An endocannabinoid-nitric oxide signaling switch triggers reciprocal inhibitory-excitatory plasticity at dopamine...

Dynamic regulation of midbrain dopamine neuron activity is necessary for diverse processes including motivation, novelty detection, reinforcement learning, and cognitive flexibility. By setting the strength of synaptic inputs to dopaminergic neurons, endocannabinoid signaling is essential for regulating dopaminergic activity. Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive substance in cannabis, is known to induce abnormal dopaminergic activity and increased susceptibility to psychopathology. However, how prenatal cannabinoid exposure (PCE) affects endocannabinoid-mediated synaptic plasticity of dopamine neurons remains largely unknown. Here, we use a rat model of PCE to directly determine this. We found that endocannabinoid-mediated synaptic plasticity at excitatory synapses on dopamine neurons of the ventral tegmental area (VTA) was absent in PCE male rat offspring, where the presynaptic nanoscale architecture of excitatory afferents onto VTA dopamine neurons was reorganized to impair the control of type-1 cannabinoid receptors on glutamate release. We demonstrate that, in response to postsynaptic depolarization, PCE dopamine cells switch to nitric oxide (NO) rather than endocannabinoid signaling to induce opposing forms of synaptic plasticity at inhibitory and excitatory inputs. We disclosed a NO-dependent long-term potentiation of GABA _A -receptor-mediated synaptic transmission, and a long-term depression of glutamatergic synapses requiring presynaptic activation of GABA _B -receptors. These PCE-induced reciprocal forms of synaptic plasticity reshape the balance of excitatory and inhibitory control over dopamine neurons, potentially contributing to increased vulnerability to psychiatric disorders.

Endocannabinoids (eCBs) in the midbrain regulate dopamine cell activity and plasticity to guide behavior. eCBs retrogradely activate presynaptic type-1 cannabinoid receptors to depress synaptic transmission. Here, we identify metaplastic changes driven by prenatal cannabinoid exposure (PCE) on eCB signaling at excitatory afferents on dopamine neurons. These include a switch in retrograde signaling favoring de novo synthesis of nitric oxide (NO) to replace the actions of eCBs, which are compromised at excitatory inputs. NO induces novel forms of long-term plasticity at excitatory and inhibitory inputs on male dopamine neurons. These forms of metaplasticity may be recruited in the VTA in response to PCE-induced circuit remodeling, and the resulting synaptic adaptations contribute to abnormal dopamine cell activity.