Accumulating evidence indicates that experience dependent al

Accumulating evidence indicates that experience-dependent alterations in glutamate transmission in the NAc, such as those produced by repeated exposure to cocaine, involve alterations in postsynaptic signaling mediated by AMPA-type receptors (Pierce and Wolf, 2013, Wolf and Ferrario, 2010). In the NAc shell, repeated cocaine exposure results in a progressive increase in MSN AMPAR signaling during abstinence that heightens sensitivity to glutamatergic input, and is a key factor in the development and persistence of addiction-related behavior such as behavioral sensitization, craving, and relapse (Boudreau and Wolf, 2005, Conrad et al., 2008, Kourrich et al., 2007, Pascoli et al., 2014, Pascoli et al., 2011, Terrier et al., 2016). Conversely, additional studies citing both biochemical (Boudreau et al., 2007, Ferrario et al., 2009) and physiological evidence (Kourrich et al., 2007; et al., 2011) have shown that exposure to relapse-inducing stimuli such as stress or a cocaine challenge injection reverses (depotentiates) cocaine-dependent increases in NAc shell AMPAR signaling, suggesting that this gap27 sale reversal of plasticity may play a role in driving this behavior. While the ability of relapse-inducing stimuli to bidirectionally modify NAc AMPAR signaling has been demonstrated on numerous occasions, the cellular mechanisms underlying this plasticity remain unclear. Within the striatum, pre- and postsynaptic neuromodulatory signaling plays a critical role in gating changes in MSN glutamatergic synaptic strength (Lerner and Kreitzer, 2011). Prominent among these modulators is dopamine (DA), which is known to regulate MSN intrinsic and synaptic excitability (Nicola et al., 2000, Tritsch and Sabatini, 2012). Moreover, activation of DA D1 or D2 receptors in the NAc shell reinstates cocaine seeking (Schmidt and Pierce, 2006), whereas activation of D1Rs during abstinence normalizes cocaine-induced increases in AMPAR-mediated synaptic transmission (Ortinski et al., 2012), highlighting a potential role for DA receptors in the depotentiation of AMPAR synaptic strength observed in the NAc shell following cocaine re-exposure. Similar to the striatal DA system, neurotransmission mediated by the endocannabinoid (eCB) system powerfully modulates synaptic efficacy at NAc glutamatergic synapses (Lovinger and Mathur, 2012, Piet et al., 2011, Robbe et al., 2003). Induction of eCB signaling requires post-synaptic release of eCBs which then signal retrogradely at pre-synaptic cannabinoid type 1 (CB1) receptors, depressing neurotransmitter release (Hoffman and Lupica, 2001, Kano et al., 2009). Throughout the striatum and other brain regions, eCB signaling mediates various forms of short-term and long-term synaptic depression, comprising a dominant mechanism for reducing synaptic strength at excitatory synapses (Lüscher and Huber, 2010). Recent evidence implicating NAc CB1 signaling in cocaine-primed behavioral sensitization and reinstatement (McReynolds et al., 2016, Ramiro-Fuentes and Fernandez-Espejo, 2011, Xi et al., 2006) makes this system a prime candidate in modulating cocaine-dependent reversal of AMPAR signaling in the NAc; however, our understanding of how repeated cocaine engages and alters eCB-mediated synaptic plasticity in the NAc remains relatively incomplete. The present study investigated the temporal dynamics and potential cellular mechanisms underlying cocaine-induced depotentiation of AMPAR signaling in the NAc, focusing on potential roles for dopamine and eCB signaling using in vivo and ex vivo approaches.
Materials and methods
Results
Discussion The current study investigated the temporal and mechanistic profile of bidirectional AMPAR plasticity in the NAc shell following re-exposure to cocaine during abstinence. We demonstrate that 1) enhanced AMPAR signaling produced by repeated cocaine is rapidly reversed by in vivo and ex vivo cocaine re-exposure and persists up to 4 d post challenge injection, and 2) that both endogenous dopamine and eCB signaling play necessary roles in the cocaine challenge-induced depotentiation of AMPAR synaptic transmission.