Surgery and Neuroscience of Addiction

Epidemiology of Addiction

Addiction is a harmful, compulsive physical and/or psychological need for something that cannot be readily controlled and causes symptoms on withdrawal. For the purpose of this chapter, we will focus on substance abuse, primarily cocaine and opiates. Other substances that can be abused include alcohol, nicotine, and various prescription and nonprescription drugs. However, many behaviors and other activities can become addictive, including gambling and sexual behavior. In a 2019 survey, roughly 60% of the adult US population used some substance with abuse potential (e.g., alcohol, tobacco, drugs) recreationally within 1 month before responding. Of these, roughly 20 million adults are addicted to drugs or alcohol, with alcohol dependence affecting over 70% and illicit drug dependence reported in over 40% of respondents. The prescription opiate crisis has had a devastating impact on a broad range of communities, particularly in the United States, leading to a strong push to develop better pain therapies that avoid narcotics. From 1992 to 2012, the number of people reporting abuse of prescription opiates almost tripled from 4.9 million to 12.5 million, with roughly 1.7 million people developing a chronic opioid addiction. By 2015, long-term opioid dependence affected 2.4 million adults in the United States, but this decreased to 1.6 million by 2019, likely reflecting changes in prescription patterns and increased mechanisms for abuse prevention and monitoring resulting from greater awareness of the prescription opioid problem among health care workers, local governments, and the general public. Cocaine dependence affects over 2 million people, with roughly one-half of those meeting criteria for cocaine use disorder.

Despite the magnitude of the problem, only a fraction of those with addiction undergo treatment. Part of the reason for the small percentage of patients treated is the limited options for efficacious therapy in many cases. Psychotherapy and other psychosocial interventions, such as group therapies, are the most common methods for addressing drug abuse. These can help some patients, but without addressing the underlying biologic cause of addiction, very aggressive monitoring and oversight are necessary to prevent relapse, and even this is often insufficient. Opiate and heroin abuse have long been treated with methadone, which is a mu-opiate receptor agonist that does not have the same abuse or addiction potential as other drugs. Yet patients on methadone therapy usually must remain on treatment continuously for long periods or indefinitely, which can be difficult to maintain. Naltrexone is an opiate receptor antagonist also used to treat narcotic addictions. There is no drug specifically approved by the US Food and Drug Administration (FDA) for cocaine addiction, and therapies currently in use are mostly dopamine agonists attempting to modulate reward signals (see later) or GABA agonists/glutamate antagonists, which presumably dampen CNS responses to cocaine and thereby reduce the reward from continued abuse.

Clearly, the magnitude of the problem coupled with limitations in current therapies present the need for development of novel therapeutic approaches. Neurosurgeons are particularly adept at identifying and safely reaching specific brain targets to deliver therapies that can directly block dysfunctional circuits. Postulating what to deliver and where it should be deployed depends on understanding the specific brain circuitry mediating addictive behaviors and the molecular pathways that influence responses within these circuits.

Methods for Circuit Mapping in Animal Models of Addiction

Electrophysiology, histology, and behavioral analyses have long been the staple of preclinical addiction research, but in recent years techniques have been introduced to allow an unprecedented level of specificity to dissect neuronal circuits underlying substance abuse. A key development has been the identification of Cre as a site-specific recombinase allowing for deletion of sequences residing between two LoxP sites. Sequences placed between LoxP sites can then be used to disrupt and inactivate genes, which can then be removed in the presence of Cre to activate the target gene. A major advance has been the creation of so-called Cre-driver mouse lines, with Cre expression driven by highly specific genomic promoter sequences to restrict expression to particular cell types. The successful creation of the first Cre transgenic line led to a large-scale generation of Cre-driver lines and mice with floxed target genes and reporters. This permits restriction of gene expression to those cell types through either crossing Cre-driver mice with transgenic mice harboring an inactivated “floxed” gene or through injection of a viral vector containing an inactivated gene. Further development of double-floxed inverted open reading frame (DIO) and flip/excision (FLEX) constructs, which use two pairs of lox sites, have obtained more acceptance because of their less leaky nature, even under strong promoters. Combining this ability to target highly specific neuronal subtypes with powerful new methods for on-demand manipulation of neuronal activity, such as optogenetics and chemogenetics, has led to a much broader and more detailed understanding of the circuitry underlying addiction ( Fig. 125.1 ).

Animal Models of Addiction

Even though animal models of addiction, as in any other field, have limited translational predictive power, neuroanatomic and neurochemical similarities between rodents and humans in drug-intake behavior make the various models particularly attractive for testing hypotheses regarding human addiction. Furthermore, the animal models reviewed later in this chapter have been crucial to understanding the mechanisms involved in the reward system and to identify possible targets and therapeutic approaches.