Opioids excite dopamine neurons in the ventral tegmental area (VTA) by hyperpolarizing local GABA-containing interneurons. This mechanism reduces the inhibitory input to dopamine neurons, leading to their excitation. The study shows that opioids, particularly μ-receptor agonists, hyperpolarize secondary interneurons, which in turn reduce the spontaneous GABA-mediated synaptic input to principal dopamine neurons. This disinhibition leads to increased dopamine neuron activity, contributing to the reinforcing effects of opioids like morphine and heroin. In vitro experiments using rat brain slices revealed that opioids do not directly affect dopamine-containing neurons but hyperpolarize secondary interneurons. These interneurons, when depolarized, release GABA, which inhibits dopamine neurons. Opioids reduce this inhibition by hyperpolarizing the interneurons, thereby increasing dopamine neuron activity. This effect was observed in both in vitro and in vivo settings, where opioids increased the firing of VTA dopamine neurons. The study also found that opioids reduce the frequency of spontaneous GABA-mediated synaptic potentials in principal dopamine neurons. This reduction is likely due to hyperpolarization of interneurons, which decreases their firing rate. The effect of opioids on these potentials was blocked by μ-receptor antagonists, confirming the involvement of μ-receptors. In addition, opioids inhibited evoked synaptic potentials, particularly those mediated by GABA_A receptors. This inhibition was more pronounced at higher opioid concentrations and was associated with reduced GABA release from interneurons. The findings suggest that opioids exert their reinforcing effects by disinhibiting dopamine neurons through the hyperpolarization of local interneurons. This mechanism is consistent with the role of dopamine neurons in reward and reinforcement, and it supports the idea that opioids enhance dopamine release in the nucleus accumbens, a key region in reward processing. The study also highlights the importance of μ-receptors in mediating these effects and provides a framework for understanding how opioids interact with the dopaminergic system.Opioids excite dopamine neurons in the ventral tegmental area (VTA) by hyperpolarizing local GABA-containing interneurons. This mechanism reduces the inhibitory input to dopamine neurons, leading to their excitation. The study shows that opioids, particularly μ-receptor agonists, hyperpolarize secondary interneurons, which in turn reduce the spontaneous GABA-mediated synaptic input to principal dopamine neurons. This disinhibition leads to increased dopamine neuron activity, contributing to the reinforcing effects of opioids like morphine and heroin. In vitro experiments using rat brain slices revealed that opioids do not directly affect dopamine-containing neurons but hyperpolarize secondary interneurons. These interneurons, when depolarized, release GABA, which inhibits dopamine neurons. Opioids reduce this inhibition by hyperpolarizing the interneurons, thereby increasing dopamine neuron activity. This effect was observed in both in vitro and in vivo settings, where opioids increased the firing of VTA dopamine neurons. The study also found that opioids reduce the frequency of spontaneous GABA-mediated synaptic potentials in principal dopamine neurons. This reduction is likely due to hyperpolarization of interneurons, which decreases their firing rate. The effect of opioids on these potentials was blocked by μ-receptor antagonists, confirming the involvement of μ-receptors. In addition, opioids inhibited evoked synaptic potentials, particularly those mediated by GABA_A receptors. This inhibition was more pronounced at higher opioid concentrations and was associated with reduced GABA release from interneurons. The findings suggest that opioids exert their reinforcing effects by disinhibiting dopamine neurons through the hyperpolarization of local interneurons. This mechanism is consistent with the role of dopamine neurons in reward and reinforcement, and it supports the idea that opioids enhance dopamine release in the nucleus accumbens, a key region in reward processing. The study also highlights the importance of μ-receptors in mediating these effects and provides a framework for understanding how opioids interact with the dopaminergic system.