Shaping vulnerability to addiction - the contribution of behavior, neural circuits and molecular mechanisms

Abstract

Substance use disorders continue to impose increasing medical, financial and emotional burdens on society in the form of morbidity and overdose, family disintegration, loss of employment and crime, while advances in prevention and treatment options remain limited. Importantly, not all individuals exposed to abused substances effectively develop the disease. Genetic factors play a significant role in determining addiction vulnerability and interactions between innate predisposition, environmental factors and personal experiences are also critical. Thus, understanding individual differences that contribute to the initiation of substance use as well as on long-term maladaptations driving compulsive drug use and relapse propensity is of critical importance to reduce this devastating disorder. In this paper, we discuss current topics in the field of addiction regarding individual vulnerability related to behavioral endophenotypes, neural circuits, as well as genetics and epigenetic mechanisms. Expanded knowledge of these factors is of importance to improve and personalize prevention and treatment interventions in the future.

Keywords: Dopamine D2 receptor; Drug abuse; Endophenotypes; Epigenetics; Genetics; Prodynorphin; Striatum.

Figure 1. Individual differences exist in genetically highly homogeneous populations

Scatter plot depicting individual differences within alcohol preferring Marchigian-Sardininan (msP) and Wistar rat populations in (A) operant alcohol self-administration under fixed ratio condition, (B) break point under progressive ratio contingency, (C) relapse to alcohol seeking elicited by exposure to environmental cues previously associated to alcohol self-administration, and (D) relapse elicited by the pharmacological stressor yohimbine (1.25 mg/kg, i.p.) in rats previously trained to self-administer 10% alcohol solution.

Figure 2. Syn3 impairments underlie heightened impulsivity and addiction risk

(A) Expression of Syn3 in tissue from the striatum of 40 strains of BXD mice exhibits a pattern of genetic correlation with reversal learning abilities. BXD strains demonstrating relatively low Syn3 expression in the striatum exhibit heightened impulsivity in the reversal learning test. (B) Hypothetical mechanistic relationship between alleles influencing Syn3 expression and impulse control and addiction risk phenotypes. DA: dopamine.

Figure 3. A genetically influenced microRNA-mRNA interaction affects novelty seeking and reward learning

(A) Specific expression of miRZip-365 in nucleus accumbens striatonigral neurons results in inhibition of miR-365's binding to its endogenous targets including Prodynorphin. miRZip-365 leads to significant increases in (B) novelty seeking in Open Field and (C) positive reinforcement-based decision making in fixed ratio and progressive ratio food self-administration paradigms. PDYN: prodynorphin, * p<0.05, **p<0.01.

Figure 4. Individual addiction vulnerability

High and low risk for developing substance use disorders is determined by a complex interaction of (A) genetic/molecular factors (e.g. genetic variants affecting microRNA binding and epigenetic regulation of gene expression), (B) neural pathways (e.g. changes in direct and indirect striatal pathway activity), (C) behavioral endophenotypes (e.g. heightened impulsivity and novelty seeking), and environmental factors. SNP: single nucleotide polymorphism, 3′UTR: 3′ untranslated region, miRNA: microRNA.