For a very detailed review on link between MOR and glutamatergic transmission in the mesolimbic DA system, see the review by Chartoff and Connery 95.
Table 1. The mechanistic classification of addictive drugs. Drugs of abuse can be classified into 3 distinct categories, depending on the receptor they target. Opioids belong to the category that activates GPCRs, while psychostimulants activate transporters of biogenic amines (104.
As for all other drugs of abuse, opioid intake increases the extracellular DA concentration in the NAc
102,154,155. However, addictive drugs do not constitute a homogeneous chemical group; they vary according to their different molecular targets and often target more than receptor each 104. The ways that they generate the same increase in dopamine release vary according to the drug group that they belong to. As we already mentioned, opioids act on the MORs located on the VTA GABA interneurons
156. MOR activation has two impacts on the VTA GABA interneurons. First, they hyperpolarize them, and second, they inhibit GABA release. The hyperpolarization is mediated by the activation of Kir3/ G protein–coupled inwardly rectifying K+ (GIRK) channels, which are coupled to the MORs 157. The inhibition of GABA release is mediated by presynaptic activation of MORs, which results either in the inhibition of Ca2+ channels or in the activation of voltage-gated K+ channels. These effects lead to the disinhibition of DA neurons. Those are the mechanisms that occur in an opioid-naïve brain, but repeated exposure induces long-term neuronal adaptions in the mesolimbic DA system.
5.1 Effects of acute opioids on NAc neurons
Acute administration of opioids in the NAc mostly activates MORs and increases extracellular levels of DA 102. MOR activation in the NAc also suppresses both basal and evoked increases in extracellular glutamate release 158. This opioid-induced decrease in glutamatergic transmission is thought to cause an increase in the surface expression of AMPARs 159. However, a decrease in AMPA and NMDA subunit expression in the NAc core was reported 3 days after acute morphine treatment 160, and another study found that surface levels of NAc GluR1 decrease 24h after morphine injection 161. Consistent with these two studies, it has been shown in slices that MOR activation depresses NMDA and non-NMDA (putative AMPA) EPSPs via a presynaptic mechanism involving reductions in Ca2+
currents 162 and the inhibition of presynaptic voltage-gated Ca2+ channels 163.
Figure 17. Effects of acute opioids on NAc neurons. Acute MOR activation in an opioid-naïve animal suppresses both GABA and glutamate release via inhibition of Ca2+ channels and activation of K+ conductances. MOR activation also impairs the cAMP-mediated activation of non-selective cation pacemaker currents (Ih). Postsynaptic NMDAR currents are augmented via MOR-induced PKC
activation. There is no known data on the acute effects of opioids on AMPAR expression, localization, or function in naïve animals. Adapted from Chartoff and Connery, (2014).
5.2 Effects of chronic opioids on NAc neurons
Figure 18. Effects of chronic opioids on NAc neurons. The inhibitory action of presynaptic mGluR2/3, localized on the glutamatergic afferents, is increased during chronic opioid treatment, resulting in inhibition of glutamate release. On MSNs, surface expression of GluR1 subunits is decreased. Finally, levels and/or function of the NR2A NMDAR subunit are increased. Adapted from Chartoff and Connery, (2014).
Opioids can be administered in a broad range of ways, such as the steady, stable and well dosed intake of extended release painkillers, intermittent abuse, and binge-like drug taking. These
differences probably influence the neural adaptations that result from chronic consumption. In most of the studies in rodents, heroin is either self-administered intravenously by the animal itself or
systemically by the experimenter. In both cases, the dose administered and the pace of drug intake is very well controlled, principally to avoid overdose.
After chronic exposure to opioids, several neuroadaptations occur. Counter adaptations in cAMP signaling that lead to an increase in adenylate cyclase (AC) function have been reported 96,164, as have alterations in the activity of other GPCRs. As shown in figure 17, chronic opioid treatment increases the inhibitory actions of presynaptic mGluR2/3 receptors on glutamate release. On D1 MSNs in the NAc shell, and on all MSNs in the core, it has been shown that chronic morphine treatment is associated with decreased surface expression of GluR1 subunits 165. Another study using a different opioid treatment reported no changes in the distribution of AMPAR in the NAc (neither GluR1 nor GluR2 subunits) 166. Finally, a more recent study found that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs but reduces signaling in D2-MSNs after 10-14 days of forced abstinence 167. Taken together, these studies show that the mechanisms by which chronic opioid exposure modulates the distribution of AMPAR are not yet clearly known. The current leading hypothesis suggests an internalization process 168,169. While numerous studies have investigate the effects of chronic psychostimulants on AMPAR-mediated synaptic transmission in the NAc 91,170–172, very little is known about chronic opioid exposure.
However, the effects of chronic opioid administration on NMDAR-mediated synaptic transmission in the NAc have been more thoroughly investigated. Chronic opioid treatment appears to decrease the affinity of the NMDAR for glycine, its co-agonist. The cellular mechanisms underlying these effects are not totally known, but it could be in part due to an increase in expression and/or function of the NRA2 subunit 162.
5.3 Effects of acute opioids on VTA neurons
Figure 19. Effects of acute opioid exposure on VTA neurons. Acute MOR activation inhibits both glutamatergic and GABA neurons through an arachidonic acid-dependent potentiation of voltage-dependent K+ channels and a G protein-mediated inhibition of CA2+. GABA release is also reduced via inhibition of cAMP-dependent systems. This leads to the disinhibition of VTA DA neurons and increased DA release. Adapted from Chartoff and Connery, (2014).
Immediately following an acute opioid injection there is an inhibition of the VTA GABA neurons, that contain MORs and make strong synaptic contacts on the soma and dendrites of dopamine neurons, and a decrease in LTP of these GABAergic 103,156,173. Additionally, presynaptic glutamate terminals are inhibited via MOR-mediated arachidonic acid-dependent activation of voltage-sensitive K+ channels
174, and there is an increase in AMPAR-mediated transmission in DA neurons 24h later 175–177. This increase in AMPAR-mediated transmission is caused by increased surface expression AMPARs. In line with these findings, an increase in GluR1 177 can be seen as early as 1h following a morphine injection
178. The mechanisms underlying the insertion of the GluR1 subunits and the resulting LTP are not yet totally elucidated, but they are thought to involve activation of dopamine D5 receptors 177,179.
5.4 Effects of chronic opioids on VTA neurons
Figure 20. Effects of chronic opioid exposure on VTA neurons. While DA firing rates remain increased, a tolerance mechanism on the GABAergic neurons following MOR activation begins to occur via an upregulation of cAMP systems. K+ channels on DA neurons are inhibited, leading to an increase in both basal firing rate and burst activity of DA neurons. Adapted from Chartoff and Connery, (2014).
MOR activation has an indirect but strong effect on VTA DA neurons. Indeed, after chronic morphine treatment, both basal firing rates and burst activity of VTA DA neurons are increased, leading to elevated levels of DA in the NAc 180,181. Moreover, in addition to this indirect effect on VTA DA neurons it has also been shown that chronic morphine increases the intrinsic excitability of VTA DA neurons through downregulation of K+ channels 173. Chronic opioid exposure therefore has both indirect (inhibitory action on VTA GABA neurons) and direct (higher sensitivity of VTA DA neurons to excitation) effects on VTA DA neurons. Chronic opioid treatment also increases surface levels of GluR1 (in both DA and non DA neurons) and NMDA NR1 subunits 182.