Desipramine enhances the ability of paliperidone to decrease alcohol drinking

Highlights

• Paliperidone alone reduces alcohol drinking in P rat (initiation) and hamster.

• Paliperidone and desipramine abolish initiation of alcohol drinking in P rat.

• Paliperidone and desipramine reduce chronic alcohol drinking in the hamster.

Abstract

Alcohol use disorder commonly occurs in patients with schizophrenia and dramatically worsens their course. The atypical antipsychotic clozapine has been associated with reduced drinking in these patients, but its toxicity reduces its use. We have attempted to create a clozapine-like drug by combining agents that capture components of clozapine's pharmacologic action, including its weak dopamine D2 blockade and noradrenergic modulation. The current study assessed whether paliperidone, a dopamine D2 receptor and adrenergic alpha-2 receptor antagonist like clozapine, would attenuate alcohol drinking in the alcohol-preferring P rat and the Syrian golden hamster, and whether desipramine, a norepinephrine reuptake inhibitor, would potentiate the ability of paliperidone to attenuate alcohol drinking in the P rat and the Syrian golden hamster. Daily subcutaneous injections of paliperidone (5 mg/kg for the rat; 1 mg/kg for the hamster) over 20 days slightly and transiently attenuated initiation of alcohol consumption in both animals. Desipramine (3 mg/kg) or lower doses of paliperidone alone did not affect alcohol drinking. However, the combination of desipramine (3 mg/kg) and paliperidone essentially prevented initiation of alcohol drinking and acquisition of alcohol preference in the P rat (2.5 or 5 mg/kg), and almost as dramatically suppressed chronic alcohol intake and alcohol preference in the hamster (2.5 mg/kg). Taken together, the current data suggest that (1) the desipramine and paliperidone combination attenuates alcohol drinking in a synergistic manner, and (2) desipramine and paliperidone may serve as an effective new treatment for alcohol use disorder in patients with schizophrenia.

Introduction

Alcohol use disorder (AUD) occurs in over one-third of patients suffering from schizophrenia (SCZ), which is threefold higher than AUD's prevalence in the general population (Drake et al., 1989, Regier et al., 1990). Patients with schizophrenia tend to consume moderate quantities of alcohol on a regular basis without developing physical withdrawal symptoms upon cessation of drinking, and tend to display alcohol abuse more frequently than alcohol dependence (Drake et al., 1989, Lehman et al., 1996, Test et al., 1989). However, even moderate use of alcohol is known to worsen the clinical course of schizophrenia (Alterman et al., 1981, Drake and Mueser, 1996, Gupta et al., 1996, Owen et al., 1996). Our group and others have consistently shown that treatment of patients with schizophrenia using clozapine is associated with substantially lower rates of alcohol and drug abuse in this population (Drake et al., 2000, Green et al., 1999, Machielsen et al., 2014). We have proposed that clozapine's unique and broad-ranging pharmacological profile, including its weak blockade of the dopamine D2 receptor, its potent antagonism of the noradrenergic alpha-2 receptor, and its ability to greatly and chronically elevate levels of norepinephrine may be responsible for its anti-alcohol abuse property (Green et al., 1999).

Risperidone is an atypical antipsychotic with pharmacologic properties partially overlapping with those of clozapine. Like clozapine, risperidone is an antagonist of dopamine D2 receptors and noradrenergic alpha-2 receptors (Richelson and Souder, 2000). Its metabolite paliperidone (9-OH-risperidone) has similar affinity for alpha-2 receptors but lower affinity (and rapidity of binding) for D2 receptors than risperidone (Leysen et al., 1994, Richelson and Souder, 2000, Schotte et al., 1995), making it more clozapine-like in its actions on these receptors.

Risperidone, however, may differ from clozapine in regard to norepinephrine reuptake, since it does not appear to elevate norepinephrine levels in patients with schizophrenia to the same extent as clozapine (Elman et al., 2002, See et al., 1999). We suggest that this difference between the clozapine and risperidone may explain why risperidone does not appear to limit alcohol drinking in patients with schizophrenia (Green et al., 2008, Smelson et al., 2002). In support of this suggestion, we have shown that while risperidone itself has little effect on alcohol drinking in the Syrian golden hamster, its co-administration with the norepinephrine reuptake inhibitor desipramine chronically suppresses alcohol drinking (Gulick et al., 2014). The effect of paliperidone on levels of norepinephrine is less clear. In this regard, however, we note that one study indicated that risperidone, and not paliperidone, inhibited the firing of serotonergic neurons; moreover, this ability of risperidone to inhibit serotonergic neurons was antagonized by the addition of the norepinephrine reuptake inhibitor desipramine, suggesting that paliperidone may potentially have some norepinephrine reuptake inhibitor-like effects in vivo (Dremencov et al., 2007).

We tested the ability of paliperidone alone, or in combination with desipramine, to reduce alcohol drinking, in two models of alcohol drinking-- the alcohol preferring rat (P rat) and the Syrian golden hamster. These two animal models were chosen to represent two distinct stages of alcohol use disorder in patients with schizophrenia. As we have done previously, we selected the alcohol-preferring P rat to model the initiation of alcohol drinking, and we used the Syrian golden hamster model chronic alcohol drinking. The P rat differs from patients with SCZ in that it develops high blood alcohol levels and physiologic dependence (McBride et al., 2014). Moreover, our previous research has shown that clozapine, but not haloperidol, impairs initiation of alcohol drinking, but not maintenance of alcohol drinking in the P rat (Chau et al., 2013), suggesting that this animal model only has predictive validity for patients with SCZ under the initiation phase. The hamster models chronic alcohol drinking in patients with schizophrenia for the following reasons: (a) like patients with schizophrenia who tend to drink regular but moderate amounts of alcohol, the hamster consumes alcohol on a regular basis, and does not develop physiologic withdrawal (Ferris et al., 1998, Harris et al., 1979, Keung et al., 2000); and (b) like patients with schizophrenia, clozapine, but not haloperidol, reduces alcohol drinking in this animal (Green et al., 2004). Using these models, we tested how paliperidone or paliperidone plus desipramine would alter the initiation of alcohol drinking (P rat) or chronic alcohol drinking (hamster), with an eye toward developing safer clozapine-like drugs for use in patients with schizophrenia and alcohol use disorders.