Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction.

No abstract

No abstract

No abstract

Prolonged stress induces neural maladaptations in mesolimbic dopamine (DA) system and produces emotional and behavioral disorders. However, the effects of stress on activity of DA neurons are diverse and complex that hinge on the type, duration, intensity, and controllability of stressors. Here, controlling the duration, intensity, and type of the stressors to be identical, we observed effects of stressor controllability on the activity of substantia nigra compacta (SNc) DA neurons in mice. We found that both lack and loss of control over shock enhance the basal activity and intrinsic excitability of SNc DA neurons via modulation of I h current, but not via corticosterone serum level. Moreover, loss of control over shock produces more significant enhancement in the basal activity of SNc DA neurons than that produced shock per se, and therefore attenuates the response to natural reward. This attenuation can be reversed by control over shock. These results indicate that although chronic stress per se tends to enhance the basal activity of SNc DA neurons, loss of control over the stressor is able to induce a larger enhancement in basal activity of SNc DA neurons and produce more severe behavioral deficits. However, control over stress ameliorates the deleterious effects of stress, highlighting the role of stress controllability. Significance statementThe impact of stress on the DA system significantly modifies immediate and guide future behaviors. Stress does not have unitary effects on VTA DA neurons, but the effects of stress controllability on SNc DA neurons are unclear. The present work studied the effects of controllability on the activity of SNc DA neurons by controlling the duration, intensity, and pattern of footshocks to be identical. The results show that loss of control over shock produces larger enhancement in basal activity of SNc DA neurons and worse behavioral deficits than what caused by uncontrollable shock per se. The results demonstrate the critical role of stress controllability in modulating activity of SNc DA neurons and inducing behavioral deficits.