Abstract
In this review, we describe proposed circuits mediating the mechanism of action of pherines, a new class of synthetic neuroactive steroids with demonstrated antianxiety and antidepressant properties, that engage nasal chemosensory receptors. We hypothesize that afferent signals triggered by activation of these peripheral receptors could reach subgroups of olfactory bulb neurons broadcasting information to gamma-aminobutyric acid (GABAergic) and corticotropin-releasing hormone (CRH) neurons in the limbic amygdala. We propose that chemosensory inputs triggered by pherines project to centrolateral (CeL) and centromedial (CeM) amygdala neurons, with downstream effects mediating behavioral actions. Anxiolytic pherines could activate the forward inhibitory GABAergic neurons that facilitate the release of neuropeptide S (NPS) in the locus coeruleus (LC) and GABA in the bed nucleus of the stria terminalis (BNST) and inhibit catecholamine release in the LC and ventral tegmental area (VTA) leading to rapid anxiolytic effect. Alternatively, antidepressant pherines could facilitate the CRH and GABAergic neurons that inhibit the release of NPS from the LC, increase glutamate release from the BNST, and increase norepinephrine (NE), dopamine (DA), and serotonin release from the LC, VTA, and raphe nucleus, respectively. Activation of these neural circuits leads to rapid antidepressant effect. The information provided is consistent with this model, but it should be noted that some steps on these pathways have not been demonstrated conclusively in the human brain.
Highlights
In the early 1990s, we reported that naturally occurring steroidal molecules in humans androsta4,16-dien-3-one (ER670, PH56 or androstadienone (ADO)) and estra-1,3,5,(10,16-tetraen-3-ol (ER830, PH78 or estratetraenol (ETE)), administered in concentrations below olfactory threshold can induce depolarization of the local electrogram recorded from the nasal chemosensory mucosa in human subjects.[1]
They are wired to the limbic amygdala, HYP, and hippocampus, which provides olfaction with a unique and potent power to influence mood, acquisition of new information, and its use in many different contexts including social interaction, fear, emotions, and the memory components of behavior.[74,75,76,77,78,79,80]
It is reasonable to assume that in humans, there are functional neural circuits reporting afferent information from olfactory chemosensory receptors, via the olfactory bulbs (OB), to the basal forebrain areas (Figure 3) that influence behavior, mood, and emotions, and that the neuroanatomical areas involved are the same as the dysfunctional areas described in laboratory animals with bilateral olfactory bulbectomy[81,82,83] and in subjects with congenital absence of OB, who develop anxiety and depression in early life.[84,85,86,87,88]
Summary
Natural steroidal chemosignals active in human nasal receptorsIn the early 1990s, we reported that naturally occurring steroidal molecules in humans androsta4,16-dien-3-one (ER670, PH56 or androstadienone (ADO)) and estra-1,3,5,(10,16-tetraen-3-ol (ER830, PH78 or estratetraenol (ETE)), administered in concentrations below olfactory threshold can induce depolarization of the local electrogram recorded from the nasal chemosensory mucosa in human subjects.[1]. These results are not consistent with the positive effects of low doses of odorless ADO (below olfactory threshold and without using odor masking) reported in women volunteers.[3,5] the “high social anxiety” subjects had lower baseline LSAS scores than those required (LSAS ≥ 60) in studies of the therapeutic effect of intranasally administered pherines in subjects with social anxiety disorder (see section: mean LSAS on entrance was 97.9).[24,25]
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