Following this operant learning paradigm, we wanted to assess how adolescent drug exposure might impact nicotine reinforcement in adulthood. In our previous studies we have found that exposure to the synthetic cannabinoid WIN 55,212-2 and co-exposure to nicotine and WIN together in adolescence increases subsequent adulthood intake of a low dose of nicotine in males, but decreases intake of low and moderate nicotine doses in females. Our current experiments revealed that females exposed to the higher dose of THC in adolescence self-administered more nicotine in adulthood at a moderate nicotine dose than control subjects. Males exposed to either the lower or higher dose of THC or co-exposed to nicotine and the lower dose of THC also self-administered more nicotine at this dose. These findings differ compared to our previous studies where we did not see any differences in nicotine intake at this dose following adolescent cannabinoid drug exposure in males and reduced nicotine intake in females. But given that the method of drug exposure, oral as compared to previously injected, and the drug itself, THC compared to WIN, are changed, these differences are not too surprising. Rather, it further adds to the complexity of this story when parsing out the effects of adolescent drug exposure on later drug-taking behaviors. In humans, women with a history of cannabis use are four times more likely to become regular cigarette smokers and almost three times as likely to develop nicotine dependence which is supported by our finding of increased nicotine intake in adult female mice who were previously exposed to THC.
Additionally, men with a history of cannabis use are also more likely to become daily cigarette smokers which aligns with our current findings as well. Of note,flood and drain hydroponics it was unexpected that the groups co-exposed to nicotine and the higher dose of THC did not exhibit any differences in nicotine intake. These groups did have the initial differences in cotinine levels which we suspected would alter later drug-taking. While all of the nicotine exposed groups in both sexes had a significant level of cotinine in their blood, both males and females co-exposed to the higher dose of THC and nicotine together had lower cotinine levels than those exposed to nicotine vapor alone and those co-exposed to the lower dose of THC and nicotine vapor. This suggests that the higher dose of THC may impact the metabolism of nicotine. In support of these findings, another study confirms that in human smokers, co-users of both nicotine and THC have lower cotinine levels than tobacco only smokers. Yet although males co-exposed to nicotine and the higher dose of THC exhibited a greater drive to obtain food reward that was not reflected in their nicotine intake. Thus, taken together, findings from these experiments demonstrate that in males, THC or nicotine and lower dose THC co-exposure in adolescence, and in females exposure to higher doses of THC during adolescence have persistent developmental effects and increase the drive to consume both food and nicotine in adulthood.Finally, we wanted to assess the impact of this adolescent drug exposure on cueinduced nicotine seeking in adulthood. We were first able to reliably demonstrate the incubation of nicotine craving effect in both male and female control mice. Then we found that chronic adolescent exposure to nicotine or THC differentially alters later incubation of nicotine craving based on route of administration and dose.
Specifically, both male and female mice that were exposed to nicotine via injections and females exposed to nicotine vapor during adolescence did not have enhanced nicotine-seeking as adults following an extended withdrawal period. These findings indicates that nicotine-associated cues may not induce craving across abstinence in some subjects that have an adolescent history of nicotine exposure. Surprisingly, males that were exposed to nicotine vapor during adolescence did have the incubation of nicotine craving effect in adulthood. It is important to note that the cotinine levels for males exposed to nicotine alone regardless of route of administration did not differ, which emphasizes that the duration of the daily nicotine exposure has unique implications on this later drug seeking behavior. This contention needs to be further explored with more specific studies but the notion is supported with prior findings that duration of nicotine exposure via osmotic minipumps compared to injections at the same dose alters nicotine withdrawal. Furthermore, given the differences in nicotine intake among the male THC exposure groups, we were surprised to find that they maintained the incubation of nicotine craving effect. However, another study found similar results in which adolescent THC exposure in male mice does not alter later stress- and cue-induced reinstatement of nicotine-seeking following extinction. In females, while the lower dose THC exposure group did have an increase in nicotine-seeking on day 24 as compared to day 1 of the incubation, the higher dose THC group did not. Instead, the higher dose THC female subjects exhibited an increase in active lever presses on day 1 as compared to their lever pressing during nicotine self administration.
This finding suggests that the higher dose of THC during adolescence may have led to overall increased active lever pressing, which is consistent with the higher level of responding for food training, or it may be a premature incubation effect with higher immediate and persistent drug seeking behavior. Importantly, co-exposure to nicotine vapor and THC at either dose does result in the incubation of nicotine craving effect. We expected these results as human adult co-users are twice as likely as tobacco smokers who do not use cannabis to continue smoking tobacco. This could be due to the cannabinoids enhancing the effects of nicotine-associated cues in reinstating the drug-seeking behavior after a quit attempt. Moreover, for the females, although single drug exposure to nicotine or the higher dose of THC alone does not result in the incubation effect, perhaps in these poly-drug exposure conditions the nicotine and cannabinoids interact during development to alter the responsivity of nicotine-associated cues in reinstating drug-seeking behavior. Thus, the adolescent co-exposure to both drugs could result in a heightened response to the drug-associated cues later in life. Patients’ drug histories are an important factor for treating substance use disorders. Our prior findings demonstrated that acute and chronic pre-treatment with a synthetic cannabinoid can reduce nicotine intake in male and female mice; however, if either sex had been previously exposed to nicotine or cannabinoids during adolescence, this reduction does not occur. Thus, prior drug history may be a mediating factor in the effectiveness of pharmacological cessation treatments. Furthermore, in another study, the offspring mice of parents who were exposed to nicotine do not demonstrate an incubation of nicotine craving effect. This indicates that the effects of drug exposure persist not only for the later drug seeking and cue responsive behaviors in one subject, but it could have lasting generational impacts for their offspring as well. In conclusion, adolescent exposure to nicotine and/or THC does alter operant learning, drug intake, and relapse-related behaviors in adulthood in a sex-dependent manner. Taken together, these results indicate that adolescent use of cannabinoids have a persistent effect on reward consumption, which is dependent on THC dose, nicotine coexposure, and type of reward. These studies emphasize the impact of prior drug history on later drug-associated behaviors and susceptibility to relapse as well as the importance of being cognizant of adolescent drug use in patient populations when navigating personalized approaches to treating adulthood substance abuse.Diversity, equity, and inclusion have been hot topics in recent years. In particular since the worldwide protests against police brutality and social injustices in 2020, there has been a resurgence in the push for creating more equitable and inclusive environments within the field of neuroscience and academia as a whole. However, true DEI work must go beyond just increasing the number of historically excluded scholars in the laboratories and classrooms; they must also be actively included, given a voice to push for change, and supported in their efforts. My DEI efforts as a graduate student have included serving as an Interdepartmental Neuroscience Program graduate student representative, Competitive Edge peer mentor,indoor vertical farming and department representative for the Diverse Educational Community and Doctoral Experience program. In each of these roles, I strived to create safe spaces for first-generation, Black, Indigenous, Latinx scholars and women to feel welcomed in neuroscience. I also offered reassurance that they belong in the field, advocated on their behalf, and provided needed support as they navigate academia. In doing so, I went beyond simply recruiting a more diverse cohort into the neuroscience program to help ensure their retention by cultivating a community in which they could thrive.
Perhaps my greatest achievement outside my scientific research has been my efforts to support historically marginalized people in neuroscience and founding the global nonprofit, Black In Neuro. Black In Neuro is an international organization that aspires to diversify the neurosciences by building a community that celebrates and empowers Black scholars and professionals in neuroscience-related fields. We also aim to provide professional development resources and increase the visibility of Black neuroscientists to inspire the next generation and dismantle stereotypes of what a neuroscientist can be.As a PI and mentor, your reactions about these events can dictate whether your trainees ever feel safe to speak up again. Before we are scientists, we are people. Our self advocacy requires an immense amount of bravery. It is consuming, is psychologically draining and could cause future troubles for us. So, not every underrepresented person wants to confront all instances of racism head-on. But with the perpetual anti-Black violence still occurring, I want to give a few suggestions for mentors to better support their Black trainees. Make it very clear that you are an ally. Don’t wait for us to start the conversation, because your silence speaks volumes. Let it be known if your office is a safe space. Host quarterly lab meetings that are focused on efforts the lab is making to become anti-racist and on current issues affecting diverse students. Call out your colleagues on their racism. Educate yourself. Become aware of the systemic hurdles that every Black student has had to overcome to get to this point. Black Americans hold ~2% of the national wealth, which means less access to private schooling, tutors and prep programs. Standardized tests have been shown to be biased against minority students and those belonging to a lower socioeconomic status. Almost half of Black students enrolled in a post secondary institution are first-generation college students, which means they may not know about as many scholarship or internship opportunities as their peers do. This isn’t even addressing the racial profiling, subpar medical care and over-policing that takes a physiological toll. Take these into consideration when considering graduate school applicants and hiring. Furthermore, actively encourage applicants from nationally funded diversity initiatives that uplift Black students in the biomedical sciences, such as Maximizing Access to Research Careers, and Diversity Specialized Predoctoral to Postdoctoral Advancement in Neuroscience. Speak up for your Black trainees. Advocate for us when we’re not in the room. Nominate us for awards and speak highly of our efforts. Let us know about fellowships, travel grants and other opportunities that can help advance our careers. Teach us how academia works and the ‘unspoken’ etiquette in the field. Use your position of power to be a champion for equality and racial justice. You do not have to belong to an underrepresented group to support the people in that group. Demand that your departments and schools hire diversity and inclusion experts to host implicit-bias workshops and cultural-competency trainings. When they do want to hear from the current Black student and faculty perspective, find ways to compensate them for this diversity work. But also recognize that the one Black student cannot speak for all Black people. Black experiences are not a monolith. Ensure Black leaders in your field are invited to give research talks at conferences, symposia and departmental seminar series. Encourage everyone to attend, not just the underrepresented students, because perceptions and stereotypes can be changed all around. If you do not identify as the same gender, race or background as your trainee, help them find a mentor who does. My advisor and I have a mutual understanding of sexism in science. But as a white woman, she cannot fully understand how racism is compounded in my experience. One of the best things she did was to connect me with another Black neuroscientist and professor.