Exogenous progesterone exacerbates running response of adolescent female mice to repeated food restriction stress by changing α4-GABAA receptor activity of hippocampal pyramidal cells

Abstract

Adolescent females are particularly vulnerable to mental illnesses with comorbidity of anxiety, such as anorexia nervosa (AN). We used an animal model of AN, called activity-based anorexia (ABA), to investigate the neurobiological basis of vulnerability to repeated, food restriction (FR) stress-evoked anxiety. Twenty-one of 23 adolescent female mice responded to the 1st FR with increased wheel running activity (WRA), even during the limited period of food access, thereby capturing AN's symptoms of voluntary FR and over-exercise. Baseline WRA was an excellent predictor of FR-elicited WRA (severity of ABA, SOA), with high baseline-runners responding to FR with minimal SOA (i.e., negative correlation). Nine gained resistance to ABA following the 1st FR. Even though allopregnanolone (3α-OH-5α-pregnan-20-one, THP), the metabolite of progesterone (P4), is a well-recognized anxiolytic agent, subcutaneous P4 to these ABA-resistant animals during the 2nd FR was exacerbative, evoking greater WRA than the counterpart resistant group that received oil vehicle, only. Moreover, P4 had no WRA-reducing effect on animals that remained ABA-vulnerable. To explain the sensitizing effect of P4 upon the resistant mice, we examined the relationship between P4 treatment and levels of the α4 subunit of GABAARs at spines of pyramidal cells of the hippocampal CA1, a parameter previously shown to correlate with resistance to ABA. α4 levels at spine membrane correlated strongly and negatively with SOA during the 1st ABA (prior to P4 injection), confirming previous findings. α4 expression levels were greater among P4-treated animals that had gained resistance than of vehicle-treated resistant animals or of the vulnerable animals with or without P4. We propose that α4-GABAARs play a protective role by counterbalancing the ABA-induced increase in excitability of CA1 pyramidal neurons, and although exogenous P4's metabolite, THP, enhances α4 expression, especially among those that can gain resistance, it also interferes with α4-GABAARs’ protective role by desensitizing α4-GABAARs.

NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise

“…During these periods of elevated stress, transient inactivation of α4βδ-GABA A Rs enables animals to fully utilize NMDARs for hippocampal LTP induction, learning and memory formation (Shen et al 2010). As expected, exogenous progesterone, which metabolizes to allopregnanolone, exacerbates ABA vulnerability, characterized by food-restriction-evoked hyperactivity (Wable et al 2015a). Other candidate receptors that have yet to be analyzed for their correlation with wheel running include AMPA receptors, for which no data are yet available, and serotonin 5HT4 receptors, shown to lead to anorexia-like behavior when over-expressed in the prefrontal cortex (Compan et al 2015).…”

“…While capturing the above symptoms of AN, ABA also reveals individual differences in vulnerability, quantified as the extent of food-restriction-evoked hyperactivity and weight loss (Aoki et al 2014; Chen et al 2016; Chowdhury et al 2013; Wable et al 2015a, b; Nedelescu et al 2016). Since excitability of the hippocampus is strongly linked to stress-induced anxiety (Shen et al 2007), and the extent of food-restriction-evoked anxiety is correlated with wheel running (Wable et al 2015b), we hypothesized that individual differences in wheel running might be influenced by the excitability of hippocampal neurons.…”

Synaptic changes in the hippocampus of adolescent female rodents associated with resilience to anxiety and suppression of food restriction-evoked hyperactivity in an animal model for anorexia nervosa

“…While most reviews consider the role of estrogen in anorexia nervosa, as it interacts with the dopamine, serotonin and neuropeptide systems within brains of individuals with anorexia nervosa (Casper et al, 2008; Kaye et al, 2009). In addition, the metabolite of progesterone, THP (3α,5α[β]-tetrahydroprogesterone, or 3αOH–5α [β]-pregnan-20-one), may increase an individual’s vulnerability to anorexia nervosa, through a Cl − flux-dependent desensitization of the ionotropic GABA (γ-aminobutyric acid) receptors expressed by CA1 pyramidal cells (Shen et al, 2007; Smith et al, 2009; Wable et al, 2015a). …”

“…This involves the up-regulation of α4βδ-GABA A receptors (GABA A Rs) that occur adjacent to excitatory synapses formed onto dendritic spines in SR of the CA1. Quantitative electron microscopic immunocytochemistry reveals that the more that animals were able to suppress wheel running, higher is the frequency of α4βδ-GABA A Rs occurring adjacent to excitatory axo-spinous synapses of the dorsal hippocampal CA1 pyramidal cells (Wable et al, 2015a)(Fig. 6).…”

The Role of Psychotropic Medications in the Management of Anorexia Nervosa: Rationale, Evidence and Future Prospects

“…That study indicated that 20 and 40mg/kg of agmatine ameliorated ABA weight loss and plasma corticosterone increase suggesting a protective effect, possibly mediated via blockade of dopamine D2 and activation of 5-HT1A receptors [129]. A recent ABA study suggested that progesterone interacts with α4-GABA receptors and worsens wheel-running behavior [130], supporting the notion the increased hormone release during puberty is a vulnerability in some to develop AN [131]. Brain reward learning is altered in AN, behavior that has been associated with brain dopamine function suggesting that dopaminergic agents could ameliorate this dysfunction [132].…”