Signaling via Dopamine D1 and D3 Receptors Oppositely Regulates Cocaine-Induced Structural Remodeling of Dendrites and Spines

Abstract

Repeated exposure to cocaine can induce persistent alterations in the brain. The structural remodeling of dendrites and dendritic spines is thought to play a critical role in cocaine addiction. We previously demonstrated that signaling via dopamine D1 and D3 receptors have opposite effects on cocaine-induced gene expression. Here, we show that cocaine-induced structural remodeling in the nucleus accumbens (NAc) and caudoputamen (CPu) is mediated by D1 receptors and inhibited by D3 receptors. In addition, chronic exposure to cocaine results in an altered number of asymmetric spine synapses via the actions of both D1 and D3 receptors. The contradictory effects of D1 and D3 receptor signaling on cocaine-induced structural remodeling is associated with NMDA-receptor R1 subunit (NR1) phosphorylation, and is dependent upon the activation of extracellular signal-regulated kinase (ERK). In addition, we found that D1 and D3 receptor signaling has contradictory effects upon the activation of the myocyte enhancer factor 2 (MEF2), which is involved in the dendritic remodeling after cocaine treatment. Together, these data suggest that dopamine D1 and D3 receptors differentially regulate the cocaine-induced structural remodeling of dendrites and spines via mechanisms involving the consecutive actions of NR1 phosphorylation, ERK activation, and MEF2 activity in the NAc and CPu.

Activation of Dopamine D1 Receptors Regulates Dendritic Morphogenesis Through Rac1 and RhoA in Prefrontal Cortex Neurons

“…Next, we found that pretreatment of PFC neurons with a D1 receptor inhibitor impaired the ability of DA to induce dendritic morphogenesis. Together with our previous data indicating that treatment with SKF81297, an agonist of the D1 receptor, led to an increase in the dendritic branching and spine density of PFC neurons [52, 60], the current data suggest that the DA-induced structural morphogenesis of the dendrites and spines of PFC neurons is regulated by the D1 receptor.…”

The Addiction-Related Gene Ankk1 is Oppositely Regulated by D1R- and D2R-Like Dopamine Receptors

“…The D2R-like agonist 7-OH-DPAT, that causes Ankk1 inhibition, has been associated with an inhibitory effect on the mesocorticolimbic dopaminergic system (Devoto et al 1995) and with attenuation of the rewarding effects of cocaine and cocaine-seeking behavior (Pilla et al 1999). A pattern of opposite regulation enhanced by D1R-like and inhibited by D2R-like has also been found, after cocaine administration, in the striatum for the extracellular-signal regulated kinases 1 and 2 (ERK1 and ERK2) (Zhang et al 2004) as well as in the structural remodeling of dendrites and spines (Zhang et al 2012).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…A short withdrawal period (2 days) results in increased dendritic spine formation-mediated by a variety of transcription factors and epigenetic mechanisms as discussed later-in both D 1 R-and D 2 R-MSNs, whereas this increase is only sustained in D 1 R-MSNs after prolonged withdrawal of 30 days . In addition, both D 1 R-and D 2 R-MSNs exhibit dendritic remodeling on chronic cocaine exposure, which can be mediated by D 1 R activation Zhang et al, 2012). Furthermore, spine structure varies considerably as well.…”