The Genetically Informed Neurobiology of Addiction (GINA) model

Abstract

Addictions are heritable and unfold dynamically across the lifespan. One prominent neurobiological theory proposes that substance-induced changes in neural circuitry promote the progression of addiction. Genome-wide association studies have begun to characterize the polygenic architecture undergirding addiction liability and revealed that genetic loci associated with risk can be divided into those associated with a general broad-spectrum liability to addiction and those associated with drug-specific addiction risk. In this Perspective, we integrate these genomic findings with our current understanding of the neurobiology of addiction to propose a new Genetically Informed Neurobiology of Addiction (GINA) model.

Fig 1:. Corticostriatal and corticolimbic circuits underlying addiction.

Anatomical locations of (a) and connections between (b) the primary nodes within the corticostriatal and corticolimbic circuits that support reward, emotion, and their regulation and are proposed to influence the binge-intoxication, withdrawal-negative affect, and preoccupation-anticipation stages of addiction. The corticostriatal circuit is critical for reward processing and largely contributes to the binge-intoxication stage of addiction. The striatum (comprised of the putamen, caudate and ventral striatum) is the primary node of this network. Through its connections with other nodes, the striatum supports learning reward contingencies, hedonic responsiveness, generating motivation to pursue rewards and goals, forming and implementing plans to obtain reward, adjusting behavior and plans according to changing contingencies, and coordinating motor movements in the service of obtaining reward. More specifically, dopaminergic projections from the ventral tegmental area to the nucleus accumbens within the ventral striatum support reward prediction and learning in combination with multimodal sensory information received from the basolateral amygdala and contextual information from the hippocampal formation. Projections from the striatum to the pallidum support hedonic responsiveness through endogenous opioid stimulation and provide motivational signals to the VMPFC (supporting integration of contextual and interoceptive information, bottom-up drive and top-down regulation) and the DLPFC (supporting goal-directed planning) through thalamic relays. Afferents from the PFC to the ventral striatum further serve to facilitate the implementation of plans to obtain reward (DLPFC) as well as flexible behavioral adjustment when expected actions do not obtain predicted outcomes (ACC) and can facilitate or inhibit the motivational significance of reward predictive cues in the environment. The corticolimbic circuit is critical for affective processing and behavioral vigilance; it largely contributes to the withdrawal-negative affect stage of addiction. The amygdala (inclusive of the amygdala and the extended amygdala) is the primary node of this network; through its connections with other nodes it supports responses to environmental challenges, including threat and stress, by generating and regulating emotional responses. Low and high resolution sensory information arrives in the basolateral complex of the amygdala from the thalamus and sensory cortices, respectively. Efferent projections from the centromedial and extended amygdala, including the bed nucleus of the stria terminalis (BNST), to autonomic nuclei (such as the parabrachial nucleus), the hypothalamus and the hippocampus drive emotional responses, including fear conditioning and the generation of stress-related physiological changes. Direct and indirect connections between the amygdala and insula facilitate interoception (awareness and importance of our physiological states). Projections from the nucleus basalis of Meynert in the extended amygdala facilitate amygdala-driven arousal and sensitivity of the cortex. Projections from the amygdala to the VMPFC promote subjective awareness and evaluation of emotion and the integration of affective information (such as motivational information conveyed by the ventral striatum projections shown in the upper panel). Projections from the DLPFC and VLPFC to the amygdala through the DMPFC and VMPFC promote the regulation of affective responses and physiological arousal. Both the corticostriatal and corticolimbic circuits support executive function and the regulation of behavior to influence the preoccupation-anticipation stage of addiction by contributing to incentive salience (such as the ventral striatum projections to the VMPFC and OFC within the corticostriatal circuit), interoceptive signals associated with withdrawal physiology and affect (such as the insula within the corticolimbic circuit), as well as the regulation of behavior (through the DLPFC, VLPFC and ACC in both circuits). While there are many additional connections within and between these circuits, we present a heuristic model focusing on those most well linked to addiction. These circuits are explained in greater detail in prior publications^,. Note: Unlike prior depictions of the stage-based neurobiological model which show 3 circuits corresponding to each stage, we present the corticostriatal and corticolimbic circuits, which are hypothesized to predominantly drive the binge-intoxication and withdrawal-negative affect stages, respectively. The preoccupation-anticipation stage is undergirded by prefrontal connections within and across these circuits in this model.

Fig. 2:. The genomic architecture of substance use disorders.

The genetic contribution to individual substance use disorders (SUDs) is attributable to variants that influence general addiction liability and substance-specific variants. General addiction liability is driven by variants influencing traits that correspond to the 3 stages of the neurobiological model of addiction: reward and risk-taking, negative affect and urgency, and executive functioning. In contrast, variants in receptors that respond to the psychoactive components of individual substances or those in genes metabolizing individual drugs directly influence each substance use disorder in a substance-specific manner. Furthermore, genetic variants that influence other psychiatric disorders may also independently influence SUDs (solid arrows indicate the effects of variants on a specific trait/phenotype, whereas the dashed lines indicate cross-trait effects). Reciprocally, the genetics underlying general addiction liability may impact other psychiatric disorder risk (gray dashed arrownot shown). Small effects of substance-specific genetic variants on other psychiatric disordersare also predicted (gray dashed arrow). In addition to these genetic pathways, prolonged substance use and SUDs may phenotypically influence risk-taking, negative affect, executive functioning, as well as psychiatric health and well-being (double headed dashed red arrows depict phenotypic associations). Note that alcohol, nicotine, cannabis, cocaine and opioid use disorders are shown, as there are current large genome-wide association studies of these SUDs; however, the genetics of many other SUDs could be similarly classified.

Fig. 3:. Using genomics to validate hypotheses of addiction.

a| According to neurobiological models of addiction, genetic variation influences substance use, which may, in turn, exert neurotoxic effects that alter brain development. b| According to predispositional models of addiction, genetic risk for substance use disorders impacts brain development (1) prior to or concurrent with the onset of and escalating substance use and sets the neurobiological stage for substance use and future addiction (2). Consequent substance involvement (3) (also influenced by genetic risk that is not associated with neural phenotypes) may then causally influence the brain, via neurotoxic mechanisms, to further potentiate problematic substance use (4). Cyclically, these brain-related changes may further enhance risk for addiction progression (5). c| Mendelian randomization and other genetic causal methods can be used to evaluate these models. These approaches are based on the fact that parental genotypes conferring risk of exposure (i.e., chronic substance use) are equally as likely to be inherited by the offspring as genotypes that are protective or of no effect. Individuals inheriting risk alleles or polygenic risk of substance use will subsequently be more likely to use drugs; we can then test whether this chronic use causally alters brain development. In this method, the individual risk alleles or the polygenic risk of drug exposure is the genetic instrument and an independent association between this genetic instrument and the outcome (changes in brain development), as shown in the flow chart, is possible evidence for causal effects of substance exposure on the brain. The genetic instrument is assumed to influence the outcome (changes in brain development) solely via its influence on chronic substance use (dashed line). For a greater discussion of Mendelian Randomization approaches as well as their limitations see. d| Testing the association between polygenic risk for addiction and brain imaging phenotypes, including trajectories, in drug-naïve individuals (left flow chart) is an ideal approach to assess whether pre-existing brain-related differences precede addiction. Here, the effects of genetic variants are taken from a discovery GWAS of addiction and applied to a sample, ideally of individuals without a history of substance use (e.g., children), which has brain data. A polygenic score is created in this new independent sample. It is expected that this polygenic score will eventually be associated with substance use and addiction in this sample. However, if it is also associated with brain phenotypes prior to use of substances, then we can infer that genetic risk that precedes onset of substance use contributes to brain development (part b, step 1) and later substance use (part b, step.3), rather than a causal effect of substance use on the brain alone (part b, step.4). Alternatively, examining twins (or similarly aged non-twin siblings) that are discordant for substance involvement can provide information on whether substance-related neural phenotypes arise from predispositional influences and/or are induced through substance involvement (right flow chart). If the brains of genetically similar individuals differ as a function of their substance use, then non-genetic mechanisms, including substance-induced changes, might be implicated. However, if they brain phenotypes are similar among those discordant for substance use, this would suggest that predispositional effects including shared genetic variation and environmental exposures are responsible for their associations with substance involvement.

Fig. 4:. A genetically informed neurobiology of addiction (GINA) model.

Addiction may be conceptualized as a developmental process or as a syndrome comprised of stages of escalating problem use. While the GINA model described here outlines a testable gene–brain–behavior mechanism underpinning the stages of addiction, it is scalable and can be extended to advance our understanding of the process of addiction. a| An illustration of the process of addiction, and those that lead into addiction, serves as a framework for understanding the GINA model. Exposure opportunity, availability^, and initial expectations surrounding the anticipated subjective effects of substance use serve as early contributors to drug-seeking behaviors and increase the likelihood of substance use^–. Onset of substance use occurs in a subset of individuals, with some further entering a phase of casual but repeated substance use. Depending on the addictive potential of the substance, progression through periods of heavy episodic use and cessation may then occur (intervening aspects of these processes are not depicted). For some substances, periods of primarily reward-related occasional or casual use, heavy episodic use and cessation may occur (e.g., heavy drinking limited to college), during which time individuals may even meet criteria for milder forms of SUD^–. Not shown are the numerous genetic and environmental influences that promote or deter progression through these substance-interfacing behaviors. For a further subset of individuals, heavy episodic use advances into a phase of sustained heavy use, wherein the pleasurable aspects of substance use are attenuated and compulsive use emerges to ameliorate negative affect, psychological and/or physiological stress states, and physiological withdrawal symptoms. Withdrawal, and related negative mood, following substance abstinence leads to potentiated interoceptive salience through which physiological arousal associated with withdrawal and negative emotionality are potentiated. We propose that this phase reflects moderate to severe forms of SUDs. b| The neurobiological model of addiction in the GINA framework. The GINA model places the 3 stages of addiction (shown around the outside of the image) within the context of a polygenic core (grey), environmental filter (blue) and brain substrate (pink; width of circles does not correspond to any relative magnitude of effect, i.e., genes and environment may be equally important). Each stage aligns most closely with genetic predispositions that act via specific posited brain mechanisms (these are shown “stacked” below that stage of the addiction cycle). All of the addiction stages are influenced by a polygenic core, which broadly corresponds to trait representations of substance-induced stages of sustained heavy use (binge-intoxication), negative affect (withdrawal-negative affect), and preoccupation/craving (preoccupation-anticipation) and by additional drug-specific polygenic risk that influences addiction, partly via the brain (for example, variants in genes encoding neurotransmitters) as well as via non-brain mechanisms (such as metabolic variants). Polygenic liability to reward-related risk-taking contributes to initial phases of binge-intoxication and may promote later escalating use (shown as heavy - episodic and sustained - use), which plays a role in promoting the reward related neural response to pleasurable aspects of substance use (e.g., striatal brain regions). On the other hand, chronic substance use induces brain-related alterations that culminate in heightened stress states and negative affect (for instance, those with polygenic liability to negative urgency may be more vulnerable to this pathway) via a modified limbic response. Furthermore, polygenic liability to executive function is likely to be instrumental in drug craving via changes in prefrontal brain function that results in increasing difficulties regulating the emotional salience of substance-related stimuli, despite the potential of subjective and cognitive desires to stop. Despite the appearance in this schematic of a one-to-one correspondence between polygenic liability, brain region and addiction stage, the gene–brain–behavior map is likely to be more interconnected. For instance, sustained heavy use in the context of negative affect may be influenced by polygenic risk to negative urgency and affect, via limbic pathways as well as substance-induced alterations in striatal circuits. The environment provides a filter for genetic liability (i.e., the magnitude and nature of genetic effects may be different in differing environmental contexts) and also directly underpins addictions. The brain is depicted as the outer substrate from which psychological aspects of addiction emerge. While distinct brain systems are illustrated, it is likely that networks of brain regions correspond to the three stages of addiction. While not noted here, aspects of addiction arise from and impact other bodily systems as well as the brain.