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.
Highlights
Morphine is a potent analgesic with high addictive potential
In order to determine the role of glutamatergic input in the morphine-induced increase in the spontaneous firing frequency of ventral tegmental area (VTA)-DA neurons, we observed the influence of the N-methyl-D-aspartic acid (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) (50 μM) and the α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 6, 7-Dinitroquinoxalie-2, 3-dione (DNQX) (10 μM) on the effect of morphine
The average frequency of spontaneous firing was 0.7 ± 0.1 Hz before and 0.8 ± 0.1 Hz for 10–15 min after morphine application in the presence of APV and DNQX (n = 6 cells from five rats, paired t test, p > 0.05, compared to control with APV and DNQX before morphine, right panel of Figure 2B). These results suggest that the morphine-induced increase in the spontaneous firing frequency of VTA-DA neurons requires AMPA and NMDA receptormediated glutamatergic input, consistent with a recent report using the NMDA antagonist APV and the AMPA receptor antagonist 6-Cyano-7-nitroquinoxaline-2, 3-dione (CNQX) in in vivo experiments (Jalabert et al, 2011)
Summary
Morphine is a potent analgesic with high addictive potential. Morphine-induced addictive behaviors are strongly dependent on the activation of dopamine (DA) neurons of the ventral tegmental area (VTA) (Wise, 1989; Gardner, 2011; Luscher and Malenka, 2011). It was reported that the release of glutamate from least some of the glutamate terminals that synapsed on VTA-DA neurons was inhibited by opioids (Manzoni and Williams, 1999; Margolis et al, 2005). This inhibitory effect of opioids on glutamate release is puzzling (Chartoff and Connery, 2014) because one would expect morphine to produce rapid activation of VTA-DA neurons through both the inhibition of GABAergic input and the excitation of glutamatergic input. The amplitude of the inhibitory outward currents produced by opioids in postsynaptic VTA-DA neurons in the study of Ford et al was small (2.1 ± 1.5 pA in VTA-DA neurons projecting to the nucleus accumbens and 14 ± 4 pA in those projecting to the basolateral amygdaloid nucleus) (Ford et al, 2006), while only a small population of VTA-DA neurons (19%) showed depolarization or an increase in firing rate in response
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