Operant Acquisition of Marihuana by Women1

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Behavioral Evaluation of Modafinil and The Abuse-related Effects of Cocaine in Rhesus Monkeys

This article may not exactly replicate the final version published in the APA journal. It is not the copy of record.Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist-based medication to treat stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. Three studies were conducted to examine the behavioral effects of modafinil. In the first study, the discriminative stimulus effects of modafinil were evaluated in monkeys trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6/7 monkeys. In the second study, the effects of chronically administered modafinil (32-56 mg/kg/day, IV) on food- and cocaine-maintained operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate (0.003 mg/kg/inj) and peak (0.01 mg/kg/inj) reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic treatment with modafinil. In a third study, after extinction of cocaine self-administration, modafinil (32 and 56 mg/kg/day, IV) significantly increased saline self-administration on the first day of treatment. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. These data are generally consistent with clinical findings and provide new evidence that these preclinical models may be useful for predicting the effectiveness of novel medications for drug abuse treatment

The genomic basis of parasitism in the Strongyloides clade of nematodes.

Soil-transmitted nematodes, including the Strongyloides genus, cause one of the most prevalent neglected tropical diseases. Here we compare the genomes of four Strongyloides species, including the human pathogen Strongyloides stercoralis, and their close relatives that are facultatively parasitic (Parastrongyloides trichosuri) and free-living (Rhabditophanes sp. KR3021). A significant paralogous expansion of key gene families--families encoding astacin-like and SCP/TAPS proteins--is associated with the evolution of parasitism in this clade. Exploiting the unique Strongyloides life cycle, we compare the transcriptomes of the parasitic and free-living stages and find that these same gene families are upregulated in the parasitic stages, underscoring their role in nematode parasitism

Studies of Alcohol: Past, Present and Future

Copy of the article Mendelson, J. H., & Mello, N. K. (1989). Studies of Alcohol: Past, Present and Future. Journal of Studies on Alcohol, 50(4), 293–196. Written for the fiftieth anniversary of the journal

Studies of alcohol: past, present and future.

Copy of the article Mendelson, J. H., & Mello, N. K. (1989). Studies of Alcohol: Past, Present and Future. Journal of Studies on Alcohol, 50(4), 293–196. Written for the fiftieth anniversary of the journal

Effects of Dopamine D 1-like and D 2-like Agonists in Rats that Self-Administer Cocaine 1 Materials and Methods Animals

ABSTRACT The reinforcing effects of D 1-like and D 2-like agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D 1-like agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D 2-like agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped doseeffect functions. Pretreatment with the D 1-like agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the doseeffect function for cocaine self-administration downward, whereas pretreatment with the D 2-like agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D 1-like and D 2-like agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D 1-like agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D 2-like agonists increased the intervals between self-administered cocaine injections. The results suggest that D 2-like agonists, but not D 1-like agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D 2 receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine. Drug self-administration procedures have been useful for investigating the neurobiological and pharmacological mechanisms underlying the reinforcing effects of cocaine, and such information may lead to the development of new and effective medications for cocaine abuse and dependence Studies with direct dopamine receptor agonists offer another pharmacological method for elucidating the neurobiological mechanisms underlying the abuse-related effects of cocaine. In contrast to cocaine or other dopamine reuptake inhibitors, which increase the activation of dopamine receptors nonselectively, direct dopamine agonists can be used to receptors which, in turn, have different anatomical and functional characteristics. For example, D 1-like agonists modulate the expression of dynorphin and Substance P within striatonigral neurons, whereas D 2-like agonists regulate enkephalin expression within striatopallidal neurons ABBREVIATIONS: 7-OH-DPAT, 7-hydroxy-dipropylaminotetralin; FR, fixed ratio; A 50 , dose calculated to produce 50% of the measured effect; TO, timeout. JPET 291:353-360, 1999 353 D 1-ike and D 2-like agonists may provide one way to clarify the roles of distinct neural pathways and molecular mechanisms involved in cocaine addiction. Although it is generally believed that both D 1-like and D 2-like receptor mechanisms may be involved in the reinforcing and other behavioral effects of cocaine, recent studies suggest that D 1-like and D 2-like agonists have differing profiles of cocaine-related actions. On the one hand, both D 1-like and D 2-like agonists have been reported to maintain i.v. self-administration in animals previously trained to self-administer cocaine The present study was designed to further evaluate differing roles of D 1-like and D 2-like receptors in mediating the abuse-related effects of cocaine by systematically comparing the effects of D 1-like and D 2-like agonists in rats trained to self-administer cocaine. First, D 1-like or D 2-like agonists were substituted for cocaine in rats with extensive cocaine selfadministration experience to rigorously evaluate and compare the reinforcing effects of these agents. Second, modification of the reinforcing effects of cocaine by D 1-like and D 2-like agonists was studied by assessing the effects of pretreatments on full dose-effect functions for cocaine self-administration. In general, the results of this study suggest that D 2-like agonists, but not D 1-like agonists, maintain selfadministration and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration training. These results are consistent with those from parallel studies in which the cocaine-discriminative stimulus generalized to D 2-like agonists, but not D 1-like agonists, in rats with extensive cocaine discrimination training (Caine et al., unpublished observations). Materials and Methods Animals Cocaine self-administration studies were conducted in 32 male Wistar rats (Charles River, Wilmington, MA). The rats weighed approximately 350 g at the start of the study and were maintained in the range of 400 to 600 g with once-daily feedings of standard rat chow (Rat Diet 5012; PMI Feeds, Inc., St. Louis, MO). Bacon-flavored biscuits (Bio-Serve, Frenchtown, NJ) were also provided once or twice weekly, primarily for enrichment. Each rat was housed individually with free access to water in a temperature-and humiditycontrolled facility that was maintained on a 12-h light/dark cycle (lights on from 7:00 AM to 7:00 PM). Behavioral testing generally began toward the end of the light cycle (4:00 PM to 6:00 PM). Animal maintenance and research were conducted in accordance with the guidelines provided by the National Institutes of Health Committee on Laboratory Animal Resources, and all protocols were approved by the Institutional Animal Care and Use Committee. The health of the rats was periodically monitored by consulting veterinarians. Apparatus Drug self-administration studies were conducted in experimental chambers (21 cm ϫ 29.5 cm ϫ 24.5 cm) placed within sound-attenuating cubicles equipped with a house light and an exhaust fan. Each chamber contained three response levers. On one wall of the chamber, two levers were located on either side of a pellet receptacle, 3 cm above the grid floor and 1.5 cm from the side walls. During preoperative training, responding on either of these two levers was maintained by 45-mg food pellets (A/I Rodent Pellets; P. J. Noyes Co., Lancaster, NH) that were delivered by a pellet dispenser to the food receptacle located between the two levers and 2 cm above the floor. A third lever, which was used for drug-maintained responding, was located on the center of the opposite wall, 3 cm above the floor. A single white stimulus light located above each lever was used to indicate that responding had scheduled consequences. A single-channel fluid swivel (Lomir Biomedical, Malone, NY) was mounted on a balance arm above the chamber and attached to a spring lead with an inner Tygon tubing. The other end of the swivel was connected to an infusion pump that permitted automated delivery of i.v. drug injections for specified durations (see below). The infusion pump (PHM-100; 3.3 rpm motor) and all other components of the operant chambers and associated hardware were supplied by MED Associates Inc. (Georgia, VT). Scheduling of experimental events and data collection were accomplished with a DOS-based microcomputer system that was equipped with programs written in MED Associates MedState Notation. Drug Self-Administration Procedures Summary of Groups and Procedures. All rats were first allowed to respond in 2-h drug self-administration sessions (5-6 days per week) with a single unit dose of cocaine (0.32 mg per injection; approximately 1.0 mg/kg/injection). After stable self-administration behavior was established (see below), the rats were divided into two groups of 16 rats each. One group of rats was trained further, with a multiple-component drug self-administration procedure. In this procedure, the unit dose of cocaine was varied during the test session to obtain cocaine self-administration dose-effect functions. After stable cocaine dose-effect functions were established (see below), D 1-like and D 2-like dopamine agonists were either substituted for cocaine or administered as pretreatments to cocaine self-administration, until at least eight rats had been tested with each of the following dopamine agonists: SKF 82958, SKF 77434, quinelorane, and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT). The benzazepine D 1-like agonist SKF 82958 was extensively studied, because this agent was previously shown to maintain responding, and additionally, to attenuate cocaine's reinstating effects after extinction of cocaine self-administration in both rats and monkey

THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Copyright Alcohol Effects on Luteinizing Hormone-Releasing Hormone Stimulated Luteinizing Hormone and Follicle-Stimulating Hormone in Ovariectomized Female Rhesus Monkeys'

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