Article summary with Effects of early life stress on cocaine self-administration in post-pubertal male and female rhesus macaques by Wakeford a.o. - 2019

Introduction

Cocaine use disorder (CUD) is a major public health concern in the USA. CUD is defined as a chronic relapsing disorder where users continue to seek out and use cocaine despite harmful consequences. Despite these risks, it’s not clear why only a fraction of users transition from initial use to dependence. Researchers have spent a lot of effort trying to identify genetic and environmental variables that confer specific vulnerabilities to the reinforcing effects of cocaine.

Adolescence has been described as a vulnerable period, as this is typically the time at which drug use is initiated. Preclinical studies indicate that adolescent rodents also show heightened vulnerability to the reinforcing effects of cocaine compared with adults. Superimposed on this vulnerability to cocaine use is the fact that the occurrence of adverse events early in life, or early life stress (ELS), represents one of the most predictive risk factors for the emergence of CUD in adolescence. ELS includes:

• Childhood maltreatment
• Early adverse experiences taking the form of physical/sexual abuse, neglect, or emotional maltreatment

These experiences have long-lasting psychological and neurobiological consequences to the victim, including heightened vulnerability to the development of mood and anxiety disorders.

Sex has also emerged as a critical variable determining vulnerabilities to drug abuse. Specifically, women progress form recreational drug use to drug dependence faster at a younger age, display a propensity to relapse more readily, and consume more cocaine following a relapse in comparison with men.

The goal of the present set of experiments was to examine if ELS was associated with increased sensitivity to the reinforcing effects of cocaine in post-pubertal (late adolescent to young adulthood) male and female rhesus macaques. This study adds important information to the existing literature by examining cocaine self-administration in post-pubertal monkeys that have had no previous experience with operant tasks or drugs of abuse.

Method

Sample and Procedure

Total sample of 14 rhesus monkeys (8 male, 6 female). Infants were randomly assigned at birth to be fostered to multiparous mothers with either a history of nurturing maternal care (control) or histories of infant maltreatment (maltreated) according to published protocols in an effort to control for heritable/biological factors that may confound the effects of ELS. Around age 4-5 the animals were transferred to the main station for the cocaine self-administration studies. The animals were fitted with primate collars, chair-trained to sit comfortably in chairs specifically designed for nonhuman primates and implanted with intravenous (I.V.) catheters at around 5-6 years of age.

Focal observations of maternal care and infant behaviour were performed at the field station following birth and cross-fostering over the first 3 months of life to verify and quantify early maternal caregiving experienced by infants and its impact on socioemotional behavioural development. Observations were collected by experienced coders form observation towers.

Drug used was cocaine hydrochloride dissolved in 0.9% sterile saline and administered I.V.

Measures

• ELS: rates of abuse and rejection were computed by averaging the frequency of abusive and rejection events towards the infant by the mother. Frequencies of screams and tantrums were computed into overall rates by averaging the frequency of screams or tantrums over all observations. Anxiety was also computed as an overall composite score and averaged across all observations.
• Cocaine self-administration: days to acquire self-administration were operationalized as the number of days required before meeting stability criteria under terminal performance conditions. Two-way ANOVAs were used to examine performance at each stage of acquisition, and the max dose of cocaine.

Discussion & Conclusion

The goal of the study was to examine if ELS influenced sensitivity to the reinforcing effects of cocaine in post-pubertal animals. During infancy, maltreated animals displayed significantly greater rates of abuse and rejection, as well as behavioural distress measured by rates of screams, compared with control animals. The major findings of this initial set of self-administration experiments were that control males required more days to acquire terminal performance criteria compared to females. They also required more total days to acquire cocaine self-administration compared with other experimental groups. Together, these data suggest that ELS in the form of infant maltreatment results in a phenotype that includes heightened emotional reactivity and faster acquisition of cocaine self-administration in drug-naïve post-pubertal males.

This is the first study to examine infant maltreatment as a form of specific ELS that may induce a unique vulnerability to the reinforcing effects of cocaine in post-pubertal nonhuman primates. The most translationally relevant models of psychosocial stress include the occurrence of chronic and unpredictable stressors, given that these two aspects of stress are frequently responsible for sustained changes in behaviour as a result of maladaptive change sin hormonal and physiological systems regulating the stress-response system.

Much work has characterized the role of stress in drug abuse, with a key finding being that stress exacerbates the reinforcing effectiveness of many drugs of abuse. The results of the control monkeys are consistent with other preclinical findings showing that females are more sensitive to the reinforcing effects of cocaine compared with males. Data would suggest that males without a history of ELS demonstrate a resiliency towards the initial reinforcing effects of cocaine compared to maltreated males.

Sex was explicitly examined as a biological variable in these experiments, given the extensive literature demonstrating that women have a higher susceptibility to several aspects of psychostimulant abuse. In the experiments described, post-pubertal females regardless of early life care required fewer days than males to demonstrate stability under terminal performance conditions, suggesting that females may show an initial sensitivity to the reinforcing effects of cocaine as evidenced by a quicker progression through terminal performance criteria when compared to males.

While results from this study suggest a relationship between the occurrence of ELS and sensitivity to the reinforcing effects of cocaine in post-pubertal males and females, there are some limitations to the study. The sample size is relatively small. However, this is the first published study assessing ELS-induced vulnerability to the reinforcing effects of cocaine using post-pubertal, drug-naïve nonhuman primates and adds to the existing literature investigating the effects of ethologically valid models of social stress as a risk factor for the development of substance use disorders in adolescence.