Therapeutic potential of histaminergic compounds in the treatment of addiction and drug-related cognitive disorders

Abstract

Addiction is a behavioral disorder characterized by the compulsive seeking and taking of drugs despite serious negative consequences. In particular, the chronic use of drugs impairs memory and cognitive functions, which aggravates the loss of control over drug use and complicates treatment outcome. Therefore, cognitive enhancers targeting acetylcholine have been proposed to treat addiction. Interestingly, histamine H₃ receptor (H₃R) antagonists/inverse agonists stimulate acetylcholine transmission in different brain areas, facilitate memory in animal models and can reverse learning deficits induced by drugs such as scopolamine, dizocilpine and alcohol. Moreover, several studies found that compounds capable of activating the histaminergic system generally decrease the reinforcing effects of drugs, namely alcohol and opioids, in preclinical models of addiction. Finally, several H₃R antagonists/inverse agonists increase histamine in the brain and have proven to be safe in humans. However, no studies have yet investigated the therapeutic potential of cognitive enhancing H₃R antagonists/inverse agonists in the treatment of addiction in humans. The present review first describes the impact of addictive drugs on learning processes and cognitive functions that play an important role for addicts to remain abstinent. Second, our work briefly summarizes the relevant literature describing the function of histamine in learning, memory and drug addiction. Finally, the potential therapeutic use of histaminergic agents in the treatment of addiction is discussed. Our review suggests that histaminergic compounds like H₃R antagonists/inverse agonists may improve the treatment outcome of addiction by reversing drug-induced cognitive deficits and/or diminishing the reinforcing properties of addictive drugs, especially opioids and alcohol.

Introduction

Drug addiction is characterized by the loss of control of drug consumption despite the occurrence of serious negative consequences [1]. Relapse represents a major issue in this disorder since it refers to the sudden resumption of drug taking in addicts that were abstinent for long periods. Numerous studies have demonstrated that specific associative learning processes play a central role in drug relapse. Through these learning processes, the stimuli or cues present in the environment where the drug is consumed progressively gain control over behavior and can precipitate relapse in humans and in animal models of addiction [1], [2]. Cognitive therapies are based on the view that drug addicts must learn to resist the control that drug-associated stimuli can take over behavior and eventually cause relapse. In other words, when drug-associated stimuli elicit cravings in addicts, they need to actively inhibit behaviors leading to drug consumption. What complicates the treatment of drug addiction is that many addictive drugs such as psychostimulants, opioids and alcohol impair cognitive functions essential to remain abstinent [3], [4]. Therefore, drugs with cognitive enhancing properties, such as cholinergic, glutamatergic or noradrenergic compounds, have been proposed to treat drug addiction [5], [6], [7], [8]. Interestingly, histamine has been shown to improve learning and memory processes, in part by modulating the release of acetylcholine in relevant brain areas [9], [10]. In this regard, several histamine H₃ receptor (H₃R) antagonists/inverse agonists capable of activating histaminergic neuron activity facilitate learning in animal models and can reverse learning deficits induced by drugs such as scopolamine and dizocilpine [11]. Importantly, some of these histaminergic compounds have already been scheduled for testing in humans [12], [13], [14]. In addition to its effect on cognitive function, activation of the histaminergic system generally decreases the reinforcing properties of addictive drugs such as alcohol and opioids [15]. However, to date, no studies have investigated the therapeutic potential of H₃R antagonists/inverse agonists to treat drug dependence in human addicts.

The aim of the present review is to present evidence supporting that histaminergic compounds could be useful to treat drug addiction by reversing cognitive disorders caused by the chronic use of drugs and by decreasing their reinforcing properties. First, we will present an overview of the cognitive processes that are affected by the prolonged intake of drugs of abuse. Second, we will inform the reader about the studies showing that activation of the histaminergic system improves memory and decreases reinforcement processes. In addition, we will summarize the brain mechanisms through which histamine affects memory and drug reward. Finally, the therapeutic potential of H₃R antagonists/inverse agonists in the treatment of addiction will be discussed.