Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activitydependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D 5 receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaineinduced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spiketiming-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocaine in vivo or in vitro.

Summary A single exposure to drugs of abuse produces an NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA receptor (AMPAR) currents in DA neurons; however, the importance of LTP for various aspects of drug addiction is unclear. To test the role of NMDAR-dependent plasticity in addictive behavior, we genetically inactivated functional NMDAR signaling exclusively in DA neurons (KO mice). Inactivation of NMDARs results in increased AMPAR-mediated transmission that is indistinguishable from the increases associated with a single cocaine exposure, yet locomotor responses to multiple drugs of abuse were unaltered in the KO mice. The initial phase of locomotor sensitization to cocaine is intact; however, the delayed sensitization that occurs with prolonged cocaine withdrawal did not occur. Conditioned behavioral responses for cocaine-testing environment were also absent in the KO mice. These findings provide evidence for a role of NMDAR signaling in DA neurons for specific behavioral modifications associated with drug seeking behaviors.

Neurotrophins play an important role in modulating activitydependent neuronal plasticity. In particular, threshold levels of brain-derived neurotrophic factor (BDNF) are required to induce long-term potentiation (LTP) in acute hippocampal slices. Conversely, the administration of exogenous BDNF prevents the induction of long-term depression (LTD) in the visual cortex. A long-standing missing link in the analysis of this modulatory role of BDNF was the determination of the time-course of endogenous BDNF secretion in the same organotypic preparation in which LTP and LTD are elicited. Here, we fulfilled this requirement in slices of perirhinal cortex. Classical theta-burst stimulation patterns evoking LTP lasting >180 min elicited a large increase in BDNF secretion that persisted 5-12 min beyond the stimulation period. Weaker theta-burst stimulation patterns leading only to the initial phase of LTP (Ϸ35 min) were accompanied by a smaller increase in BDNF secretion lasting <1 min. Sequestration of BDNF by TrkB-IgG receptor bodies prevented LTP. Low-frequency stimulations leading to LTD were accompanied by reductions in BDNF secretion that never lasted beyond the duration of the stimulation. N eurotrophins, in particular brain-derived neurotrophic factor (BDNF), play an important modulatory role in activitydependent neuronal plasticity (1-5). The physiological relevance of this action is based on the observation that BDNF differentially modulates activity-dependent changes in synaptic strength, as reflected by long-term potentiation (LTP) and long-term depression (LTD), which are cellular paradigms for learning and memory (6). Hippocampal LTP is strongly impaired in both BDNF (7-9) and TrkB (10, 11) knock-out mice. Conversely, LTD in the visual cortex is facilitated by blocking anti-BDNF Abs or TrkB-IgG receptor bodies (12). It is of particular interest that in the hippocampus of BDNF knock-out mice (7) the extent of LTP reduction is the same in both homozygote and heterozygote animals, indicating that a minimal, critical concentration of BDNF has to be available to fulfill its modulatory functions. LTP could be rescued by adenoviral-mediated (re)expression of BDNF in the CA1 region (8) or administration of exogenous BDNF (9). Relatively detailed studies have been performed on the regulation of BDNF synthesis (13-17) and secretion (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). The studies concerned with the regulation of BDNF secretion have been conducted in reductionistic systems, such as synaptosomes (18) and dissociated neuronal cultures in which BDNF secretion was evoked by high potassium depolarization or exogenous neurotransmitter administration (19-24). Recent studies using primary cultures of hippocampal neurons were designed specifically to investigate the relationship between electrical stimulation parameters and BDNF secretion. However, to reach this goal either the overexpression of BDNF (25, 26) or long stimulation periods in nontranduced cultures (27) were necessary to permit the determination of BDNF secret...