In order to simplify this drawing only selected intracellular events are presented. Upon binding of their ligand (L), G-protein coupled receptors (GPCR, red receptor) such as metabotropic glutamate receptors (mGluR), 5-HT receptors, GABA_B receptors, µ opioids receptors, α- and β-adrenergic receptors activate different intracellular signaling pathways through their G protein (made of α and β subunits). The activation of the G protein can lead to the activation of phospholipase C (PLC; not shown) that catalyzes the hydrolysis of membrane-associated phosphatidyl-inositol 4,5-biphosphate (PIP2) into 1,4,5 triphosphate (IP₃) and diacylglycerol (DAG). IP₃ induces calcium release from the intracellular stores (reticulum endoplasmic). DAG activates protein kinase C (PKC). In turn, PKC can stimulate, through phosphorylation (P), the activity of adenylate cyclase (AC) to produce cAMP and activate protein kinase A (PKA). PKA can also phosphorylate various proteins such as other receptors, ion channels (such as Type-L voltage-gated Ca²⁺ channels [L-VGCC], G-protein-coupled, inwardly rectifying K⁺ channels [GIRK] or the small conductance, Ca²⁺-dependent K⁺ channel [SK]) or cAMP-responsive binding protein (CREB). Rapid non genomic signaling: 1/ Estradiol (E₂, yellow star) can allosterically modulate the activity of ionotropic receptors (such as acetylcholine, kainate or NMDA receptors, orange receptors) or GPCR by directly interacting with this receptor. 2/ E₂ can also activate a membrane-bound estrogen receptors (mER, blue receptor; the term is used here in a general way to cover both ERα and ERβ associated with the membrane and the more recently identified estrogen membrane receptor [GPR30, ER-X, etc] specifically named mER) that is coupled to a G protein. Thereby, E₂ can modulate the activity of ionic conductance through phosphorylation of ionotropic receptors or uncoupling (dashed arrows) of GPCR from their ionic channels or intracellular effectors (not shown). It can also mobilize intracellular Ca²⁺ through activation of PLC or uncoupling of a GPCR from PLC (not shown). Delayed genomic signaling: E₂ can bind to nuclear estrogen receptors (ER) that form dimers and bind the estrogen-responsive element (ERE) on the DNA resulting in the activation of the transcription of specific genes. In addition, rapid effects of E₂ mediated through mER resulting in the activation of protein kinases can lead to phosphorylation of CREB, which can alter gene transcription through its interaction with the cAMP responsive element (CRE; indirect genomic effect).

On the one hand, genomic effects are associated with a slow rise of testosterone concentrations in the plasma. These changes are correlated with changes in testis function at puberty and across seasons. This rise in plasma testosterone results in an increased aromatase activity in the brain (through an activation of transcription of its gene). The estrogens produced locally by the aromatization of testosterone influence the transcription of various genes ultimately resulting in long lasting behavioral changes. On the other hand, non-genomic effects are associated with rapid changes in estrogens bio-availability. Such rapid changes in brain estrogen concentrations could result from variations of plasma testosterone that is subsequently aromatized locally into estrogen by brain aromatase as well as from variations in neurotransmitters’ activity, such as glutamate or dopamine, that rapidly regulate brain aromatase activity and the subsequent production of estrogen. These fast changes in brain estrogen concentrations could in turn induce fast non-genomic actions in specific cell populations that would ultimately result in fast behavioral effects. In both cases, aromatase concentration remains constant and either the substrate of the enzyme (testosterone) rapidly becomes more concentrated resulting in an increased product formation or the substrate remains constant but the rate of conversion into estrogen (the enzymatic efficiency) is rapidly increased.