Tobacco\u27s Minor Alkaloids: Effects on Place Conditioning and Nucleus Accumbens Dopamine Release in Adult and Adolescent Rats

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8 mg/kg), cotinine (0.5-5.0 mg/kg), anatabine (0.5-5.0 mg/kg), and myosmine (5.0-20.0 mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated

A Gear Cutting Predictive Model Using the Finite Element Method

AbstractCurrent processes for producing transmission gears involve hobbing, milling or shaping of a forged stock to obtain the gear shape. Gears are typically formed by hobbing tools made from solid tooling material, such as tungsten carbide, and have dozens of teeth. The gear hobbing process entails several teeth in cut simultaneously. Generation of in-volute tooth profiles results in varying chip loads from pass to pass. In this paper, details are provided for a finite element-based model of gear hobbing and milling processes. The model explicitly meshes gear cutter geometries with dozens of teeth. These cutters are used to simulate the complicated kinematic motion between tool and workpiece. Thermo-mechanical coupled calculations within an explicit dynamic formulation are per-formed on the tool and workpiece during chip removal. The complex geometry of involute tooth profiles results in complicated contact scenarios on the evolving workpiece geometry during tooth profile generation. Tooth-workpiece-chip contact is enforced rigorously and is particularly complicated with the confined space of gear hobbing. Advanced adaptive meshing strategies are developed and employed to maintain the resolution of the tool-workpiece interaction while multiple teeth are in contact. Cutting forces, temperatures and stresses in the tool and workpiece are predicted for steel workpiece materials. Models are validated through a set of initially simplified experiments where incremental complexity is added, allowing for direct comparison between predicted and measured forces and chip shapes

Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats

•Female rats are more sensitive to the discriminative stimulus effects of Δ9- tetrahydrocannabinol (THC).•Synthetic cannabinoids (SCBs) produce THC-like effects in rats of both sexes.•Sex differences in rate suppressing effects do not occur for all SCBs.•Disparity across assays precludes pharmacokinetic explanation of results.Women report greater sensitivity to the subjective effects of Δ9-tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats.A cumulative dosing THC discrimination procedure was utilized to evaluate sex differences in the discriminative stimulus effects of THC and three synthetic cannabinoids: CP47,497, WIN55,212-2, and JWH-018. Sex differences in the effects of these four compounds and a degradant of A-834735 on response rates also were assessed in a food-reinforced discrete dosing procedure.Females required a lower training dose than males for acquisition of the discrimination. Further, THC was more potent at producing rimonabant-reversible discriminative stimulus and response rate effects in females. While synthetic cannabinoids were more potent in producing THC-like effects than was THC in female rats, greater discrepancies were observed in male rats. Similar sensitivity to the response rate-decreasing effects induced by most, but not all (A-834735 degradant), synthetic cannabinoids was seen in both sexes.This study represents one of the first direct comparisons of sex differences in THC discrimination. Females were more sensitive to THC’s effects, which may be related, in part, to sex differences in THC metabolism. Synthetic cannabinoids were more potent than THC in both sexes, but were considerably more so in male than in female rats. Future research should emphasize further characterization of sex differences in cannabinoid pharmacology

The impact of gonadal hormones on cannabinoid dependence

Cannabis is the most widely used illicit substance in the United States. Women report greater positive subjective effects of cannabis, and greater cannabis withdrawal compared to men. Female rodents are more sensitive than males to some acute effects of Δ⁹-tetrahydrocannabinol (THC), and females also develop greater tolerance to THC in some assays. The purpose of this study was to determine whether gonadal hormones modulate THC dependence in rats. Adult rats were gonadectomized (GDX) or sham-GDX, and hormone was replaced in half of the GDX rats of each sex (testosterone in males; estradiol and/or progesterone in females). THC (30 mg/kg) or vehicle was administered twice daily for 6.5 days, followed on the seventh day by vehicle or rimonabant challenge and assessment for withdrawal-related behaviors. Sham-GDX females developed greater tolerance than males to THC-induced hypothermia, and GDX females given progesterone showed greater tolerance to THC-induced locomotor suppression. Rimonabant precipitated withdrawal, as evidenced by increased somatic signs (forepaw tremors, licking) and increased startle amplitude. Testosterone in GDX males decreased withdrawal-induced licking. Estradiol and progesterone in GDX females increased withdrawal-induced chewing, and progesterone increased withdrawal-induced sniffing. These results suggest that estradiol and progesterone may promote the development of dependence, whereas testosterone may protect against dependence. While the present study indicates that testosterone and estradiol produce opposite effects on THC-induced behavior, estradiol appears to play a broader role than testosterone in modulating THC's behavioral effects

The impact of gonadal hormones on cannabinoid dependence.

Cannabis is the most widely used illicit substance in the U.S. Women report greater positive subjective effects of cannabis, and greater cannabis withdrawal compared to men. Female rodents are more sensitive than males to some acute effects of Δ(9)-tetrahydrocannabinol (THC), and females also develop greater tolerance to THC in some assays. The purpose of this study was to determine whether gonadal hormones modulate THC dependence in rats. Adult rats were gonadectomized (GDX) or sham-GDX, and hormone was replaced in half of the GDX rats of each sex (testosterone in males; estradiol and/or progesterone in females). THC (30 mg/kg) or vehicle was administered twice daily for 6.5 days, followed on the seventh day by vehicle or rimonabant challenge and assessment for withdrawal-related behaviors. Sham-GDX females developed greater tolerance than males to THC-induced hypothermia, and GDX females given progesterone showed greater tolerance to THC-induced locomotor suppression. Rimonabant precipitated withdrawal, as evidenced by increased somatic signs (forepaw tremors, licking), and increased startle amplitude. Testosterone in GDX males decreased withdrawal-induced licking. Estradiol and progesterone in GDX females increased withdrawal-induced chewing, and progesterone increased withdrawal-induced sniffing. These results suggest that estradiol and progesterone may promote the development of dependence, whereas testosterone may protect against dependence. While the present study indicates that testosterone and estradiol produce opposite effects on THC-induced behavior, estradiol appears to play a broader role than testosterone in modulating THC’s behavioral effects