Relapse to cocaine-seeking after abstinence is regulated by cAMP-dependent protein kinase A in the prefrontal cortex

Abstract

Abstinence from cocaine self-administration (SA) is associated with neuroadaptations in the prefrontal cortex (PFC) and nucleus accumbens (NAc) that are implicated in cocaine-induced neuronal plasticity and relapse to drug-seeking. Alterations in cAMP-dependent protein kinase A (PKA) signaling are prominent in medium spiny neurons in the NAc after repeated cocaine exposure but it is unknown whether similar changes occur in the PFC. Because cocaine SA induces disturbances in glutamatergic transmission in the PFC-NAc pathway, we examined whether dysregulation of PKA-mediated molecular targets in PFC-NAc neurons occurs during abstinence and, if so, whether it contributes to cocaine seeking. We measured the phosphorylation of CREB (Ser133) and GluA1 (Ser845) in the dorsomedial (dm) PFC and the presynaptic marker, synapsin I (Ser9, Ser62/67, Ser603), in the NAc after 7 days of abstinence from cocaine SA with or without cue-induced cocaine-seeking. We also evaluated whether infusion of the PKA inhibitor, 8-bromo-Rp-cyclic adenosine 3′, 5′-monophosphorothioate (Rp-cAMPs), into the dmPFC after abstinence would affect cue-induced cocaine-seeking and PKA-regulated phosphoprotein levels. Seven days of forced abstinence increased the phosphorylation of CREB and GluA1 in the dmPFC and synapsin I (Ser9) in the NAc. Induction of these phosphoproteins was reversed by a cue-induced relapse test of cocaine-seeking. Bilateral intra-dmPFC Rp-cAMPs rescued abstinence-elevated PKA-mediated phosphoprotein levels in the dmPFC and NAc and suppressed cue-induced relapse. Thus, by inhibiting abstinence-induced PKA molecular targets, relapse reverses abstinence-induced neuroadaptations in the dmPFC that are responsible, in part, for the expression of cue-induced cocaine-seeking.

Synaptic mechanisms underlying persistent cocaine craving

“…Postsynaptic mechanisms may also contribute. On WD7, PKA phosphorylation of GluA1 and CREB was increased in the dorsal mPFC and intra-mPFC infusion of a PKA inhibitor reversed this effect and decreased cue-induced cocaine seeking 76 . These latter results suggest that strengthened AMPAR transmission in the mPFC may contribute to incubated cocaine seeking, given that PKA phosphorylation of GluA1 primes AMPAR for synaptic insertion in PFC neurons 77 .…”

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

“…For example, our recent studies demonstrated that normalizing the prefrontal ERK signaling pathway during the early withdrawal from repeated cocaine exposure leads to a long-term inhibitory effect on cocaine relapse 120,121 and restores the extracellular glutamate dysregulation in the NAc 260 . In contrast, after prolonged withdrawal from cocaine, an increase of PKA-mediated signaling is dominant in the PFC and NAc responsible for cocaine seeking 85,121,261–263 , implicating that ERK activity in the PFC-NAc projection is dynamically regulated by multiple intracellular pathways. Future studies will evaluate the ability of novel therapeutic interventions to restore normal ERK signaling activity in the brain for inhibiting addictive drug-seeking behavior.…”

Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking

“…However, intervention immediately after cocaine self-administration ends is critical because phospho-ERK levels in the prelimbic cortex do not differ from yoked-saline control values one day or one week after the end of cocaine self-administration (Whitfield et al, J Neurosci 2011-supplementary figure 1). Moreover, phospho-CREB levels are normal at 24 hr and elevated one week later and the latter increase is mediated by PKA, not ERK (Sun et al, Addiction Biol 2014). Further, because the suppressive effect of BDNF on cocaine-seeking is ERK-dependent (Whitfield et al, 2011), if BDNF is infused one week after the end of cocaine self-administration when ERK levels in PFC are normal, BDNF has no effect on reinstatement (Berglind et al, 2007).…”