On the early life origins of vulnerability to opioid addiction

Abstract

The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function, and cause opioid addiction vulnerability, is unknown. We simulated ELA in female rats and this led to a striking opioid addiction-like phenotype. This was characterized by resistance to extinction, increased relapse-like behavior, and, as in addicted humans, major increases in opioid economic demand. By contrast, seeking of a less salient natural reward was unaffected by ELA, whereas demand for highly palatable treats was augmented. These discoveries provide novel insights into the origins and nature of reward circuit malfunction that may set the stage for addiction.

Figure 1:. Early-Life Adversity Potentiates Heroin Seeking Behaviors:

(A) Total heroin self-administration did not differ between control and ELA rats (t₁₂=1.550; P=0.1471), nor did (B) remifentanil self-administration at low effort (t₂₉ = 0.5844; P = 0.5634). (C) Once response-contingent heroin was withdrawn, the ELA group resisted extinction more than controls (t₁₂=2.509; P=0.0274). (D) Accordingly, the probability that ELA rats achieve extinction criterion (<20 active lever presses) each day was lower than in controls (Kaplan-Meier probability of survival; Log-rank curve comparison Chi square(df) = 4.491(1), P = 0.0341). (E,F) ELA augmented reinstatement of heroin-seeking by heroin-associated cues (main effect of cue/no cue: F_(1,12) = 89.20; P<0.0001; main effect of rearing condition: F_{(1, 12)} = 9.982; P = 0.0082; cue × ELA interaction: F_(1,12) = 12.49; P = 0.0041. Bonferroni’s post-hoc tests CTL vs ELA: no cue: t₂₄ = 0.2543; P > 0.9999; cue: t₂₄ = 4.676; P = 0.0002), and by a heroin priming injection (main effect of heroin/saline prime: F_(1,12) = 27.00; P = 0.0002; main effect of rearing condition: F_{(1, 12)} = 4.891; P = 0.0471; prime × ELA interaction: F_(1,12) = 5.447; P = 0.0378. Bonferroni’s post-hoc tests CTL vs ELA: saline prime: t₂₄ = 0.01554; P > 0.9999; heroin prime: t₂₄ = 3.210; P = 0.0075). Circles within each bar represent individual animals in CTL (green) and ELA (orange) groups. *p<0.05; **p<0.01; ***p<0.001.

Figure 2:. Early-Life Adversity Increases Demand for Opioids and Highly Palatable Food:

(A) ELA-reared rats had a decreased sensitivity to cost, or an ‘inelastic’ demand, for remifentanil compared to controls (t₂₈=2.630; P=0.0137). (B) However, no changes were observed in the intake of remifentanil by the ELA group when the drug was essentially “free”, measured as the hedonic set-point, or Q₀ (t₂₈=0.8159; P=0.4215). (C) Average (±SEM) drug intake at each effort step is depicted. (D) ELA rats were willing to pay a significantly higher price (effort) for a highly palatable food, indicating decreased demand elasticity, or α (t₁₅=2.341, P=0.0334), whereas (E) consumption at low effort (Q₀) did not differ between ELA and CTL rats (t₁₅=1.199, P=0.2490). (F) Average palatable food intake at each effort step is depicted. (G) In contrast to palatable food, no difference was seen in demand elasticity (α) between ELA and CTL rats for chow pellets (t₁₅=0.4619, P=0.6508), and (H) Consumption at low effort (Q₀) also did not differ between ELA and CTLs (t₁₅=0.7922, P=0.4406). (I) Average chow pellet intake at each effort step is depicted. Circles within each bar represent individual animals in CTL (green) and ELA (orange) groups. *p<0.05.