Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis

Abstract

In this review we propose that there are sex differences in how men and women enter onto the path that can lead to addiction. Males are more likely than females to engage in risky behaviors that include experimenting with drugs of abuse, and in susceptible individuals, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression. For this reason women enter into the downward spiral further along the path to addiction, and so transition to addiction more rapidly. We propose that this sex difference is due, at least in part, to sex differences in the organization of the neural systems responsible for motivation and addiction. Additionally, we suggest that sex differences in these systems and their functioning are accentuated with addiction. In the current review we discuss historical, cultural, social and biological bases for sex differences in addiction with an emphasis on sex differences in the neurotransmitter systems that are implicated.

Figure 1

The downward spiral from sensation-seeking into addiction. The spiral depicts individuals initiating drug use (large orange arrow) primarily due to positive reinforcement (i.e., seeking the hedonic effects of drugs, such as euphoria, increased energy and alertness, or “the thrill,” which are indicated by yellow shading), which are attributed to acute increases in dopamine (DA, green arrow), norepinephrine (NE, yellow arrow), endogenous opioids (ENK/END/EM, light blue arrow), and acute increases in acetylcholine (ACh, orange arrow). A post-intoxication “crash” follows these acute positive effects due to an “over-correction” by compensatory mechanisms leading to a transient dysphoria (blue-grey shading), which is largely attributed to reduced DA function, ongoing NE activity, and increased dynorphin (DYN, dark blue/purple arrow) and corticotropin releasing factor (CRF, pink arrow) signaling. Neurochemical function and affective state eventually normalize during drug-free periods (white shading between grey arrows). Following repeated use, drug-induced adaptations can also result in the development of psychopathologies and physical symptoms that further reinforce drug use out of negative reinforcement (as depicted by the transition in the spiral from blue to red). A larger proportion of men compared to women may initiate drug use for their positive effects. However, sex differences in the highlighted neurochemical systems may also lead to different trajectories from sensation-seeking toward dependence in men and women. (The magnitude of neurochemical responses is indicated by the relative sizes of the arrows, refer to text for details on sex differences). Modified from Koob and Moal [1].

Figure 2

The central pathways of addiction and their associated neurochemical systems. A. Sagittal rat brain section depicting the systems involved in reward/aversion and addiction. B. Medium spiny neurons (MSN) are the primary sites of synaptic integration in the DS/NAc, which regulate locomotion and reward processes. Striatonigral MSN (DYN), are essential for the reinforcing effects of drugs, whereas striatopallidal MSN (ENK) oppose the actions of striatonigral MSN and promote aversion. Cholinergic interneurons provide ACh in the DS/NAc, which is critical for regulating the balance between striatonigral and striatopallidal MSN (among other functions). The CeA/BST contain several neuron types expressing neuropeptides (and other neurotransmitters). CRF and DYN neurons contribute to negative affect, whereas ENK neurons contribute to positive affect. DA neurons in the SN/VTA send projections throughout the forebrain, which convey motivational salience and value, as well as providing an alerting signal for stimuli with potential significance. NE neurons in the LC/NTS send projections throughout the forebrain, which enhance attention and arousal and modulate systems critical for maintaining homeostasis. C. The cycle of drug abuse/withdrawal alters the balance of signaling in the DS/NAc and CeA/BST. Individuals initiating drug use primarily for “sensation-seeking” (refer to Figure 1) or “self-medication” (refer to Figure 5) have different neurochemical profiles in the basal state and during acute intoxication and the post-drug “crash.” The relative size of the pie pieces (e.g., DYN, ENK and CRF) indicates the predominance of each system, whereas the shading density (e.g., DA and NE) indicates the relative extracellular monoamine concentrations. Neurochemical profiles are further altered during dependence, with plasticity mechanisms in the DS/NAc potentiating striatonigral circuits driving compulsive drug-seeking behavior (indicated by the raised pie wedge). The collective neurochemical changes and their associated effects on DS/NAc and CeA/BST neurotransmission contribute to more frequent cycles of abuse and relapse that are the hallmarks of the spiral to addiction (refer to Figures 1 and 5).

Figure 3

Sex differences in basal neurochemical systems involved in reward, aversion and addiction. A summary of the published information about sex differences in the neurochemistry of the reward system appears in this figure [193,225,226,228,269,329,330,332,353,354,356,370,384,392,423,430,434,435,480-521]. Abbreviations are as follows, (R): data collected from rodents; (H) data collected from humans M: male, F: female, for other abbreviations see list.

Figure 4

Sex differences and the influence of gonadal hormones in the effects of abused drugs. The contents of this figure complement Figures 1 and 5 and emphasize sex differences (when known) and hormone effects (when known) in the effects of drugs of abuse (as depicted in the figures) with initial drug use without preexisting psychopathology (euphoria-seeking), initial drug use when using as self-medication, and during dependence. Yellow shading indicated changes associated with euphoria/positive effects, and blue shading indicated effects associated with dysphoria/negative symptomatology (M: male, F: female, for other abbreviations see list).

Figure 5

The downward spiral from self-medication into addiction. The spiral depicts individuals who start using drugs primarily due to negative reinforcement mechanisms, such as seeking relief from chronic negative feelings, stress-related psychopathologies or victimization (indicated by the blue/grey shading). The drug-induced (large orange arrow) euphoria is likely attenuated in these individuals and the following post-intoxication “crash,” may temporarily exacerbate their initial dysphoria that continues unabated during drug-free periods (large grey arrows). As drug use becomes less regulated, the intervals between intoxicating events become shorter (as depicted by the narrowing of the spirals), intake increases, the positive effects become further attenuated and the dysphoria/negative affective state becomes more protracted/exacerbated. These features of addiction are the result of several interacting neurochemical changes in reward-related brain regions, including a hypodopaminergic state, characterized by reduced basal and stimulated DA concentrations (green arrows), and augmented NE (yellow arrow), CRF (pink arrow) and DYN (dark purple/blue arrow) signaling. The inhibition of other opioid systems (e.g., ENK/END/EM) (blue arrow) that contribute to positive affective state may also contribute to the dysphoria experienced by those with stress-related psychopathologies and during the development of dependence. Since many of these adaptations are already present in individuals coping with chronic stress and its associated psychopathologies even before drug use, the downward spiral may be accelerated. Women are more likely to develop stress-related psychopathologies, suggesting that a greater proportion of women may initiate drug use for self-medication, whereas a larger proportion of men may initiate drug use for their positive effects (Figure 1). Sex differences in individuals with comorbid psychopathology may also lead to different trajectories toward dependence in men and women, and in sex-specific neurochemical changes. (The magnitude of neurochemical responses is indicated by the relative sizes of the arrows, refer to text for details on sex differences).