Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation

Abstract

One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.DOI: http://dx.doi.org/10.7554/eLife.09275.001

Morphine selectively promotes glutamate release from glutamatergic terminals of projection neurons from medial prefrontal cortex to dopamine neurons of ventral tegmental area

“…What needs to be explained is that in our previous study in the VTA (Chen et al, 2015), when we use a pair of electrical pulses at intervals of 50 ms at 0.1 Hz to evoke EPSC, it always produces paired pulse facilitation, but here when we use a pair of optical pulses at intervals of 50 ms at 0.1 Hz to evoke EPSC in the VTA, it always produces paired pulse depression. This phenomenon also existed in the study by Vincent Pascoli et al (Pascoli et al, 2011).…”

“…Each side of the mPFC (final coordinates: AP, 1.95 mm; ML, ± 0.33 mm; DV, −2.4 mm from the skull surface), the BLA (final coordinates: AP, −1.4mm; ML, ± 3.0 mm; DV, −4.8 mm from skull surface) and the LH (final coordinates: AP, −2.8 mm; ML, ± 0.4 mm; DV, −4.2 mm from the skull surface) were respectively injected with 0.5 μl hChR2 (H134R)-mCherry. Each side of the mPFC (final coordinates: AP, 1.95 mm; ML, ± 0.33 mm; DV, −2.4 mm from the skull surface) was injected with 0.5 μl DIO-hM4D(Gi)-mCherry and each side of the VTA (final coordinates: AP, −3.08 mm; ML, ± 0.35 mm; DV, −4.8 mm from skull surface) was injected with 0.5 μl CAV-GFP-cre in the same manner (Chen et al, 2015). After the injection of virus, the animals were housed individually and were allowed to recover for over one week.…”

“…One previously reported mechanism for morphine to activate VTA-DA neurons is the disinhibition model of VTA-DA neurons (Johnson and North, 1992, Kalivas, 1993, White, 1996). Recently, we found that morphine could promote presynaptic glutamate release of VTA-DA neurons, which constituted the main mechanism for morphine-induced increase in VTA-DA neurons firing and related behaviors (Chen et al, 2015). However, what source of presynaptic glutamate release of DA neurons in the VTA is promoted by morphine remains unknown.…”

“… Abstract Recently, we found that morphine promoted presynaptic glutamate release of dopamine (DA) neurons in the ventral tegmental area (VTA), which constituted the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors (Chen et al, 2015). However, what source of presynaptic glutamate release of DA neurons in the VTA is promoted by morphine remains unknown.…”

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats

“…It is well established that presynaptic GABA B receptors are important regulators of vesicular neurotransmitter release (see e.g., Takahashi et al, 1998; Sakaba and Neher, 2003; Padgett and Slesinger, 2010) and, in the VTA, GABA B receptors have been reported to regulate both GABA (Chen et al, 2015) and glutamate (Padgett et al, 2012) release. Cocaine seeking and dopamine neurons in the VTA are negatively regulated by GABAergic efferents from several brain regions, including the ventral pallidum (Mahler et al, 2014) and the rostromedial tegmental area (Huff and LaLumiere, 2015).…”