Mechanisms by which Dopamine Receptors May Influence Synaptic Plasticity

Abstract

While dopamine (DA) receptors mediate acute effects of amphetamine and cocaine, chronic drug administration produces many glutamate-dependent adaptations, including LTP in reward-related neuronal circuits. An important question presents itself: How do DA receptors influence glutamate-dependent synaptic plasticity? Alterations in AMPA receptor phosphorylation and trafficking are critical for LTP. We hypothesize that D1 DA receptors modulate these processes, that chronic drug-induced adaptations in D1 receptor signaling, therefore, trigger compensatory changes in AMPA receptor function, and that this ultimately contributes to inappropriate plasticity in addiction-related neuronal circuits. Postnatal rat nucleus accumbens (NAc) cultures were used to study D1 receptor regulation of the AMPA receptor subunit GluR1. We found that D1 receptor stimulation enhances phosphorylation of GluR1 at the protein kinase A (PKA) site. Furthermore, D1 receptor stimulation increases GluR1 surface expression by increasing the rate of GluR1 externalization. The latter effect is prevented by the PKA inhibitors KT5720 and RpcAMPS, whereas the PKA activator SpcAMPS increases the rate of GluR1 externalization. These findings indicate that PKA phosphorylation is important in determining AMPA receptor surface expression and suggest a mechanism by which DA-releasing drugs of abuse may directly tap into fundamental mechanisms that enable synaptic plasticity. A limitation of our current model is that there are no intrinsic glutamate neurons in the NAc and thus no glutamate synapses in NAc cultures. To address this problem, we have restored excitatory synaptic inputs to NAc neurons by co-culturing them with prefrontal cortex (PFC) neurons. We are also studying GluR1 trafficking in PFC cultures. In both systems, synaptic AMPA receptors can be defined based on colocalization of GluR1 and the synaptic marker synaptobrevin. Preliminary results suggest that D1 receptor stimulation or PKA activation leads to increased surface GluR1 expression in PFC neurons but not to insertion into synaptic sites.

The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-Like Behavior

“…Consistent with the effects observed in the present study, previous in vivo and in vitro studies show that chronic lithium or VPA treatments attenuate adenylyl cyclase activity via distinct mechanisms (Du et al, 2003b(Du et al, , 2004. Previous work suggests a significant delay between attenuation of GluR1 surface expression and a decrease in GluR1 at functional synapses in cultured cortical neurons (Wolf et al, 2003). This model is also confirmed by the in vivo study, in which TAT-S845 peptide attenuated synaptic GluR1/2.…”

Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3

“…This kinase is activated in response to increasing concentrations of cAMP and phosphorylates a vast number of protein kinases, including the MAPKKK c-Raf (36). Furthermore, PKA facilitates synaptic transmission (13) and assumes an important function as a regulator of dopamine synthesis (17). In this context, the occurrence of the recently published PKA phosphorylation site S935 in LRRK2 (12) implicates a possible involvement of PKA in regulating LRRK2 function.…”

“…PKA is a key regulator of a vast number of signaling molecules and is critical for neuronal functions such as synaptic plasticity, protein trafficking, protein degradation, neuronal excitability, and regulation of dopamine physiology (13)(14)(15)(16)(17). In LRKK2, the conserved residue (S935) was shown to be phosphorylated by PKA (12), and recently this site was proposed as a biomarker for LRRK2 activity (10,18,19).…”

Drosophila Vesicular Monoamine Transporter Mutants Can Adapt to Reduced or Eliminated Vesicular Stores of Dopamine and Serotonin

“…It also is unclear how the complete elimination of VMAT activity might affect complex behavior; VMAT2 homozygous knockouts die soon after birth and relatively limited information is available on the behavioral phenotype of cat-1 (Duerr et al 1999). In addition, little is known about the relationship between changes in amine release and the function of downstream circuits (Nicola et al 2000;Wolf et al 2003). The modulation of glutamatergic neurons may be particularly important since interactions between dopamine and glutamate have been linked to both addiction and schizophrenia (Wolf et al 2003;Carlsson 2006;Lewis and Gonzalez-Burgos 2006).…”