Most of the studies on drugs of abuse use only psychostimulants (mostly cocaine), and although it is now generally acknowledged that VTA DA neuron activation are both necessary and sufficient for the progression to addiction 87, the question is still open for other drugs of abuse, including opioids. This debate about the validity of the dopamine hypothesis of addiction in the case of opioids has gone on for years 183 and continues today 148,184,185.
The dopamine hypothesis of addiction is very appealing because it proposes a common endogenous reward system in the brain that mediates all types of reward, from natural reinforcers to drugs of abuse, and also accounts for electrical or optogenetic self-stimulation. 183,186
Administration of opioids activates MORs and increases extracellular levels of DA in the NAc 102. However, some studies suggest that DA is not necessary for the acute reinforcing properties of opioids. In non-dependent animals, blocking DA receptors in the NAc or lesioning the DA terminals in the NAc with 6-OHDA does not prevent self-administration 186,187. One could argue that those are blunt, non-specific techniques which could mask the opposing effects of distinct neuronal populations, such as D1 and D2 MSNs.
In the late 1980s and 1990s, two studies challenged the DA hypothesis of reward and are still referenced today when challenging DA involvement in the reinforcing or rewarding properties of opioids. Van Ree and Ramsey 183 attempted to directly test the dopamine hypothesis of opioid reward by blocking DA receptor systems with haloperidol (a D2R antagonist). When administered either systematically or locally into different brain areas in rats, the haloperidol treatments did not block the acquisition of opioid SA behavior. The authors thus concluded that DA is not critically involved in opioid reward. A few years later 188, the same group used the same experimental
procedures to examine the involvement of D1 receptors in the reinforcing properties of opioids. They administered the D1 antagonist SCH23390 either systemically or locally in the NAc (although they did not distinguish between the shell and the core) and looked at the initiation of heroin SA. It appeared that systemic antagonist treatment significantly decreased heroin consumption during the initiation of heroin SA, whereas intra-NAc infusion of the D1 antagonist did not affect heroin intake at any dose. One thing to mention is the difference in receptor occupancy depending on the way the antagonist is administered. Indeed, it has been reported that injected systematically, the SCH23390 occupies 72-100% of D1Rs but only 40-60% when administrated intra-cranially. This could explain the discrepancy between the systemic and intra-cranial results 189
However, other studies show the opposite and demonstrate a requirement for a functional NAc dopamine system in opioid reinforcement. Mice learn to self-administer MORs agonists directly into the NAc 190,191, and lesions or inactivation of the NAc reduce opioid self-administration 192–194. Further in favor of a role for dopamine in the reinforcing properties of opioids, electrolytic lesions of the NAc result in significantly decreased responding for intravenous self-administration of cocaine and morphine under a progressive ratio schedule of reinforcement (a paradigm used in order to assess drug wanting while avoiding difficulties in interpretation that can occur with a classic SA
paradigm)195.These results are contradictory to those reported in a recent study using a siRNA strategy, though. The authors reported that impairments of the D1aR in the NAc shell prevented the acquisition of cocaine but not heroin self-administration 196. However, this study focused on cocaine SA and the distinct involvements of the NAc shell and NAc core in the reinforcing properties of cocaine. Thus, they did not attempt to further investigate a mechanism to explain the results they obtained with heroin.
Notably, most of the studies referenced above rely on pharmacology and/or lesions, and the results therefore reflect a global net effect which doesn’t account for the potential of selective or
differential opioid activation of D1 and D2 MSNs in the NAc. However, the data are equivocal even from experiments that focus on these more specific opioid effects. In one study, the authors used the immediate-early gene cFos as a marker of neuronal activity to investigate the specific populations of ventral striatal neurons that are activated by morphine withdrawal and acute morphine. They found that D1Rs are activated by acute morphine while D2Rs are activated during morphine withdrawal 197. These results reveal a clear distinction in neuronal responses that occur in the two populations of MSNs of the NAc. However, in another study, the authors examined delta Fos B activation (another transcription factor of the Fos family) and reported an activation of both D1 and D2 MSNs in the NAc (both shell and core) following both acute morphine administration (via osmopumps) and heroine self-administration 198.
Finally at the end of the 1990s, a study using mice deficient for the DA transporter (DAT KO mice) showed that these animals were still able to self-administer cocaine 199.This observation was for sure very challenging for the DA hypothesis and it took a decade to the field to fully understand it.
However the same year a study showed 200 that DAT KO mice but also mice deficient for the serotoninergic transporter (SERT) were still developing conditioned placed preference (CPP) for cocaine. Actually, this observation led to the hypothesis that hat either DAT or SERT might be able to mediate cocaine reward in the other's absence. In fact in DAT knockout mice (and reciprocally in SERT KO mice), a compensatory reuptake of DA through other monoamine transporters (SERT, NERT) occurred, and because cocaine blocks uptake of DA by these transporters, DA still increased with
drug exposure even in the absence of DAT 201. Closure came when an experiment using a knockin mouse line carrying a functional DAT that is insensitive to cocaine showed that self-administration of cocaine, but not amphetamine, was abolished in these animals 202. The observation that morphine still induced CPP in DA-deficient mice has also challenged the DA hypothesis 203.However the data obtained with this model have to be handled very carefully. Indeed, these animals suffered from severely reduced locomotion and other developmental adaptations, which precluded the testing for later-stage drug-adaptive behavior.
6.1 The deprived/non-deprived hypothesis of opioid reinforcement
Opioids are tricky substances to study. The presence of an endogenous opioid system, tightly linked to the mesolimbic DA system, but also linked to both glutamatergic and GABAergic transmission, all has to be considered. Moreover, the action of opioids on the mesolimbic DA system is mostly indirect, through the disinhibition of the VTA GABA (via GABAA receptors) neurons.
As we discussed above, the study of opioids and their reinforcing or rewarding properties have produced a lot of data, but not all of it points to the same conclusions. But what seems to emerge from all of these studies is that opioids have both DA-dependent and DA-independent rewarding properties. In the 1990s, a theory that could reconcile these divergent views was put forward. The non-deprived/deprived hypothesis of opiate motivation is an attempt to explain the relationship between dopamine-dependent and dopamine-independent rewarding properties.
Figure 21. The non-deprived/deprived hypothesis 204. (A) Schematic of a rat brain, showing the main actors in the non-deprived/deprived hypothesis of opiate motivation. TPP mediates the rewarding effects of opioids in non-deprived subjects, while the VTA takes control in deprived subjects. (B) Schematic of the basic brain circuitry proposed to be involved in the non-deprived/deprived model.
This hypothesis involves an area less highlighted as the VTA when studying addiction. In the non-deprived/deprived hypothesis, the brainstem tegmental pedunculopontine nucleus (TPP) plays a crucial role. This hypothesis was proposed by Bechara and van der Kooy in the early 1990s 205. They showed that lesions of the TPP blocked morphine CPP in drug-naive rats. Moreover, TPP lesions failed to block both morphine CPP and morphine withdrawal CPA in rats that were morphine-dependent. From these data, the authors suggested that deprivation and non-deprivation induced motivation are mediated by distinct neural substrates 205. Another study showed that lesions of the TPP reduced the rewarding effects of opioids despite failing to disrupt the ability to learn either an operant response or the response requirements of a PR schedule 206. In this model, a determinant parameter is the “drug history” of the animal. Indeed, it appears that TPP lesions only block opioid reward in drug naïve animals, while failing to block opioid reward in animals that have been exposed to opioids for long enough that a withdrawal state, or deprived state, can be induced. Conversely, disruption of dopamine transmission affects only deprived animals. Another study from the van der Kooy group showed that bilateral lesions of the TPP blocked the acquisition of a place preference for an environment paired with a dose of heroin that did not induce withdrawal but had no effect on place preference for an environment paired with a dose that did induce withdrawal. Conversely, a dopamine antagonist pre-treatment produced the exact opposite pattern of results 207. From these studies, the idea emerged that the amount of drug exposure was not the most important parameter per se, but rather the relative motivational state (deprived vs. non deprived) 204. To further
investigate, Nader and van der Kooy tested the effect of direct morphine infusions into the VTA in either deprived or non-deprived rats. They found that pre-treatment with alpha-flupentixol (a broad spectrum DA antagonist) blocked the acquisition of conditioned place preferences for environments paired with morphine microinjections in the VTA in morphine-dependent and withdrawn animals, but not in drug-naive rats. Lesions of the TPP produced exactly the reversed pattern of results 208. They concluded that there are two independent reward substrates within the VTA itself and that one of them is DA-independent.
Figure 22. The deprived/non-deprived hypothesis: an integrated model of opioid reinforcement in the VTA 204. In non-deprived subjects (left side), the activation of VTA GABAAR causes
hyperpolarization of VTA GABA neurons. When opioids bind to MORs, they reduce the activation of VTA GABA neurons, which become depolarized because of the loss of the inhibitory tone. This leads to a reinforcing signal in the TPP, while inhibition of the VTA DA neurons maintained. Conversely, in deprived subjects, when opioids bind to MORs, they cause hyperpolarization of the VTA GABA neurons leading to the disinhibition of VTA DA neurons, which then increase their firing and send a DA-dependent reinforcing signal to the NAc.
The proposed mechanism of the deprived/non-deprived model is based on a switch from control by the TPP and the “classic” inhibitory functions of VTA GABAAR to control by a DA-dependent state where GABAAR are now excitatory. This switch is also dependent on the “drug history” of the animal, either naïve (non-deprived) or already with previous drug exposure (deprived).
However this model does not explain the increased extracellular DA levels in the NAc following acute administration of opioids 102 or the morphine-induced changes in synaptic strength observed in NAc MSNs such as AMPAR-signaling, AMPAR subunit composition, and neurotransmitter release after only 5 days of morphine i.p. injections 167. These results suggest an acute effect of opioids in the NAc that involves DA at the very early stages of opioid exposure.