Homers regulate drug-induced neuroplasticity: Implications for addiction

Abstract

Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

Introduction

The hypothesis that abnormal corticolimbic glutamate transmission contributes to the pathophysiology of addiction emerged from decades of neurological, brain imaging, pharmacological, genetic and biochemical research in affected individuals, as well as behavioral, molecular, electrophysiological and neurochemical data derived from preclinical animal models of addiction [1], [2], [3], [4]. The vast number of clinical neuroimaging studies conducted on addicted individuals reveal striking abnormalities in prefrontal cortex (PFC) activity, relative to control subjects, that include reduced basal metabolic activity, reduced regional activation upon presentation of cues associated with non-drug primary reinforcers and enhanced metabolic activity upon presentation of drug-associated cues [5], [6], [7], [8], [9]. Importantly, these abnormalities in PFC activity appear to be common across various drug addictions (incl. cocaine, methamphetamine, alcohol, cannabis, heroin and dissociative anesthetics), as well as across such non-drug addictions as gambling, and correlate with self-reports of “craving” and impairments in self-control in addicted individuals [6], [9], [10], [11], [12], [13], [14], [15], [16], [17].

Preclinical efforts to understand the cellular basis for drug addiction-related abnormalities in mesocorticolimbic glutamate function have employed a variety of experimental approaches to examine the psychobiological consequences of repeated, non-contingent drug administration [18], [19], [20], [21], [22] and many of these findings have been confirmed in various animal models of drug-taking or drug-seeking [23], [24], [25], [26], [27]. The integrity of the corticoaccumbens glutamate pathway is required for expressing many drug-induced changes in behavior, including the sensitization of a drug's psychomotor-activating effects [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], the development of tolerance to a drug's psychomotor-inhibiting effects [38], [39], drug-conditioned place-preference [36], [38], [40], [41], [42], [43], the maintenance of drug self-administration [44], [45], [46] and the reinstatement of drug-seeking [47], [48], [49], [50], [51], [52], [53], [54], [55], [56]. Further, in vivo microdialysis studies have revealed pronounced effects of either acute or repeated drug-induced changes in NAC or PFC extracellular levels of glutamate by a number of drugs of abuse, including: cocaine [31], [35], [37], [47], [53], [57], [58], amphetamines [20], [59], [60], [61], [62], [63], alcohol [38], [39], [64], nicotine [65], [66], [67], [68] and opiates [69], [70], implicating drug-induced changes in presynaptic aspects of corticoaccumbens glutamate transmission in mediating the changes in behavior produced by drugs of abuse. Finally, postsynaptic aspects of corticoaccumbens glutamatergic signaling regulate either the self-administration of various drugs of abuse, or the potential to relapse to drug-seeking, in both humans and laboratory animals. Acamprosate, a mixed antagonist at the NMDA ionotropic glutamate receptor (iGluR) and the mGluR5 subtype of the Group1 metabotropic glutamate receptor (mGluR) [71], [72], is clinically effective at treating alcoholism [73], [74] and may prove to be effective for treating psychomotor stimulant and opiate addiction [75], [76]. Moreover, direct pharmacological manipulation of glutamate receptors within the PFC or the NAC result in reduced behavioral responsiveness to various drugs of abuse, including cocaine [48], [50], [53], [77], [78], [79], [80], alcohol [44], [81], [82], amphetamines [83], [84], [85], [86], [87], [88], [89] and opiates [40], [90], [91], [79], and systemic administration of antagonists of glutamate receptors blocks several aspects of nicotine reward in laboratory animals [92], [93], [94], [95], [96], [97], [98], [99], [100]. Taken together, these data pose cellular factors regulating pre- and postsynaptic aspects of corticoaccumbens glutamatergic transmission as likely molecular candidates contributing to an addicted phenotype. This review summarizes the evidence supporting a key role for the Homer family of proteins in corticoaccumbens glutamate transmission as it relates to the psychomotor-activating and rewarding properties of drugs of abuse.