Lost in translation: why don't dopamine D2 antagonists cure addictions?

From the 1950s to 1970s, three inter-related effects of dopamine were identified, each with clinically important implications. First, Arvid Carlsson reported that reserpine-induced behavioral immobility could be reversed by the immediate dopamine precursor, L-DOPA.^1,2 The implications were quickly understood and within a decade L-DOPA was established as a treatment for Parkinson's disease.^3,4 Second, the first antipsychotic medications were identified^5,6 and by the 1970s their mechanism of action had been linked to effects at dopamine receptors.^7–9 Third, dopamine manipulations altered the willingness of laboratory animals to approach rewards^10,11 and self-administer stimulant drugs.^12,13 When the reinforcing substances were available on a fixed ratio-1 (FR1) schedule, low doses of antipsychotic medications led to sustained increases in operant output; high doses led to transient increases followed by decreases.^12,13 This pattern of effects suggested that the decreased self-administration was not secondary to motor deficits. Moreover, when the drugs were available on a progressive ratio schedule, providing a better index of motivation to obtain the reward, drug-seeking behaviors were decreased by even low doses of antipsychotic medications.¹⁴ Here again, the clinical implications were clear. Indeed, in human laboratory studies, experimental manipulations that increased vs. decreased dopamine release led to increased vs. decreased willingness to work for both drug and non-drug rewards.^15–19 It has therefore remained surprising that dopamine receptor antagonists—even at doses that alleviate psychoses—exhibit little efficacy for treating addictions.^20–22 Something has been lost in translation. A speculative interpretation is proposed here.

As a start, it is worth recalling that most antipsychotic medications preferentially bind to dopamine D2 receptors relative to other dopamine receptors.^8,23,24 Inhibition of D2 receptors can increase dopamine cell firing and release through actions at both pre-synaptic autoreceptors and post-synaptic striato-pallidal feedback pathways leading to increased extracellular dopamine levels^34,43,44 (Boxes 1A, 1B, and 1C). This, in turn, presumably increases dopamine transmission at non-D2 receptors.⁴⁵ Since the stimulation of D1 receptors can promote reward-related behaviors in both rodents^46–48 and humans,⁴⁹ substance use might even increase following the administration of typical D2 antagonists.⁵⁰

Box 1A.

Dopamine D2 receptors

Dopamine D2 class receptors (D2, D3, D4) are distinguished from D1 receptors (D1, D5) by their ability to inhibit vs. activate adenylyl cyclase. This noted, D2 signalling can occur through multiple intracellular pathways, including canonical G-protein-dependent (Gi/o) and non-canonical β-arrestin-dependent cascades.^25,26 These two pathways preferentially influence different behaviors, with β-arrestin recruitment driving locomotor activity but not incentive motivation, which requires intact G-protein signalling.²⁷

Box 1B.

Effects of D2 receptor antipsychotic medications: it is even more complicated

Traditional D2 antipsychotic medications affect both the canonical Gi/o and non-canonical β-arrestin-dependent cascades.²⁸ In rodent models, this can be sufficient to decrease the willingness to work for addictive drugs¹⁴ and the reinstatement of drug-seeking behaviors following periods of extinction.²⁹ However, extinction of drug-seeking has proven difficult to accomplish in humans.³⁰ Moreover, to the extent that D2 antagonists can disrupt the motivational circuitry, this will also affect the processes needed for healthy reward-seeking while leaving unsuppressed drug-seeking promoted by non-D2 mechanisms. Aripiprazole, in comparison, is a D2 partial agonist with functionally selective properties; it shows some efficacy but fails for SUDs without comorbid psychosis.²² In addition to other features discussed in the main text, this might reflect that aripiprazole's biased profile of partial Gi/o agonism with D2 β-arrestin translocation antagonism³¹ does not adequately preserve the G-protein-dependent motivational signalling needed for recovery. Complicating things further, D2 antagonists can induce supersensitivity of post-synaptic D2 receptors,³² decrease dopamine reuptake,³³ and increase dopamine cell firing through long-loop actions on descending striato-nigral GABAergic projections.^33,34 Finally, D1/D2 receptor heteromers in the striatum form functional complexes coupled to Gq/11 with a pharmacology that is distinct from either receptor alone.^35–37 These heteromers are upregulated by cocaine exposure, are more abundant in primate than rodent striatum, and their activation decreases both drug- and drug cue-induced reinstatement of cocaine seeking.³⁸ Collectively, these features may well account for why targeting D2 alone is insufficient for the treatment of addictions, whereas engaging both D1 and D2 family binding sites may be advantageous.

Box 1C.

Are D2 antipsychotic medications ever given to patients with SUDs?

Antipsychotics are used in SUD populations to treat stimulant-induced psychosis and as adjuncts to benzodiazepines in alcohol withdrawal delirium.^39,40 However, these uses are typically short-term and at moderate doses and are aimed at psychotic symptoms, not addiction per se. Substance-induced psychosis is expected to resolve after approximately 30 days of sobriety, and antipsychotics are gradually discontinued (either by the patient or the providers) once the patient is stable.⁴¹ Acute psychosis onset within 24–48 h of initiating substance use predicts a favorable treatment response.⁴² Critically, these brief, symptom-targeted antipsychotic exposures differ substantially from the sustained high-dose D2 blockade used in schizophrenia treatment that is thought to be associated with depolarization block, underscoring the distinction central to our hypothesis.

With extended D2 inhibition, depolarization block can occur with cell firing now ceasing altogether.^34,51–53 The onset of this effect is more rapid in a rodent model of hyper-dopaminergic states.⁵⁴ This observation raises the possibility that depolarization block might arise readily in people with psychoses, at least some of whom show elevated striatal dopamine synthesis capacity (indexed by high [¹⁸F]/[¹¹C]F-DOPA PET)^55,56 representing a trait-level presynaptic abnormality with large effect sizes (Hedges g = 0.87).⁵⁷ This contrasts with substance-use disorders (SUDs) where dopamine elevations are episodic and stimulus-driven rather than reflecting a tonic increase in presynaptic activity;^58,59 indeed, in the absence of drug use triggers, people with severe addictions might spend much of their time in a low dopamine state.^58,59–61

The above observations suggest that dopamine D2 antagonist medication-induced depolarization block is less likely to develop in people with SUDs than in people with schizophrenia. Despite this, if dopamine depolarization block were to develop in some cells, the behavioral effects are likely to be complex. This includes a shift from seeking highly desired rewards even if they are hard to obtain toward more easily available rewards even if they are less valued.^62,63 In someone with a severe addiction, this might express itself as continued substance use coupled with diminished motivation to work for healthier but distal and hard-to-get rewards. The failure of antipsychotic medications to decrease drug use might be further aggravated by the continued experience of drug-induced pleasure that arises from dopamine-independent mechanisms.^64,65

Together, the chain of events hypothesized above might allow D2 antagonists to provide relatively good treatment efficacy for psychoses but not addictions. It might also inform our understanding of how dopamine transmission contributes to recently proposed treatments that show more promise for SUDs. Two examples follow.

Clozapine

In rodent models, FR1 cocaine self-administration can be decreased by both low and high doses of clozapine, unlike what occurs with most antipsychotic medications.⁶⁶ Some evidence suggests that these effects transfer to human SUDs.^67,68 This might reflect the affinity of clozapine for a wide range of dopamine receptors (D1, D2, and D4) as well as non-dopamine targets.²³ Caution is needed, though. Most participants in these studies have SUDs that are comorbid with psychosis, and the decreased substance use might reflect secondary benefits from the superior treatment of psychotic symptoms⁶⁸ or non-specific sedative effects that can improve sleep.^69,70

Glucagon-like peptide-1 agonists (GLP-1A)

GLP-1 agonists were initially marketed for diabetes and then weight loss. However, recent evidence suggests that they might also be efficacious for SUDs.⁷¹ For example, weekly administration of a GLP-1 agonist is reported to decrease alcohol use in heavy drinking humans^72,73 and non-human primates.⁷⁴ The mechanism of action remains unknown, but there is evidence that GLP-1 agonists can increase dopamine responses to some rewards⁷⁵ while decreasing spikes in dopamine release induced by addictive drugs and high-fat foods.^76–78 Since in humans GLP-1A can also increase the willingness to work for monetary rewards,⁷⁹ this combination of effects might facilitate engagement with healthy day-to-day goals while diminishing the prolonged ingestion of drugs and highly palatable foods.^57,78,80

Conclusions

The above speculative integration suggests that most antipsychotic medications have properties that make them unsuitable to treat SUDs. Indeed, at present, there seems little interest in pursuing this avenue and ClinicalTrials.Gov lists only two addiction-related trials for dopamine antagonists, both targeting D3 receptors. Despite this, a critical role of dopamine in drug-seeking behaviors remains evident, and ClinicalTrials.Gov lists three studies of agonist medications, each in the context of their ability to trigger addiction-like problems. Although dopamine is unlikely to account for all important features of addictions, obtaining a better understanding of D3 and other dopamine-related effects (e.g., at D1, D4, and D5 receptors) might identify more effective ways to target their contribution.

Data availability

This manuscript does not report data.

Author contributions

Conceptualization: ML

Formal analysis: ML

Writing – original draft: ML, LP

Writing – review & editing: ML, LP