Date of Award

12-2023

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Developmental and Brain Sciences

First Advisor

S. Tiffany Donaldson

Second Advisor

Erik Blaser

Third Advisor

Randy Corpuz, Jamie Maguire

Abstract

Adolescent psychostimulant (e.g., amphetamine) use is on the rise in the United States, partly due to social and brain developmental changes that heighten risk-taking for this age group. Unfortunately, many adolescents move beyond casual use to impulsive use, escalating to long-term use and later substance use disorders. At still other times in the life course, such as after the birth of a child, stark shifts in the hormonal milieu in the mother may lead to postpartum depression and self-medicating with substances in both mothers and fathers. Many users achieve less reward with repeated use and begin to feel more out of control; in fact, they may shift from goal-oriented to habitual behavior and, eventually, to compulsive behavior. Given the widespread use and high abuse potential for licit and illicit substances in adolescents, and at other life events (e.g., postpartum), understanding the neural modification contributing to compulsion and relapse during critical stages is vital. Thus, the current dissertation focuses on understanding changes in neuroimmune function and activation that may contribute to neuroplasticity and the learning involved in compulsions to use drugs following environmental and life stressors. First, I completed a review to highlight studies describing the role of neuroinflammation in the effects of environmental stress, anxiety, and drug-taking behavior (i.e., use of amphetamines) at critical developmental and life stages (e.g., postpartum). Next, I completed an experiment and secondary data analysis, the first experiment used an adolescent rodent model and induced stress with lipopolysaccharide (LPS; 0.1 μ g/ml, IP; LPS, a gram-positive bacteria that induces inflammation) injection to identify underlying neural and neuroimmune factors in escalation and relapse to repeated amphetamine (4.0 mg/kg, IP; 4-day). The secondary data analysis investigated the relations between postpartum depression, substance use, and C-reactive protein in new mothers and fathers. In the first study, we found that the environmental stress induction with LPS increased amphetamine sensitization over the repeated regimen and on Challenge Day (amphetamine, 1.0 mg/kg/ml). Brain analysis of pro-inflammatory response and markers used as a proxy for excitation and plasticity were explored in mesocorticolibmic regions of LPS+AMPH-treated adolescents. Increased D2 receptor levels were found in the ventral and dorsal striatum, a hallmark of compulsion. Together, these findings support the hypotheses that (1) exaggerated neuroinflammation is found when environmental stress is combined with repeated amphetamine and (2) neuroplasticity in dopaminergic regions is involved in escalation and relapse, particularly regions involved in reward learning associations. In our second experiment, we assessed depression and anxiety, C-reactive protein (a marker of neuroinflammation), and substance use in new mothers and fathers in the postpartum period. Here, we found evidence for increased endorsement of physical ailments (RAND subscales) in a cohort of new fathers that correlated with change in CRP levels over time. In these participants, we also found that change in RAND scores and CRP levels significantly predicted drinking behavior in new fathers. Taken together, our data support our hypothesis that stress associated with hormonal decline after birth can impact the affective and physical states of parents, induce CRP levels, and likely lead to increased substance use. In all, the review highlights marked changes in neuroinflammation that occur across developmental stages, in response to stress and/or drug use. The rodent work provides further support for the findings from the review - neuroinflammation-induced changes correspond to a vulnerable profile for developing augmented responses to amphetamine in adolescent male rats. Finally, the secondary analysis of the clinical data also highlights that stressful life events, such as delivery and the postpartum period, also present physiological changes including neuroinflammation that may underlie greater response to, and escalation of, use of licit and illicit substances. Together, the findings from this dissertation point to the importance of understanding neuroinflammation and neuroplasticity at critical stages of development and life stages as they may underlie greater vulnerability to an escalation of drug and alcohol use.

Comments

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