Drugs Of Abuse Influence Synaptic Plasticity In The Nucleus Accumbens

The NAc occupies a key position in the neurocircuitry of motivation and reward and is the site of many persistent changes associated with chronic drug exposure (96). Neurons in the NAc consist of medium spiny GABA neurons (90%) and several populations of interneurons (10%). The medium spiny neurons are the output neurons of the NAc and receive convergent DA and glutamate inputs. The interneurons play important roles in information processing within the NAc and may also be regulated by DA and glutamate (97). DA exerts neuromodulatory effects within the NAc, both by directly influencing synaptic transmission and by modulating voltage-dependent conductances (98). There are many controversies about the effects of drugs of abuse on glutamate transmission in the NAc. One debate is whether glutamate transmission, particularly originating in prefrontal cortex, is required for the expression of sensitization. Another is whether psychostimulants increase glutamate levels in the NAc. There are also discrepant findings about the effect of psychostimulants on glutamate receptor subunit expression. These issues are beyond the scope of this chapter (see ref. 4). Rather, this section will focus on the hypothesis that abnormal synaptic plasticity in the NAc, triggered by drug exposure, leads to dysregulation of motivation- and reward-related circuits and thereby contributes to addiction.

Activity-dependent plasticity of the corticostriatal pathway in drug-naive rats has been well characterized. Repetitive activation of corticostriatal glutamatergic fibers produces LTD of excitatory synap-tic transmission in the striatum measured using in vitro recording techniques (e.g., ref. 99). Striatal LTD requires membrane depolarization and action potential discharge of the postsynaptic cell during the conditioning tetanus, coactivation of D1 and D2 receptors, activation of metabotropic glutamate receptors, and release of nitric oxide from striatal interneurons (99,100). Striatal LTP is produced under in vitro conditions that enhance NMDA receptor activation and in vivo after tetanic stimulation of cortical fibers (e.g., refs. 101 and 102). Interestingly, pulsatile application of DA during a conditioning protocol that normally results in LTD shifts the effect toward potentiation of EPSP amplitude (103). Activity-dependent plasticity has also been demonstrated for excitatory synapses in the NAc. Recordings from NAc slices showed that tetanic stimulation of prefrontal cortical afferents produced both LTP and LTD, although LTP was more frequently observed (104). Tetanization of the fimbria-fornix produces LTP of field potentials in the NAc (105). LTP in NAc neurons is NMDA receptor dependent (104,106) and may be modulated by DA (see below). LTD in NAc neurons requires NMDA receptor activation and consequent rises in postsynaptic Ca2+ levels, does not require metabotropic glutamate receptor activation, and is not affected by bath application of DA (82). The latter two features distinguish it from LTD in the dorsal striatum (see above).

Striatal and NAc neurons are normally quiescent, and their activation requires synchronous activation of multiple excitatory inputs (107). LTP or LTD in excitatory pathways impinging on these neurons would have profound effects on their output, because these processes would influence the likelihood of synchronized activation. It is therefore exciting that several recent studies have found alterations in corticostriatal plasticity after chronic drug treatment. Studies addressing two different but related questions will be discussed in turn.

One question is whether chronic drug exposure alters the likelihood of LTP or LTD in a manner that outlasts the presence of drug in the brain. Pulvirenti et al. (108) compared evoked field responses in the NAc after stimulation of fimbria afferents in rats exposed to either 1 or 5 d of cocaine self-administration and found that the acquisition of cocaine-seeking behavior is associated with enhancement of hippocam-pal-accumbens transmission. Thomas et al. (109) treated mice for 5 d with cocaine, challenged with cocaine after 10-14 d withdrawal to demonstrate behavioral sensitization, and prepared slices of NAc 1 d later. Although no changes in the size of field EPSPs were found, cocaine-treated mice showed a reduction in the amplitude of AMPA receptor-mediated quantal events, specifically at synapses activated by cortical afferents. This was found in the shell but not core. No changes in NMDA receptor-mediated synaptic responses or the probability of transmitter release were observed. Furthermore, the magnitude of LTD that could be evoked in vivo was reduced in cocaine-treated mice, suggesting that the decrease in synaptic strength produced by cocaine shares expression mechanisms with LTD.

These findings suggest that chronic cocaine induces a long-lasting depression of excitatory synap-tic transmission in the NAc (109). This is consistent with our findings of decreased responses of NAc neurons to iontophoretic glutamate after 3-14 d withdrawal from amphetamine or cocaine (69). However, the correspondence is not perfect, as the latter effect was not restricted to the NAc shell (69) and decreased responses to both AMPA and NMDA were observed in a follow-up study (Hu and White, unpublished findings). Decreased peak amplitudes of AMPA/kainate-induced inward currents have also been observed in acutely dissociated striatal neurons prepared from chronic cocaine-treated rats (64). Repeated cocaine administration decreases glutamate immunolabeling in nerve terminals of the NAc shell (110), an effect that appears more persistent when cocaine is self-administered (111). AMPA receptor subunit expression in the NAc is not altered after short (1-3 d) withdrawals from repeated cocaine or amphetamine (73,74,112,113). However, protein and mRNA levels for the AMPA receptor subunits GluR1 and GluR2 are significantly decreased after 10-14 d withdrawal from repeated amphetamine administration (112,113). In contrast, repeated cocaine treatment and 3 wk of withdrawal produce increased GluR1 levels, decreased GluR3 mRNA levels, and a trend toward increased GluR1 mRNA levels in the NAc (74,76). These studies, along with other results showing alterations in NMDA and metabotropic glutamate receptor expression in the NAc after repeated drug administration (76,114-116), do not lend themselves to the formulation of a simple working model. However, the bulk of evidence seems to suggest that the NAc is more quiescent after long withdrawals from repeated drug administration, perhaps as a result of a combination of enhanced LTD (synaptic level), decreased AMPA receptor expression (cellular level), and other types of changes (e.g., changes in voltage-dependent conductances; 117). Decreased excitability of the NAc could be related to withdrawal symptoms such as anergia, anhedonia, and depression (see ref. 117).

A different question is whether the modulatory effects of drugs of abuse, or DA itself, on LTP and LTD are altered after repeated drug exposure. Li and Kauer (118) reported that bath application of amphetamine blocked the induction of LTP in NAc slices prepared from naive rats. This effect was reproduced by DA + deprenyl (an MAO-B inhibitor), but not DA alone, consistent with a previous report that DA alone does not modulate NAc LTP (104). However, when slices were prepared from rats previously treated with amphetamine for 6 d, bath application of amphetamine no longer blocked LTP (118). In contrast to these observations for LTP, LTD in the NAc is apparently not subject to acute modulation by DA (82), although LTD itself is promoted by prior exposure to the DA-releasing agent cocaine (109; above). Chronic exposure to ethanol (119) or methamphetamine (120) has also been reported to alter plasticity in the rat neostriatum. Tetanic stimulation induced LTD in naive rats or saline-treated rats, whereas the same stimulation produced a slowly developing form of LTP was observed in slices prepared 6 d after discontinuation of methamphetamine injections or 15-20 h after ethanol withdrawal. D2 receptor activation depressed the magnitude of LTP in ethanol-withdrawn rats. Drawing upon these and other findings, the authors speculated that the "switch" to LTP might reflect increased NMDA receptor tone coupled with the loss of normal D2 receptor-mediated negative control over LTP induction (119).

It is very exciting that all of these studies support the same hypothesis; that is, that DA receptor activation normally suppresses activity-dependent increases in synaptic strength in the striatal complex, but that this regulatory mechanism is lost after repeated drug exposure. If the normal effect of DA is to keep motivational circuits "in check" despite the high rewarding value of drugs of abuse, loss of this mechanism could contribute in a fundamental way to the loss of control over drug-seeking behavior that characterizes addiction. Indeed, there is good evidence that glutamate transmission in the NAc plays an important role in responses to drug-conditioned cues and in reinstatement of drug self-administration (121-130). However, whereas loss of regulatory DA tone after chronic cocaine would favor potentiation of synaptic transmission, the chronic cocaine-induced enhancement of LTD at some synapses in the NAc would have the opposite effect (109). This underscores the complexity of addiction-related adaptations, which can be viewed as a set of interacting positive and negative feedback loops.

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