Michelle Ren, MS; Shahrdad Lotfipour, PhD

Disclosures

Western J Emerg Med. 2019;20(5):696-709. 

In This Article

Results

All Drugs of Abuse Share a Final Common Brain Pathway

Drugs of abuse provide rewarding, pleasurable feelings that contribute to its reinforcement (i.e. repeated use). Reward and reinforcing efficacy are measured in animals with drug self-administration on fixed and progressive ratio schedules of reinforcement, intracranial self-stimulation, oral intake, inhalation, and/or conditioned place preference. Although common drugs of abuse, like marijuana, cocaine, alcohol, and opioids, act on different neurotransmitter systems, they all exert their reinforcing effects via the mesolimbic pathway, a dopaminergic pathway that connects the ventral tegmental area to the nucleus accumbens.[60–66] The development, projections, and functions of this pathway are strongly influenced by acetylcholine, glutamate, serotonin, and GABA.[67–71] Dopamine release into the nucleus accumbens regulates motivation and desire for rewarding stimuli and facilitates reward prediction.[72,73] As nAChRs modulate dopamine release, the gateway hypothesis posits that adolescent nicotine exposure primes the brain's reward system to enhance the reinforcing efficacy of drugs of abuse.[74–77]

Nicotine Uniquely Activates the Adolescent Brain Reward System

Substantial epidemiological data suggest that teenagers are more vulnerable than adults to nicotine dependence following minimal tobacco exposure (fewer than seven cigarettes in one month), and individuals who begin smoking during adolescence are more likely to experience difficulty quitting than those who start as adults.[78–84] Indeed, 90 percent of adult smokers started before age 18.[34,59] Event-related functional neuroimaging studies in children, adolescents, and adults suggest that children and adolescents have over-reactive reward responses and improved task performance when earning rewards, suggesting enhanced engagement in behaviors that result in immediate gratification.[85] Such factors make adolescents more vulnerable to drug use and abuse.

Animal models allow for experimenter-controlled administration of nicotine and investigation of its direct consequences on the brain and behavior through neuroimaging, biochemical assays, and behavioral tests. Early adolescent rats exposed to intravenous nicotine levels equivalent to one to two cigarettes per day for four days (Figure 1) self-administer a greater amount of cocaine, methamphetamine, and alcohol compared to adolescent rats not exposed to nicotine, as well as compared to exposed and unexposed adults.[86,87] These data strongly suggest that adolescent nicotine use increases the reinforcing effects of other drugs. In addition, adolescent, but not adult, rodents exposed to nicotine display disruptions in hippocampal learning, long-lasting depressive phenotypes, changes in cocaine sensitivity and reward, enhanced drug-related learning, and deficits in impulse control, executive function, and cognition.[86,88–94] Improved drug-related learning following brief nicotine exposure during early adolescence is characterized by rapid initiation and cue association of cocaine and amphetamine self-administration, which is indicative of an addictive-like phenotype and is not observed in adolescent and adult controls or adults also pretreated with nicotine.[92,94] Furthermore, heightened depressive- and anxiety-like behaviors after 30 days of nicotine abstinence in mice exposed as adolescents, but not adults, indicate that nicotine exposure and withdrawal can have long-term effects on emotional and cognitive functioning, particularly when nicotine exposure occurs during adolescence.[89] The exact timing of exposure during adolescence is also significant, as nicotine's effects are far greater during early adolescence (PND 28–31 or 12–15 years) versus late adolescence (PND 38–41 or 16-18 years) or adulthood (PND 86–89).[86,95] Behavioral alterations brought on by developmental nicotine exposure are driven by molecular mechanisms, including epigenetic influences, synaptic activity, and receptor signaling and regulation.[8,96,97] Adolescent, but not adult, nicotine exposure in rodents results in the expression of distinct subunits of nAChRs (α5, α6, and β2) and persistent nAChR upregulation in the midbrain, cerebral cortex, and hippocampus.[98,99] Due to the role of nAChRs in neurotransmitter release and reward processing, alterations in their quantity and function influence reward behavior. In addition, brief nicotine exposure in early adolescent rats enhances cellular activity, dopamine D2 receptor signaling, and serotonin 5-HT receptor function in brain reward areas compared to adult rats also exposed to nicotine.[86,90,100] Moreover, chronic nicotine exposure during, but not after, adolescence alters gene expression in the ventral tegmental area and stimulates hyperresponsiveness of dopaminergic nerve terminals in the medial prefrontal cortex.[93,101,102] These nicotine-induced changes in reward-related neurotransmitters and brain regions during adolescence may contribute to alterations in reward regulation and behavior.

Figure 1.

4-day nicotine pretreatment paradigm in testing the nicotine gateway hypothesis in rats. Two intravenous nicotine (0.03 mg/kg/0.1 ml, equivalent to 1–2 cigarettes) or saline injections, spaced one minute apart, are administered daily for 4 consecutive days during early adolescence (PND 28–31) or adulthood (PND 86–89). Experimentation following nicotine pretreatment (dashed lines) varies upon the drug administered, duration of drug administration, and contingent or non-contingent injections. The daily nicotine dose yields peak serum levels of approximately 30 ng/ml in both adolescents in adults, which is well within the range of the average smoker.
PND, postnatal day; IV, intravenous; mg, milligram; kg, kilogram; ng, nanogram; ml, milliliter.

The changes in brain function and behavior from developmental nicotine exposure are long lasting and a consequence of manipulation of the brain's reward network, including the prefrontal cortex, nucleus accumbens, ventral tegmental area, hippocampus, and basolateral amygdala.[20] Specifically, adult rodents exposed to nicotine as adolescents show a persistent increase in deltaFosB in the nucleus accumbens, impaired GABA signaling in the ventral tegmental area, and changes in brain morphology and gene expression in reward regions.[93,101,103–105] Furthermore, adult rodents exposed to nicotine as adolescents have an increased preference for cocaine, amphetamine, opioids, and higher doses of nicotine.[103] The following section reviews in greater detail the impacts of adolescent versus adult nicotine exposure on subsequent drug use in animal models. Other drug-associated behaviors are beyond the scope of this review and will not be discussed.

Adolescent Nicotine Exposure Increases Alcohol Consumption

The developments of alcohol and tobacco use patterns are closely related among teenagers, but the order of progression is not universal among cultural and ethnic demographics.[106] Alcohol and nicotine products are more frequently co-abused than consumed separately, as a survey of high school seniors revealed that 88 percent of smokers were drinkers, while 55 percent of nonsmokers were drinkers.[107,108] However, tobacco use predicts subsequent alcohol use better than the reverse.[106] Individuals who initiate smoking before age 17 are at a higher risk of alcohol abuse and dependence than those who begin after 17.[109–111] These studies lead to the hypothesis that adolescent exposure to nicotine may lead to enhanced alcohol intake later in life.

Adolescent susceptibility to co-use of nicotine and alcohol is also observed in rodents, as concurrent self-administration of both drugs in adolescent, but not adult, rats is reinforcing and leads to an increase in subsequent oral alcohol intake.[112] Moreover, a different nicotine exposure paradigm promotes long-lasting increases in alcohol self-administration exclusively in nicotine-treated adolescents.[104] Nicotine exposure during adulthood can also change subsequent alcohol consumption, which indicates the influence of nicotine on alcohol reward and reinforcement; however, enhanced alcohol intake is more likely to occur if nicotine is administered prior to alcohol access.[113] These findings collectively indicate that nicotine exposure during adolescence enhances alcohol consumption more than if the same exposure occurs later in life.

Adolescent Nicotine Exposure Increases Psychostimulant Reinforcement and Reward

In humans, adolescent exposure to nicotine influences the likelihood of other psychostimulant use, including cocaine and methamphetamine.[3,5,8] Data from a 1994 National Household Survey on Drug Abuse report that individuals who smoked cigarettes before age 15 were up to 80 times more likely to use illegal drugs than those who did not, with cocaine being the most likely drug to be used among young cigarette smokers.[5] A separate study of a cohort representative of the U.S population revealed that the rate of cocaine dependence was highest among cocaine users who initiated cocaine after having smoked cigarettes (20.2 percent), and the rate of dependence was much lower among those who initiated cocaine before smoking (6.3 percent).[8]

Preclinical studies also demonstrate associations between adolescent nicotine exposure and psychostimulant consumption. Chronic nicotine exposure differentially alters cocaine-induced locomotor activity and intravenous cocaine self-administration in adolescent versus adult rodents.[103,114–116] Adolescent rats exposed to nicotine become considerably more sensitized to the locomotor-activating effects of cocaine compared to non-exposed adolescents.[115] Nicotine exposure during adolescence, but not adulthood, also encourages increased self-administration of cocaine during adulthood, suggesting that nicotine use may carry a greater risk during adolescence than adulthood.[116] The effects of adolescent nicotine pretreatment on psychostimulant reinforcement and locomotor activity are mediated by nAChRs (α7 and α4β2) and serotonergic (5-HT1A) receptors.[86] In addition, chronic and sub-chronic nicotine-exposed adolescent rats experience greater preference for and self-administration of cocaine and methamphetamine versus saline-exposed rats.[86,87,117,118] Pre-adolescent nicotine exposure in rats also leads to increased cocaine-primed reinstatement, a model of relapse behavior.[119] In contrast, alcohol pre-exposure in rats does not influence subsequent cocaine self-administration or cocaine relapse behavior, highlighting the unique gateway effects of nicotine on psychostimulant use.[120]

Nicotine Interacts With the Endocannabinoid System

In addition to the enhanced use of alcohol and psychostimulants following early nicotine use, cigarette smoking in adolescents and young adults is associated with earlier onset of cannabis use, more frequent cannabis use, and a larger number of cannabis use disorder symptoms compared to those who did not smoke cigarettes.[9,121,122] Likewise, teens who use e-cigarettes or hookah are more than three times more likely to use marijuana, and cannabis users report that nicotine enhances the pleasurable effects of tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana that exerts its effects via cannabinoid receptors.[19,123] The endocannabinoid system, which comprises cannabinoid receptors (CB1 and CB2) and endogenous ligands (anandamide and 2-Arachidonoylglycerol) throughout the central and peripheral nervous system, plays an important role in cognition, learning and memory, pain relief, emotion, stress, and reward processing.[124,125]

Although little research has been done on nAChRs interactions with THC specifically during adolescence, preclinical findings in adults suggest that cholinergic and endocannabinoid systems interact to modulate reward-related processes.[126–128] Selective antagonism of α7 nAChRs in rats blocks the discriminative effects of THC and reduces intravenous self-administration of a cannabinoid CB1 receptor agonist (WIN55,212–2).[129] This association appears to be bidirectional, as blockade of CB1 receptors reduces nicotine self-administration in rats.[130,131]

THC impacts adolescents and adults distinctively, where adolescent rats experience less of THC's anxiogenic, aversive, and locomotor-reducing effects than adult rats.[132] Nicotine also facilitates THC's hypothermic, antinociceptive, and hypolocomotive effects in mice.[126] Sub-chronic nicotine exposure in adolescent rats induces long-lasting effects in cannabinoid CB1 receptors, including increases in the hippocampus and decreases in the striatum.[133] The association between nicotine and cannabis use and the role of reward processing in both the cholinergic and endocannabinoid systems encourages the hypothesis that nicotine may encourage and perpetuate cannabis use.

Nicotine Interacts With the Opioidergic System

The endogenous opioid system is primarily involved in pain relief, reward processing, emotion, stress, and autonomic control, and consists of 3 families of receptors: mu, delta, and kappa.[134] Opioid receptors located in the brain and periphery are activated endogenously by enkephalins, dynorphins, endorphins, and endomorphins, as well as exogenously by opioids (e.g., heroin, morphine, oxycodone, fentanyl). Enkephalins, endorphins, endomorphins, and opioids act primarily through mu opioid receptors (MORs) to reduce pain perception, while dynorphins preferentially act at kappa opioid receptors (KORs) to regulate appetite, stress, and emotion. Mu and delta opioid receptors play a critical role in drug reward, whereas the KORs participate in drug aversion.[135–137]

Although opioid use has not been extensively evaluated during adolescence, an abundance of clinical and preclinical evidence suggests an important bidirectional relationship between nicotine use and opioid reward.[136] There is a significant overlap in the distribution of neuronal nAChRs and opioid receptors. Activation of nAChRs can influence excitability of opioid-containing neurons, and nicotine-induced dopamine release in the nucleus accumbens is dependent on activation of MORs in the ventral tegmental area.[138–140] Furthermore, nicotine induces a release of endogenous opioids in the brain, and repeated exposure to nicotine can alter expression and/or functioning of opioid receptors.[141–144]

Perhaps unsurprisingly, given the significant overlap of cholinergic and opioidergic systems, clinical data show that treatment with naloxone and naltrexone, both opioid receptor antagonists, reduces tobacco smoking and craving for tobacco smoke.[145,146] In addition, opioid-dependent smokers present with more severe nicotine dependence, respond poorly to smoking cessation medications, and may have a higher risk of relapse compared to non-opioid dependent smokers.[147–150]

The relationship between nicotine and the opioidergic system is similarly substantial in preclinical studies, which is important given the roles of both systems in reward processing. Early adolescent nicotine exposure in mice enhances subsequent morphine reward.[151] In addition, blocking nicotinic receptors reduces rewarding effects of morphine, and activation of MORs decreases nicotine withdrawal symptoms.[152–155] MOR antagonists increase somatic withdrawal symptoms and aversion in nicotine-dependent mice and rats, and decrease nicotine self-administration, nicotine preference, and cue-induced reinstatement of nicotine seeking.[154,156–160] However, a small number of conflicting studies report no significant differences in nicotine reward, self-administration, or withdrawal following administration of a MOR antagonist, possibly as a result of differences in route of administration, dose, duration, or pharmacodynamics of the antagonist used.[160–162] Moreover, morphine exhibits significant functional interactions with nAChRs.[163] Chronic nicotine treatment in mice enhances the effect of morphine on striatal dopaminergic pathways, thereby influencing locomotor activity and reinforcement.[164]

Although there are minimal data on nicotine and opioid interactions during adolescence, increasing evidence supports a role of the KOR system in modulating nicotine-associated behaviors. Rodent studies suggest that teen susceptibility to nicotine use is likely due to adolescents finding nicotine more rewarding and less aversive than adults.[52,165–171] These differences in sensitivity to nicotine reward and aversion may be due, in part, to the KOR system, as activation of KORs increases aversive effects and withdrawal signs of nicotine in adult rodents, but not adolescents.[172–174] Furthermore, KOR antagonists increase concurrent nicotine and alcohol self-administration in adult, but not adolescent, male rats.[112] Given the interactions between the cholinergic and opioidergic systems in reward regulation and the alarming increases in opioid-related deaths, it is important to recognize and understand risk factors of opioid addiction, including adolescent nicotine exposure.

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