Drug-evoked plasticity: do addictive drugs reopen a critical period of postnatal synaptic development?

Abstract

As in other parts of the central nervous system (CNS) of the mouse, glutamatergic synapses onto dopamine (DA) neurons in the ventral tegmental area (VTA) mature postnatally. At birth many AMPA receptors (AMPARs) lack GluA2R subunit and most NMDARs contain the GluN2B subunit. Within 2 weeks these receptors are replaced with GluA2- and GluN2A- containing AMPARs and NMDARs, respectively. Recent data suggest that a single injection of cocaine (or another drug of addiction) triggers glutamate receptor redistribution with the reappearance of the subunits typically present in immature synapses, as if addictive drugs reopen the developmental critical period. Here we review the experimental evidence for this hypothesis and discuss the implications for circuit function.

Keywords: CP-AMPARs; VTA; addictive drugs; postnatal development.

Figure 1

During the first postnatal week (“Neonatal”), transmission is dominated by CP-AMPARs and GluN2B-containing NMDARs. Subsequently (“Juvenile”) mGluR1 receptors play a role in the synaptic insertion of CI-AMPARs and GluN2A-containing NMDAR. At juvenile synapses, a single cocaine injection exchanges CP-AMPARs for CI ones and causes decrease in NMDAR function changing the relative contribution of GluN2A- and GluN2B-containing NMDARs. This switch in the glutamatergic transmission may contribute to the re-opening of a critical period seen during the development. Cocaine-induced plasticity can then be reverted by the activation of mGluR1.

Figure 2

mGluR1 activation drives the postnatal maturation of glutamatergic synapses onto DA neurons in the VTA. In particular the activation of the metabotropic receptors drives the insertion of GluN2A-containing NMDARs and GluA2-containing AMPARs from neonatal (P2–6) to juvenile synapses (P14–26). The composition of glutamatergic synapses then remains unaltered from juvenile to adult age (P > 60). In utero cocaine exposure interfere with the mGluR1-signaling pathway delaying the postnatal maturation of excitatory transmission at these synapses.