Geon Memory Extinction: The Role of Dopamine Memory

 

Dopamine has at least five receptor subtypes, designated as D1 - D5. They all belong to G protein-coupled receptors. In most reports, activation of either D1 or D2 receptor by dopamine enhanced memory extinction (Abraham et al., 2014; Abraham et al., 2016; Mueller et al., 2010). D1 and D2 mediate two distinct signaling pathways, how can both promote extinction?

The activation of D1 receptors can stimulate two different pathways, depending on the coupled G proteins. One of them involves adenylate cyclase (AC) and PKA; the other triggers the phospholipase C (PLC)/Ca2+ cascade. The D2 receptor stimulates the PLC/Ca2+ pathway but inhibits the AC/PKA pathway (Abraham et al., 2014, Figure 1). As mentioned in Chapter 17, the elevated Ca2+ level can activate the AC subtype 1 to increase PKA activity. It can also enhance the CaN activity. However, because D2 inhibits the AC/PKA pathway, its overall effects should be the enhancement of CaN which, according to the present model, should promote memory extinction.

The effects of D1 is more complex, as it may enhance the activities of PKA and CaN, the two competing factors for the phosphorylation state of S1166 in GluN2B. Recalling that the basal level of PKA is sufficient to phosphorylate S1166 in most GluN2B-containing NMDARs Chapter 17, the enhancement of PKA activity should have little impact on memory extinction. Therefore, the observation that D1 activation promotes extinction may result from S1166 dephosphorylation by CaN via the PLC/Ca2+ pathway. This interpretation is corroborate by the finding that a cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction (Abraham et al., 2016).

 

Author: Frank Lee
First published: January, 2018