Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area

Synaptic plasticity in the ventral tegmental area (VTA) is modulated by drugs of abuse and stress and is hypothesized to contribute to specific aspects of addiction. Both excitatory and inhibitory synapses on dopamine neurons in the VTA are capable of undergoing long-term changes in synaptic strength. While the strengthening or weakening of excitatory synapses in the VTA has been widely examined, the role of inhibitory synaptic plasticity in brain reward circuitry is less established. Here, we investigated the effects of drugs of abuse, as well as acute stress, on long-term potentiation of GABAergic synapses onto VTA dopamine neurons (LTP(GABA)). Morphine (10 mg/kg i.p.) reduced the ability of inhibitory synapses in midbrain slices to express LTP(GABA) both at 2 and 24 h after drug exposure but not after 5 days. Cocaine (15 mg/kg i.p.) impaired LTP(GABA) 24 h after exposure, but not at 2 h. Nicotine (0.5 mg/kg i.p.) impaired LTP(GABA) 2 h after exposure, but not after 24 h. Furthermore, LTP(GABA) was completely blocked 24 h following brief exposure to a stressful stimulus, a forced swim task. Our data suggest that drugs of abuse and stress trigger a common modification to inhibitory plasticity, synergizing with their collective effect at excitatory synapses. Together, the net effect of addictive substances or stress is expected to increase excitability of VTA dopamine neurons, potentially contributing to the early stages of addiction.