Given the rise in teenage use of electronic nicotine delivery systems (“vaping”) in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine’s gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern. Adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances, which is known as the gateway hypothesis. Adolescence is a developmentally sensitive time period when risk-taking behaviors, such as sensation seeking and drug experimentation, often begin. These hallmark behaviors of adolescence are largely due to maturational changes in the brain. The developing brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products, which activate nicotinic acetylcholine receptors (nAChRs). Disruption of nAChR development with early nicotine use may influence the function and pharmacology of the receptor subunits and alter the release of reward-related neurotransmitters, including acetylcholine, dopamine, GABA, serotonin, and glutamate. In this review, we emphasize that the effects of nicotine are highly dependent on timing of exposure, with a dynamic interaction of nAChRs with dopaminergic, endocannabinoid, and opioidergic systems to enhance general drug reward and reinforcement. We analyzed available literature regarding adolescent substance use and nicotine’s impact on the developing brain and behavior using the electronic databases of PubMed and Google Scholar for articles published in English between January 1968 and November 2018. We present a large collection of clinical and preclinical evidence that adolescent nicotine exposure influences long-term molecular, biochemical, and functional changes in the brain that encourage subsequent drug abuse.

Previously, we reported that oxycodone is a putative kappa-opioid agonist based on studies where intracerebroventricular (i.c.v.) pre-treatment of rats with the kappa-selective opioid antagonist, nor-binaltorphimine (nor-BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (mu-selective antagonist) produced the opposite effects. In the present study, we used behavioural experiments in rat models of mechanical and biochemical nerve injury together with radioligand binding to further examine the pharmacology of oxycodone. Following chronic constriction injury (CCI) of the sciatic nerve in rats, the antinociceptive effects of intrathecal (i.t.) oxycodone, but not i.t. morphine, were abolished by nor-BNI. Marked differences were found in the antinociceptive properties of oxycodone and morphine in streptozotocin (STZ)-diabetic rats. While the antinociceptive efficacy of morphine was abolished at 12 and 24 weeks post-STZ administration, the antinociceptive efficacy of s.c. oxycodone was maintained over 24 weeks, albeit with an approximately 3- to 4-fold decrease in potency. In rat brain membranes irreversibly depleted of mu- and delta-opioid binding sites, oxycodone displaced [(3)H]bremazocine (kappa(2)-selective in depleted membranes) binding with relatively high affinity whereas the selective mu- and delta-opioid ligands, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) and DPDPE ([D-Pen(2,5)]-enkephalin), respectively, did not. In depleted brain membranes, the kappa(2b)-ligand, leu-enkephalin, prevented oxycodone's displacement of high-affinity [(3)H]bremazocine binding, suggesting the notion that oxycodone is a kappa(2b)-opioid ligand. Collectively, the present findings provide further support for the notion that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations. Oxycodone appears to act as a kappa(2b)-opioid agonist with a relatively low affinity for mu-opioid receptors.

We assess the diagnostic accuracy of emergency physician-performed bedside ultrasonography and radiology ultrasonography for the detection of cholecystitis, as determined by surgical pathology. We conducted a prospective, observational study on a convenience sample of emergency department (ED) patients presenting with suspected cholecystitis from May 2006 to February 2008. Bedside gallbladder ultrasonography was performed by emergency medicine residents and attending physicians at an academic institution. Emergency physicians assessed for gallstones, a sonographic Murphy's sign, gallbladder wall thickness, and pericholecystic fluid, and the findings were recorded before formal imaging. The test characteristics of bedside and radiology ultrasonography were determined by comparing their respective results to pathology reports and clinical follow-up at 2 weeks. Of the 193 patients enrolled, 189 were evaluated by bedside ultrasonography. Forty-three emergency physicians conducted the ultrasonography, and each physician performed a median of 2 tests. After the bedside ultrasonography, 125 patients received additional radiology ultrasonography. Twenty-six patients underwent cholecystectomy, 23 had pathology-confirmed cholecystitis, and 163 were discharged home to follow-up. Twenty-five were excluded (23 lost to follow-up and 2 unavailable pathology). The test characteristics of bedside ultrasonography were sensitivity 87% (95% confidence interval [CI] 66% to 97%), specificity 82% (95% CI 74% to 88%), positive likelihood ratio 4.7 (95% CI 3.2 to 6.9), negative likelihood ratio 0.16 (95% CI 0.06 to 0.46), positive predictive value 44% (95% CI 29% to 59%), and negative predictive value 97% (95% CI 93% to 99%). The test characteristics of radiology ultrasonography were sensitivity 83% (95% CI 61% to 95%), specificity 86% (95% CI 77% to 92%), positive likelihood ratio 5.7 (95% CI 3.3 to 9.8), negative likelihood ratio 0.20 (95% CI 0.08 to 0.50), positive predictive value 59% (95% CI 41% to 76%), and negative predictive value 95% (95% CI 88% to 99%). The test characteristics of emergency physician-performed bedside ultrasonography for the detection of acute cholecystitis are similar to the test characteristics of radiology ultrasonography. Patients with a negative ED bedside ultrasonography result are unlikely to require cholecystectomy or admission for cholecystitis within 2 weeks of their initial presentation.

Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.

Cigarette smoking during pregnancy is not uncommon; 16% to 60% of pregnant women smoke, with the prevalence varying across countries and socioeconomic groups. Smoking during pregnancy is associated with several adverse outcomes among offspring. The most severe appear during early development and at birth, including spontaneous abortion, smaller birth weight, and sudden infant death syndrome.¹ Growing evidence also indicates increased rates of behavioral problems among offspring exposed in utero to maternal cigarette smoking.^2,3