publications

(14 citation statements)

References 98 publications

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“…This analysis included anxiety‐like behaviour that was tested using the elevated plus maze. However, similar to other relevant published experiments, the mice were tested at the age of 10 weeks as young adults. This might explain the different outcomes found in our experiment conducted on middle‐aged animals.…”

Section: Discussionmentioning

confidence: 99%

“…Intracerebroventricular administration of letrozole led to an increase in anxiety in male rats when assessed in the open field test . Recently, it has been demonstrated that the administration of the aromatase inhibitor, fadrozole, leads to fear generalization in the passive avoidance chamber in male rats . All of these experiments have one thing in common‐they were conducted on young adult animals.…”

Section: Introductionmentioning

confidence: 99%

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Sex‐dependent effects of letrozole on anxiety in middle‐aged rats

Borbélyová

Domonkos

Csongová

et al. 2017

Clin Exp Pharma Physio

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Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex‐dependent effects of letrozole on anxiety in middle‐aged rats

Borbélyová

Domonkos

Csongová

et al. 2017

Clin Exp Pharma Physio

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“…Recently, we found that estrogen treatment modifies CeL c-fos expression during extinction training to enhance extinction recall, increasing CeL neuronal activity as we found in this study (Maeng et al, 2017). Furthermore, Lynch et al (2016) demonstrated that contextual fear generalization, another symptomatic feature of PTSD, is more pronounced in males that had been administered Fadrozole and thus had lower levels of estrogen. This finding, together with those of the present study, strongly suggests that testosterone’s conversion to estrogen plays a critical role in enhancing the consolidation of the fear extinction memory in males.…”

Section: Discussionmentioning

confidence: 99%

Acute gonadotropin-releasing hormone agonist treatment enhances extinction memory in male rats

Maeng

Taha

Cover

et al. 2017

Psychoneuroendocrinology

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Leuprolide acetate (LEU), also known as Lupron, is commonly used to treat prostate cancer in men. As a gonadotropin-releasing hormone (GnRH) receptor agonist, it initially stimulates the release of gonadal hormones, testosterone (T) and estradiol. This surge eventually suppresses these hormones, preventing the further growth and spread of cancer cells. Individuals receiving this treatment often report anxiety and cognitive changes, but LEU’s effects on the neural mechanisms that are involved in anxiety during the trajectory of treatment are not well known. In this study, we examined the acute effects of LEU on fear extinction, hypothesizing that increased T levels following a single administration of LEU will facilitate extinction recall by altering neuronal activity within the fear extinction circuitry. Two groups of naïve adult male rats underwent a 3-day fear conditioning, extinction, and recall experiment. The delayed group (n=15) received a single injection of vehicle or LEU (1.2mg/kg) 3 weeks before behavioral testing. The acute group (n=25) received an injection one day after fear conditioning, 30 minutes prior to extinction training. Following recall, the brains for all animals were collected for c-fos immunohistochemistry. Blood samples were also collected and assayed for T levels. Acute administration of LEU increased serum T levels during extinction training and enhanced extinction recall 24h later. This enhanced extinction memory was correlated with increased c-fos activity within the infralimbic cortex and amygdala, which was not observed in the delayed group. These results suggest that the elevation in T induced by acute administration of LEU can influence extinction memory consolidation, perhaps through modification of neuronal activity within the infralimbic cortex and amygdala. This may be an important consideration in clinical applications of LEU and its effects on anxiety and cognition.

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“…As with estrogen in females, testosterone in males is likewise capable of modulating the processing of fear memory. Gonadectomized male rats exhibit generalized fear to a neutral context in a passive avoidance task, which is ameliorated by injection with testosterone (Lynch et al, 2016a).…”

Section: Molecular and Cellular Mechanisms Of Fear Generalizationmentioning

confidence: 99%

The Neurobiology of Fear Generalization

Asok

Kandel

Rayman

2019

Front. Behav. Neurosci.

131

102

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The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. When confronted with a potential threat, an animal must select an appropriate defensive response based on previous experiences that are not identical, weighing cues and contextual information that may predict safety or danger. Like other aspects of fear memory, generalization is mediated by the coordinated actions of prefrontal, hippocampal, amygdalar, and thalamic brain areas. In this review article, we describe the current understanding of the behavioral, neural, genetic, and biochemical mechanisms involved in the generalization of fear. Fear generalization is a hallmark of many anxiety and stress-related disorders, and its emergence, severity, and manifestation are sex-dependent. Therefore, to improve the dialog between human and animal studies as well as to accelerate the development of effective therapeutics, we emphasize the need to examine both sex differences and remote timescales in rodent models.

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Aromatized testosterone attenuates contextual generalization of fear in male rats

Cited by 15 publications

References 98 publications

Sex‐dependent effects of letrozole on anxiety in middle‐aged rats

Sex‐dependent effects of letrozole on anxiety in middle‐aged rats

Acute gonadotropin-releasing hormone agonist treatment enhances extinction memory in male rats

The Neurobiology of Fear Generalization

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