Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?

Abstract

The neurosteroid allopregnanolone (3α‐hydroxy‐5α‐pregnan‐20‐one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti‐inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABAA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors. In keeping with this evidence, AP has been shown to exert rapid, potent antidepressant properties and has been recently approved for the therapy of moderate‐to‐severe postpartum depression. In addition to depression, emerging evidence points to the potential of AP as a therapy for other neuropsychiatric disorders, including anxiety, seizures, post‐traumatic stress disorder and cognitive problems. Although this evidence has spurred interest in further therapeutic applications of AP, some investigations suggest that this neurosteroid may also be associated with adverse events in specific disorders. For example, our group has recently documented that AP increases tic‐like manifestations in several animal models of tic disorders; furthermore, our results indicate that inhibiting AP synthesis and signalling reduces the exacerbation of tic severity associated with acute stress. Although the specific mechanisms of these effects remain partially elusive, our findings point to the possibility that the GABAergic activation by AP may also lead to disinhibitory effects, which could interfere with the ability of patients to suppress their tics. Future studies will be necessary to verify whether these mechanisms may apply to other externalising manifestations, such as impulse‐control problems and manic symptoms.

Altered visual cortex excitability in premenstrual dysphoric disorder: Evidence from magnetoencephalographic gamma oscillations and perceptual suppression

“…During this phase, the δGABA A Rs-mediated inhibition is potentiated by ALLO (see the previous section). On the other hand, the δGABA A Rs-mediated inhibition is further increased in response to acute stress [162][163][164]. The increase in δGABA A Rs-mediated tonic inhibition is expected to dampen excitability of PV+ inhibitory neurons, whose tonic inhibition is exclusively mediated by δGABA A Rs [165,166].…”

Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology

“…Given that AP activates both extrasynaptic and synaptic GABA A receptors, and that its affinity for different targets is influenced by the specific subunit composition of these ionotropic channels 63 , it is likely that sudden elevations of AP in the mPFC can alter the balance between excitatory and inhibitory neural activity in this region and in its connectivity with the striatum. From a translational perspective, it is worth noting that activation of the PFC has been extensively linked to tic suppression in TS [64][65][66] , and that preliminary evidence suggests that the main adverse effect of acute stress in TS may lie in the disruption of tic suppression efforts 67 (see 68 for a detailed discussion of this potential mechanism).…”

Altered visual cortex excitability in premenstrual dysphoric disorder: evidence from magnetoencephalographic gamma oscillations and perceptual suppression

“…During this phase, the δGABA A Rs-mediated inhibition is potentiated by ALLO (see the previous section). On the other hand, the δGABA A Rs-mediated inhibition is further increased in response to acute stress (Bali & Jaggi, 2014; Biggio et al, 2014; Bortolato et al, 2022). The increase in δGABA A Rs-mediated tonic inhibition is expected to dampen excitability of PV+ inhibitory neurons, whose tonic inhibition is exclusively mediated by δGABA A Rs (Ferando & Mody, 2014; Lee & Maguire, 2013).…”

“…During this phase, the δGABA A Rsmediated inhibition is potentiated by ALLO (see the previous section). On the other hand, the δGABA A Rs-mediated inhibition is further increased in response to acute stress (Bali & Jaggi, 2014;Biggio et al, 2014;Bortolato et al, 2022). The increase in…”