Furthermore, female rats that were permitted to self-administer nicotine beginning in later adolescence exhibited higher levels of nicotine intake compared to those that initiated self-administration in adulthood. Thus, the stage of development when nicotine and cannabinoid exposure occur as well as the duration of the exposure are important factors that impact later drug-taking. Cannabinoid and nicotine co-exposure in adulthood also appear to alter later drug related behaviors. Of further interest, while WIN exposure decreased nicotine self administration in adult male rats at a moderate nicotine dose, this effect was reversed when the level of effort required to obtain drug infusions was increased under a progressive ratio schedule of reinforcement. Similarly, under operant conditions requiring high levels of behavioral effort, a brief history of THC administration in adulthood increased subsequent nicotine self-administration in male rats. Thus, in high effort situations, cannabinoid exposure can drive an increase in effort to obtain nicotine. Finally, cannabinoid signaling may also be involved in cue-associated nicotine seeking. Male rats administered WIN prior to a cue-induced reinstatement session exhibited increased nicotine-seeking behavior. This suggests that acute cannabinoid receptor activation heightens the responsivity to cues in triggering reward-seeking behaviors. Taken together, these studies highlight the importance of prior drug history at varying developmental stages and level of effort required on the effectiveness of cannabinoids in modulating nicotine reinforcement.Nicotine and/or cannabinoid use may also alter cognitive and emotion-associated behaviors,vertical growing systems which are often correlated with substance use disorders.

Acute cannabinoid or nicotine exposure has been shown to induce either anxiolytic or anxiogenic effects dependent on dose, age, or sex. For example, nicotine decreased anxiety associated behaviors in adolescent male rats, but paradoxically increased anxiety-associated behaviors in females. Further, male and female adolescent rats exposed to cannabinoids exhibited a decrease in short-term and spatial working memory but an increase in depressive-like behaviors. In a study assessing chronic co-exposure of nicotine and the synthetic cannabinoid CP 55,940, both male and female adolescent rats developed increased anxiety-like behavior that was further reflected physiologically by elevated corticosterone, a stress-associated hormone. In contrast, in adult mice, chronic co-exposure to both nicotine and THC decreased anxiety-like behaviors. Similarly, nicotine treatment can reduce some of the anxiogenic effects of acute THC exposure, and THC treatment can attenuate the anxiogenic effects of acute nicotine exposure. Finally, nicotine and/or cannabinoids can induce a significant developmental impact on cognitive outcomes when consumed during pregnancy. Chronic in utero exposure to nicotine, THC, or co-exposure to both drugs has been associated with long-term effects into adolescence. Specifically, adolescent male and female rats exposed prenatally to THC exhibited deficits in short-term memory. Interestingly, the adolescent male rats with a prenatal history of nicotine and THC co-exposure exhibited similar deficits in short-term memory, as well as a deficit in pre-pulse inhibition, a behavioral outcome associated with schizophrenia symptomology. It is worthwhile to note that the nicotine and THC prenatal co-exposure condition only induced memory-related effects in the males but not females, suggesting that nicotine may have buffered the effects of THC on the developing female brain.

Together, these findings indicate that nicotine and cannabinoids induce complex interactions on the brain across various stages of development.Less than 10% of those who want to quit smoking cigarettes are successful in the long-term. Most people attempt to quit ‘cold-turkey’, without the help of any nicotine replacement therapies , other pharmacotherapies, or behavioral support programs. Unfortunately, this cold-turkey approach induces significant nicotine withdrawal symptoms, such as cravings, irritability, difficulty concentrating, headaches, and insomnia, which can promote relapse as the user attempts to alleviate symptoms with drug re-exposure. By using NRTs, such as nicotine patches, lozenges, or gum, the success of quitting increases to 50-60% at the six-month time point. This is likely due to smokers being able to obtain nicotine from a source other than cigarettes, thereby reducing withdrawal symptoms and easing the transition to abstinence. ENDS were also developed as a type of NRT for adult smokers. It was proposed that this method of administration may be more successful given that the same physical and sensory cues are present as with smoking cigarettes, such as raising the hand to the mouth and inhaling/exhaling smoke. In 2014, 4% of adults in the US reported using ENDS for cigarette cessation, but by 2018, the percentage decreased to 3.2%. Furthermore, about half of adults who vape nicotine also smoke tobacco cigarettes, a behavior known as ‘dual use’. Surprisingly, a recent study found that people who quit smoking for more than a year have an increased risk of relapse if they vape nicotine during that time. Additionally, there is increasing evidence of cannabis use in vaping devices among teens and adults. People who use THC vapes report a high incidence of tobacco product use as well. As such, the absolute effectiveness of ENDS for tobacco cessation remains to be determined. Regardless of the smoking cessation tools implemented, high rates of nicotine relapse remain prevalent.

Modulation of the cannabinoid receptor has also been employed as a novel approach for smoking cessation. In rat models, CB1R antagonists were shown to decrease nicotine self administration and reduce nicotine-induced dopamine release in the NAc, which then led to the progression along the drug development pipeline. Two different CB1R antagonists, rimonabant and taranabant, underwent clinical trials for smoking cessation and were found to be marginally effective. However, both drugs have now been withdrawn from the market due to adverse psychological side effects in humans, including increased anxiety and depression. Cannabidiol, a CB1R and GPR55 antagonist and CB2R reverse agonist, has also been assessed as a modulator for nicotine withdrawal symptoms in a pre-clinical study. Coexposure to cannabidiol during chronic nicotine exposure reduced the somatic signs of nicotine withdrawal, including paw tremors, head shakes, jumps, and abdominal contractions, in rats, suggesting that cannabidiol may be a potential therapeutic in future clinical studies. Individuals with cannabis use disorder exhibit similar withdrawal symptoms as nicotine, including increased irritability, aggression and depression, sleep difficulty, and physical symptoms. Indeed, daily cannabis users who attempted to quit report similar withdrawal symptom severity as daily cigarette smokers attempting to quit. A preliminary study has shown that synthetic cannabinoids, such as nabilone, may be used to attenuate these withdrawal symptoms, which was demonstrated in a small sample of cannabis users in a clinical setting. Targeting nAChRs may also be effective as a treatment for cannabis use disorder. A pre-clinical study in rats showed that blocking a7 nAChRs with a selective antagonist, methyllacotinine, reduced self administration of the synthetic cannabinoid WIN and prevented THC from increasing dopamine in the NAc shell. This is quite promising because this putative therapeutic did not result in any depressant or toxic effects. More recently, nicotine patches have been examined for alleviation of cannabis withdrawal symptoms. A low-dose nicotine patch was shown to reduce negative affective withdrawal symptoms in subjects that were not heavy tobacco users, but a side effect of nausea was also observed. Importantly, in consideration of the co-use condition, adult tobacco smokers who also smoke cannabis are twice as likely as non-cannabis users to continue smoking tobacco even years later. This could be due to the cannabinoids enhancing the effects of nicotine-associated cues in reinstating the drug-seeking behavior after a quit attempt. However, one study found that people attempting to quit or reduce cannabis intake also report using less tobacco on abstinent days. Thus, research on effective cessation methods for co-users is heavily understudied and needs to be conducted to aid in the smoking cessation of people suffering from co-occurring cannabis use disorder and nicotine use disorder. People battling with nicotine, cannabis, or co-occurring substance use disorders may try to quit taking the drugs, but the risk of relapse is quite high as most people begin smoking again within the first week [90]. Relapse can occur due to trying to alleviate the negative withdrawal symptoms or it can be triggered by things like stress, acute exposure to the drug, or certain cues that were previously associated with drug-taking. Cues can include the physical environment, people with whom the drug taking typically occurs, as well as any associated auditory, visual, olfactory, or tactile signals. In animal models, this phenomenon is known as incubation of drug craving in which cue-induced drug-seeking behavior increases over time during abstinence after drug self-administration. In other words,pruning cannabis a rodent is allowed to intravenously self-administer a drug of abuse for a while, such as cocaine or nicotine, then the drug is taken away. During this abstinence period, when the rodent is put back in the same environment with the same sensory cues as when receiving the drug, they will actively seek it more.

This active drug seeking is usually measured in lever pressing or nosepokes . The cue-induced portion of this paradigm is highly pertinent as it is the visual, auditory, and olfactory cues that trigger this drug-seeking behavior. This phenomenon was first seen in humans experiencing progressively higher rates of cue-induced cocaine craving and cigarette craving during the first few weeks of abstinence. The incubation of drug craving effect has now been replicated in rodent models using a wide variety of drugs of abuse, including heroin, alcohol, and nicotine. Understanding how prior drug history might impact this cue-induced drug-seeking behavior can help create more effective relapse interventions for those in the early stages of abstinence.Beyond the research itself, it is important to have insight into the scientists conducting the research, the populations being studied, the dissemination of this new scientific knowledge, as well as the people being impacted by the findings. The final chapter of this dissertation explores a broader perspective of these crucial issues and the necessity of more support for people from historically marginalized backgrounds in the field of neuroscience at every level. Publications within this chapter include discussions on Black, Indigenous, and Hispanic early career scientists being cited less often, receiving less grants, having fewer authorships, and receiving lower salaries while still doing the majority of diversity, equity, and inclusion work to make academia more accessible for subsequent generations. This section also discusses the high attrition of trainees from disadvantaged backgrounds as well as the need for stronger community, professional resources, and culturally competent mentors to advocate on their behalf. Finally, it delves into the necessity of representation and accountability in the scientific community as well as the systemic issues that inhibit this progress. Valuing diversity, equity, and inclusion principles, not only makes academia more welcoming while bringing in a wealth of knowledge and unique perspectives, but it also strengthens the research being done. In fact, studies have shown how productivity, innovation and the success of research is enhanced when these ideals are embraced. Furthermore, it allows those researchers to then disseminate information effectively about critical research progresses to their own communities while conducting meaningful outreach and mentoring the next generation of researchers.Nicotine, the main psychoactive component in tobacco, is considered to be responsible for the development and maintenance of dependence in humans. Nicotine’s effects on adolescent development have become of increasing concern given the emergence of ecigarettes, which deliver vaporized nicotine. According to a nationwide CDC survey, ~30– 45% of high school students self-reported prior use of cigarettes, vaporized nicotine products, and/or cannabis. Given that legalization of recreational cannabis across states since the time of this survey, the number of adolescents exposed to this drug will likely continue to increase through both primary and second-hand exposure. Importantly, studies in humans examining co-use of these drugs have found that individuals who reported smoking both cannabis and tobacco cigarettes consumed more cigarettes than those using tobacco alone. Furthermore, the practice of mulling has been reported as frequently occurring in adolescent users, with high incidence among daily cigarette smokers in some populations. Interestingly, chronic male cannabis users show decreased activation of the caudate nucleus in relation to reward anticipation as compared to nicotine users and non-smokers [6], suggesting altered function of reward-related circuitries dependent on prior drug exposure. Chronic use of cannabis during adolescence has also been linked to an elevated risk of psychosis, anxiety disorders, and depression. For instance, Crane and colleagues found that symptoms of depression were positively correlated with both cannabis use and tobacco smoking frequency in male, but not female, subjects. In contrast, Wright and colleagues report that cannabis use predicted increased depressive symptoms in both males and females, but increased anxiety symptoms and behavioral disinhibition were only found in females.