Allelic variation in CHRNA3, the gene encoding the a3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for a3-containing (a3p) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. a3p nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3 tm1.1Hwrt hypomorphic mice, which express constitutively low levels of a3p nAChRs, self-administer greater quantities of nicotine (0.4 mg kg 21 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg 21 per infusion). Using whole-cell recordings, we found that the a3b4p nAChR-selective antagonist a-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the a3b2p nAChR-selective antagonist a-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of a-conotoxin AuIB (10 lM) but not a-conotoxin MII (10 lM) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that a3b4p nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.

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Are current diversity, equity, and inclusion initiatives addressing systemic issues? This article highlights the progress thus far and emphasizes the systemic and cultural shifts needed to support and retain historically excluded scientists.

Introduction During adolescence, exposure to nicotine or cannabis independently induces effects on neuromaturation and later cognitive function. However, the potential effect of both drugs under co-use conditions has become of increasing concern given the prevalence of e-cigarettes, legalization of cannabis, and availability of synthetic “spice” cannabinoid agonists. Aims and Methods The current studies investigated the effects of exposure to a cannabinoid receptor agonist (WIN55,212-2) and/or nicotine over a discrete time period in mid-adolescence on later intravenous nicotine self-administration in adult male and female mice. We further examined whether cannabinoid agonist administration in adulthood would alter nicotine reinforcement, with either acute or chronic pairing across 7 days. Results We found that adult males exhibited increased nicotine self-administration at a lower, rewarding nicotine dose following adolescent cannabinoid exposure, either alone or with nicotine coadministration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine coexposure resulted in decreased nicotine intake compared with the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pretreatment with a low dose of the cannabinoid agonist decreased nicotine intake in both male and female control mice, and this lowering effect was evidenced after both acute and chronic treatment. However, the cannabinoid agonist was ineffective in altering nicotine intake in mice previously exposed to nicotine, cannabinoid agonist, or both during adolescence. Conclusions These data provide evidence that adolescent drug exposure can alter later nicotine reinforcement in a sex-specific manner and can further modulate the effectiveness of interventions in reducing nicotine intake during adulthood. Implications These studies demonstrate a significant impact of nicotine, cannabinoids, or coexposure on developmental processes during adolescence. Differential effects were observed within each sex, with opposing results found for cannabinoid exposure on nicotine intake in males and females. Intriguingly, we also evidenced resistance to the lowering effects of a cannabinoid agonist on nicotine intake in adulthood based on adolescent drug exposure. Thus, these findings have important implications for our understanding of the impact of nicotine and cannabinoids (eg, Δ9-tetrahydrocannabinol (THC) and synthetic “spice” cannabinoids) during development, with further implications for the effectiveness of therapeutic interventions based on prior drug exposure in youth.

It has been postulated that glucagon, the hyperglycemic factor of the pancreatic a-cells, plays an important role in the pathogenesis of diabetes mellitus in man. 1 ' 2 This hypothesis suggests that an excessive secretion of glucagon in relation to insulin results in the diabetic state and is based on the finding of an increased a/P-cell ratio in the pancreatic islets of diabetic patients. One reason that the concept remains controversial is that efforts to induce permanent diabetes in the rat and the rabbit with glucagon have been unsuccessful. 3 ' 7 However, these experiments may be considered inconclusive for the following reasons: The rat and the rabbit are relatively insensitive to the hyperglycemic action of glucagon; 8 they also respond poorly to some diabetogenic agents; 9 and the experimental conditions used were perhaps not ideal. 610 The purpose of this study was to determine the effects of prolonged glucagon administration by various routes (including the portal vein) in the two species (cat and dog) most sensitive to glucagon 8 and to certain known diabetogenic agents. 9 METHODS Experiments were carried out in six cats and seven dogs, all adult animals. Five different glucagon preparations were used: ( i ) No. 225-20-255* (20 per cent puret); (2) No. 208-108B-234* (20 per cent pure);(3) No. 208-158B-197* (50 per cent pure); (4) crystalline glucagont (100 per cent pure); and (5) crystalline Zn-glucagon § (100 per cent pure). Only animals From the Radioisotope Service of the Veterans Administra-