Drugs of abuse are known to cause persistent modification of neural circuits, leading to addictive behaviours 1-5 . Changes in synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) may contribute to circuit modification induced by many drugs of abuse, including cocaine 6-13 . Here we report that, following repeated cocaine exposure in vivo, excitatory synapses to VTA dopamine neurons become highly susceptible to the induction of long-term potentiation (LTP) by correlated pre-and postsynaptic activity, and this facilitated LTP induction is caused by cocaine-induced reduction of GABA A receptor-mediated inhibition of these dopamine neurons. In midbrain slices from saline-or single cocaine-treated rats LTP could not be induced in VTA dopamine neurons unless GABAergic inhibition was reduced by bicuculline or picrotoxin. In slices from repeated cocaine-treated rats, however, LTP became readily inducible, but was prevented by enhancing GABAergic inhibition with diazepam. Furthermore, repeated cocaine exposure reduced the amplitude of GABAergic synaptic currents and increased the probability of spike initiation in these dopamine neurons. This cocaine-induced enhancement of synaptic plasticity in VTA may be important for the formation of drug-associated memory.To determine the impact of in vivo cocaine exposure on synaptic plasticity in VTA dopamine neurons, we examined LTP induction in these neurons in midbrain slices prepared from rats that were given single (1 d) or repeated (5-7 d) daily intraperitoneal injections of saline or cocaine. The effectiveness of the cocaine treatment was shown by the sensitization of locomotor activity ( Supplementary Fig. 1). Dopamine neurons were identified by the presence of large I h currents and distinct firing characterics 14,15 ( Supplementary Fig. 2). Extracellular stimulation was applied to the rostral region of VTA and evoked excitatory postsynaptic potentials (EPSPs) were monitored by whole-cell recordings from these dopamine neurons at −70 mV, near the reversal potential (−69.7 ± 1.5 mV, n = 5) of inhibitory postsynaptic currents (IPSCs). These EPSPs were mediated by the activation of glutamate receptors, since they were completely abolished by CNQX (6-cyaon-7-nitroquinoxaline-2,3-dione, 20 μM) and AP5 (D-2-amino-5-phosphonopentanoic acid, 50 μM), the antagonist of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) and N-methyl-d-aspartate receptors (NMDARs), respectively. To induce LTP, we used a spike-timing protocol consisting of bursts of EPSP-spike pairs, with the onset of EPSPs preceding the peak of the postsynaptic spike by ∼5 ms (Fig. 1a, see Methods). This pattern of stimulation was used to mimic bursts of spikes observed in VTA dopamine neurons of behaving rats or monkeys in response to reward-related stimuli 16,17 . We found that repetitive EPSP-spike pairing induced a long-lasting increase in the amplitude of EPSPs in VTA dopamine neurons in slices obtained from rats treated with cocaine for 5-7 d (Fig. 1c), but not fr...

Chronic exposure to opiates eventually leads to drug addiction, which is believed to involve maladaptive changes in brain function, but the underlying neuronal mechanisms remain primarily unknown. Given the known effects of opiates such as morphine and heroin on hippocampal function, we investigated the potential effect of chronic opiate treatment on long-term potentiation (LTP) at CA1 synapses in rat hippocampus, a leading experimental model for studying synaptic plasticity. Our results revealed that chronic exposure of rats to morphine or heroin, which induced severe drug tolerance and dependence, markedly reduced the capacity of hippocampal CA1 LTP during the period of drug withdrawal (from approximately 190% in control to approximately 120%). More interestingly, the capacity of LTP could be restored to the normal level by re-exposure of the animals to opiates, indicating that the synaptic function was already adapted to opiates. Morris water maze test, which measures behavioral consequences of synaptic plasticity, showed parallel learning deficits after chronic exposure to opiates. Moreover, the opiate-reduced LTP could also be restored by inhibitors of cAMP-dependent protein kinase A (PKA), suggesting that upregulation of cAMP pathway was likely one of the underlying mechanisms of the observed phenomena. These findings demonstrated that chronic opiate treatment can significantly modulate synaptic plasticity in the hippocampus, leading to an opiate dependence of the plasticity.

The neural mechanism underlying the relapse to drug use after drug withdrawal is largely unknown. We found that after withdrawal from repeated cocaine exposure, excitatory synapses onto dopamine neurons in the ventral tegmental area (VTA) of the rat midbrain became highly susceptible to potentiation by weak presynaptic stimuli, an effect requiring endogenous brain-derived neurotrophic factor-tyrosine kinase B (BDNF-TrkB) signaling. The elevated BDNF expression in the VTA after cocaine withdrawal may prime these synapses for potentiation by cue-associated activity, triggering drug craving and relapse.