The capacity of excitatory synapses in the cortico-striatal projection to undergo neuroplasticity is important for both establishing well-learned habits and for allowing well-learned behaviors to be updated according to new information imposed by a changing environment42
. Addiction has been characterized as an inability to modify or stop drug-seeking habits in spite of environmental information indicating the behavior is maladaptive2
. Critical to modifying striatal habit behavior is that the sensory information integrated in the PFC has access to the striatum via the nucleus accumbens. By employing in vivo field potentials the present study demonstrated that self-administered cocaine induces metaplasticity that impairs the ability of PFC stimulation to produce LTP or LTD in nucleus accumbens MSNs, and that N-acetylcysteine reverses cocaine induced-metaplasticity allowing the induction of both LTP and LTD.
The impairment in LTP likely results from the fact that LTP was occluded by a pre-existing state of LTP-like potentiation, as evidenced by the input-output curve being shifted to the left (), as well as the ability to potentiate the PFC-accumbens synapses after depotentiation (). A variety of other measurements are also consistent with chronic cocaine inducing LTP-like changes and enhanced glutamate responsiveness in accumbens MSN's, including increased AMPA/NMDA ratio of synaptic currents11
, increased surface expression of AMPA receptors5
, and enhanced behavioral responsiveness to microinjected AMPA24,43
. However, the simultaneous loss of LTD cannot be explained by the occlusion of synaptic grading, and indicates that cocaine self-administration induces additional metaplasticity that reduces the capacity to elicit LTD via a mechanism distinct from LTP-related metaplasticity.
The relevance of cocaine induced-metaplasticity to the behavioral pathology of addiction is indicated not only by the fact that the impairment is occurring in a cortico-striatal pathway critical for regulating adaptive behavior2
, but also by the fact that treatment with NAC, a drug known to inhibit cocaine seeking in the reinstatement model of addiction15
and drug cue reactivity in cocaine addicts16
, restored the ability to induce LTP and LTD. This raises the question of a causal relationship between synaptic potentiation and the susceptibility to relapse. The reinstatement of drug-seeking by cue or drug depends upon potentiated PFC glutamate release into the NAcore34,44
and potentiated postsynaptic glutamate receptor signaling5
. A variety of data indicate that NAC inhibits drug seeking by activating the cystine-glutamate exchanger, thereby increasing extrasynaptic glutamate and stimulating mGluR2/3 presynaptic autoreceptors to reduce synaptic glutamate release probability2
. Moreover, direct pharmacological agonist stimulation of mGluR2/3 inhibits cocaine seeking31,32
. Given the strong link between mGluR2/3 regulation of both synaptic glutamate release and drug seeking, the capacity of mGluR2/3 antagonist to inhibit NAC restoration of LTP is consistent with the possibility that normalizing the ability of PFC-NAcore synapses to become potentiated is ameliorative in the relapse to drug seeking.
In contrast to LTP, the restoration of LTD was linked to NAC-induced restoration of the tone on mGluR5. Akin to mGluR2/3, mGluR5 receptors are predominantly perisynaptic45
and thus accessible by the increased extracellular glutamate produced after NAC stimulation of cystine-glutamate exchange. In contrast to mGluR2/3, mGluR5 receptors are primarily postsynaptic45
and mGluR5 stimulation is well characterized to facilitate the induction of LTD in corticostriatal synapses28
. Accordingly, blocking mGluR5 with MPEP prevented NAC from restoring LTD. However, contrary to an mGluR2/3 antagonist preventing NAC from reducing drug-seeking, the effect of NAC was reversed by promoting mGluR5 stimulation with a positive allosteric modulator. This is consistent with the present and previous experiments showing that inhibiting mGluR5 or mGluR5 gene deletion reduces the expression of many behaviors elicited by chronic cocaine administration, including the reinstatement of cocaine seeking, conditioned reward and locomotor sensitization39,46
. These findings indicate that while the diminished glutamatergic tone on mGluR2/3 caused by down-regulated cystine-glutamate exchange promotes cocaine-seeking, reduced tone on mGluR5 has an opposing action. Consequently, the impairment in LTD may be protective and limit the intensity of drug-seeking.
The data in this report indicate that metaplasticity induced by cocaine self-administration markedly impairs the ability to induce LTP and LTD in PFC glutamatergic afferents to NAcore. The LTP impairment arises from synaptic occlusion while the abridged LTD can be attributed to reduced stimulation of mGluR5. By restoring tone onto mGluR2/3 and mGluR5 receptors, NAC was able to reverse the metaplasticity established by cocaine self-administration and restore LTP and LTD, respectively. Given the efficacy of NAC restoration of tone onto mGluR2/3 at inhibiting cocaine- and heroin-seeking,31,32
these data reveal a critical link between cocaine seeking and cocaine-induced metaplasticity that is exemplified by a loss of LTP in PFC to NAcore glutamatergic synapses. Moreover, considering the presumed importance of bidirectional neuroplasticity in acquiring new behaviors47
, it is interesting to speculate that cocaine-induced metaplasticity may reflect the well known difficulty addicts experience in acquiring new behaviors to compete with drug seeking.