Potent Dopamine D2 Antagonists Block the Reward-Enhancing Effects of Nicotine in Smokers With Schizophrenia

Alexis E. Whitton; Alan I. Green; Diego A. Pizzagalli; Robert M. Roth; Jill M. Williams; Mary F. Brunette


Schizophr Bull. 2019;45(6):1300-1308. 

In This Article

Abstract and Introduction


Antipsychotics that are potent dopamine (DA) D2 receptor antagonists have been linked to elevated levels of nicotine dependence in smokers with schizophrenia. Because activation of D2 receptors mediates motivation for nicotine, we examined whether potent D2 antagonists would diminish nicotine's ability to stimulate reward processing—a mechanism that may drive compensatory increases in smoking. Smokers with schizophrenia (n = 184) were recruited and stratified into medication groups based on D2 receptor antagonist potency. The effects of smoking on reward function were assessed using a probabilistic reward task (PRT), administered pre- and post-smoking. The PRT used an asymmetrical reinforcement schedule to produce a behavioral response bias, previously found to increase under conditions (including smoking) that enhance mesolimbic DA signaling. Among the 98 participants with valid PRT data and pharmacotherapy that could be stratified into D2 receptor antagonism potency, a medication × smoking × block interaction emerged (P = .005). Post-hoc tests revealed a smoking × block interaction only for those not taking potent D2 antagonists (P = .007). This group exhibited smoking-related increases in response bias (P < .001) that were absent in those taking potent D2 antagonists (P > .05). Our findings suggest that potent D2 antagonists diminish the reward-enhancing effects of nicotine in smokers with schizophrenia. This may be a mechanism implicated in the increased rate of smoking often observed in patients prescribed these medications. These findings have important clinical implications for the treatment of nicotine dependence in schizophrenia.


Nicotine use in individuals with schizophrenia is extremely common, with recent estimates indicating that 80% of individuals with this condition smoke.[1] Greater smoking in this population has been linked to worse symptoms,[2] susceptibility to respiratory and cardiovascular diseases, and early mortality;[3] hence, reducing smoking in these patients is a key priority. Evidence suggests that patients taking first-generation antipsychotics, many of which produce potent dopamine (DA) D2 receptor antagonism, experience greater difficulty quitting with evidence-based cessation treatment.[4,5] Because these medications are foundational to the management of schizophrenia, an important question is whether DA D2 receptor antagonists modulate nicotine's reinforcing effects.

Nicotine's addictive properties are driven in large part by activity within the mesolimbic DA reward system.[6,7] Nicotine stimulates DA neurons via nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area, causing the release of DA into striatal synapses.[8,9] Human positron emission tomography studies have shown evidence of acute increases in DA signaling in the ventral striatum following nicotine intake.[10] Nicotine has been found to enhance reward processing on several paradigms in both animals[11] and humans,[12] and is associated with increased neural activation in key reward regions.[13] Conversely, nicotine withdrawal has been linked to decreases in reward processing.[14]

Mesolimbic DA system dysfunction is central to the pathophysiology of schizophrenia,[15,16] and may be a pathway through which comorbid schizophrenia and nicotine dependence develops.[17] Supporting this notion, deficits in reward learning—a process reliant on phasic striatal DA signaling[18]—is correlated with increased nicotine dependence in schizophrenia.[19] Furthermore, the nAChR partial agonist varenicline has been shown to restore nicotine withdrawal-related deficits in reversal learning (a process that is also reliant on phasic striatal DA signaling)[20] in rodents,[21] and has been found to improve cessation and prolong abstinence,[22] and boost reward processing in patients with schizophrenia.[23]

Central to reducing smoking rates in schizophrenia is understanding how antipsychotic medications moderate nicotine's rewarding effects. Evidence indicates that treatment with potent DA D2 receptor antagonists increases smoking in individuals with schizophrenia.[24–26] Although the precise mechanisms are unknown, potent DA D2 receptor antagonists may diminish nicotine's ability to stimulate mesolimbic DA release, which may drive a compensatory increase in smoking to achieve the same level of stimulation. Supporting this, studies in psychiatrically healthy smokers show that pretreatment with the potent DA D2 antagonist haloperidol resulted in increased blood plasma nicotine (due to greater smoking during a free smoking period) compared to placebo.[27] Pretreatment with haloperidol has also been linked to a faster rate of smoking and greater total puffing time than treatment with the DA agonist, bromocriptine.[28] Similarly, 8 weeks of haloperidol treatment has been linked to significant increases in nicotine dependence in individuals with schizophrenia.[26]

Conversely, smoking reductions have been observed in patients treated with lower DA D2 receptor affinity medications.[26,29] Specifically, clozapine—a potent blocker of the serotonin 5-HT2A receptor and the norepinephrine α2 receptor, as well as a weak DA D2 receptor antagonist[30]—has been associated with reduced daily cigarette use.[29] Similarly, aripiprazole—a partial agonist at both pre- and post-synaptic DA D2 and 5-HT1A receptors—has been associated with reduced nicotine dependence compared to haloperidol.[26] Quetiapine is also of interest, given its broad spectrum of action, including weak DA D2 receptor antagonism.[31]

Together, these findings suggest that potent DA D2 receptor antagonists may reduce the effects of nicotine on reward processing in smokers with schizophrenia; however, no study to date has tested this hypothesis. We aimed to address this gap by examining the effects of smoking on reward learning, a key aspect of reward processing that is defined as the process by which behavior is modified as a function of prior reinforcement. Reward learning was assessed using a behavioral probabilistic reward task (PRT)[32] that uses an asymmetrical reinforcement schedule to induce a response bias toward a more frequently rewarded (rich) stimulus. In healthy individuals, stimulants that increase phasic DA signaling—including nicotine—potentiated response bias.[12] Individual differences in response bias have also been linked to DA release,[33] DA transporter binding,[34] and functional connectivity between key reward system nodes in nonsmokers.[34] Furthermore, response bias has been found to be inversely related to cigarette craving intensity in smokers.[35] Consistent with prior studies,[12] we predicted that individuals with schizophrenia would show greater response bias after smoking compared to following abstinence, but that this increase would be attenuated in individuals taking potent DA D2 receptor antagonists.