Amygdalar activation of group I metabotropic glutamate receptors produces anti- and pro-conflict effects depending upon animal sex in a sexually dimorphic conditioned conflict-based anxiety model

Jesus-Burgos, Maria Ines De; Gonzalez-Garcia, Stephanie; Cruz-Santa, Yanira; Pérez-Acevedo, Nivia L.

doi:10.1016/j.bbr.2016.01.009

Cited by 14 publications

(8 citation statements)

References 50 publications

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“…While mGlu5 receptors represent a promising target for reducing conditioned fear, mGlu5 agonists can produce anxiogenic effects under certain conditions (De Jesús-Burgos et al, 2016; Rahman et al, 2017). Therefore, we evaluated the ability of CDPBB to alter unconditioned fear in the light-dark box.…”

Section: Discussionmentioning

confidence: 99%

The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats

Shallcross

Hámor

Bechard

et al. 2019

Front. Behav. Neurosci.

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Post-traumatic stress disorder (PTSD) currently has no FDA-approved treatments that reduce symptoms in the majority of patients. The ability to extinguish fear memory associations is impaired in PTSD individuals. As such, the development of extinction-enhancing pharmacological agents to be used in combination with exposure therapies may benefit the treatment of PTSD. Both mGlu5 and CB1 receptors have been implicated in contextual fear extinction. Thus, here we tested the ability of the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and cannabidiol (CBD) to reduce both conditioned and unconditioned fear. We used a predator-threat animal model of PTSD which we and others have previously shown to capture the heterogeneity of anxiety responses observed in humans exposed to trauma. Here, 1 week following a 10-min exposure to predator scent stress, rats were classified into stress-Susceptible and stress-Resilient phenotypes using behavioral criteria for elevated plus maze and acoustic startle response performance. Two weeks after classification, rats underwent 3 days of contextual fear extinction and were treated with vehicle, CDPPB or CBD prior to each session. Finally, the light-dark box test was employed to assess phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety. CDPBB but not CBD, reduced freezing in Susceptible rats relative to vehicle. In the light-dark box test for unconditioned anxiety, CBD, but not CDPPB, reduced anxiety in Susceptible rats. Resilient rats displayed reduced anxiety in the light-dark box relative to Susceptible rats. Taken together, the present data indicate that enhancement of mGlu5 receptor signaling in populations vulnerable to stress may serve to offset a resistance to fear memory extinction without producing anxiogenic effects. Furthermore, in a susceptible population, CBD attenuates unconditioned but not conditioned fear. Taken together, these findings support the use of predator-threat stress exposure in combination with stress-susceptibility phenotype classification as a model for examining the unique drug response profiles and altered neuronal function that emerge as a consequence of the heterogeneity of psychophysiological response to stress.

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Section: Discussionmentioning

confidence: 99%

The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats

Shallcross

Hámor

Bechard

et al. 2019

Front. Behav. Neurosci.

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“…The research addressing female anxiety-like responses is somewhat mixed. For example, while female rodent anxiety-like behavior is lower than males in an elevated plus maze and open field (see [ 199 ]), other studies find greater female anxiety-like behavior with predator odor (see [ 200 ]) and foot-shock induced licking [ 201 , 202 ]. Additionally, females generally display greater locomotion than males during open field tests and other anxiety tasks [ 203 , 204 , 205 ], and seem to show greater active responses under several anxiety-related conditions, including where females tend to dart (whereas males tend to freeze) in response to fear [ 197 ], females avoid rather than freeze in a shuttle-box task [ 203 ], and females display more active defensive behaviors under some social stressors vs. males [ 193 , 200 , 203 ].…”

Section: Sex Differences In Anxiety Are Likely Important For Alcohmentioning

confidence: 99%

“…Studies of the estrous cycle and anxiety-like behavior in rodents have both consistent patterns but also mixed findings. For example, several studies find reduced anxiety-like behavior during proestrus [ 74 , 105 , 106 ], while shock-licking behavior can be unrelated to estrous cycle phases [ 201 ]. Thus, understanding how anxiety/addiction are impacted by estrous cycle phases will be especially important for a nuanced and complete understanding of female anxiety and comorbid conditions.…”

Section: Sex Differences In Anxiety Are Likely Important For Alcohmentioning

confidence: 99%

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking

Radke

Sneddon

Frasier

et al. 2021

IJMS

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Alcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment.

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“…Regarding this topic and anxiety-related behaviors, direct infusion of Group 1 mGlu agonists, stimulating both mGlu 1a and mGlu 5 , into the basolateral amygdala (BLA) produces anxiolytic effects only in the presence of estradiol in ovariectomized female rats in a generalized anxiety model conducted in the absence of white light [69]. Similarly, in a conflict-based anxiety model, stimulation of group 1 mGlu in the BLA had sex specific effects, presenting anxiolytic effects in ovariectomized females but anxiogenic effects in males [70]. These manuscripts suggest a significant and widespread sex-sensitive role in ER/ mGlu interactions in the context of various types of anxiety.…”

Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor subtype 5 (mGlu5) is necessary for estradiol mitigation of light-induced anxiety behavior in female rats

Miller

Krentzel

Patisaul

et al. 2020

Physiology & Behavior

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Anxiety-related behaviors are influenced by steroid hormones such as 17β-estradiol and environmental stimuli such as acute stressors. For example, rats exhibit increased anxiety-related behaviors in the presence, but not the absence, of light. In females, estradiol potentially mitigates these effects. Experiments across behavioral paradigms and brain regions indicate that estradiol action can be mediated via activation of metabotropic glutamate receptors, including Group I subtype five (mGlu 5 ). mGlu 5 has been implicated in mediating estradiol's effects upon psychostimulant-induced behaviors, dopamine release and neuron phenotype in striatal regions. Whether estradiol activation of mGlu 5 modulates anxiety or locomotor behavior in the absence of psychostimulants is unknown. Here we test if mGlu 5 is necessary for estradiol mitigation of lightinduced acute anxiety and locomotor behaviors. Ovariectomized adult female rats were pretreated with either the mGlu 5 antagonist MPEP or vehicle before estradiol or oil treatment. Anxiety and locomotor behaviors were assessed in the presence or absence of white light to induce high and low acute anxiety behavior phenotypes, respectively. In the presence of white light, estradiol treatment mitigated light-induced anxiety-related behaviors but not overall locomotor activity. MPEP treatment blocked estradiol effects upon light-induced anxiety-related behaviors but did not affect overall locomotor activity. In the absence of white light, estradiol or MPEP treatment did not influence anxiety-related behaviors or locomotor activity, consistent with a low anxiety phenotype. These novel findings indicate that mGlu 5 activation is necessary for estradiol mitigation of anxiety-related behaviors induced by an acute stressor.

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Amygdalar activation of group I metabotropic glutamate receptors produces anti- and pro-conflict effects depending upon animal sex in a sexually dimorphic conditioned conflict-based anxiety model

Cited by 14 publications

References 50 publications

The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats

The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking

Metabotropic glutamate receptor subtype 5 (mGlu5) is necessary for estradiol mitigation of light-induced anxiety behavior in female rats

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