Ronald W. Wood - US grants

psychopharmacology; solvents; anesthetics; inhalation drug abuse; inhalation drug administration; self medication; psychological reinforcement; acetone; irritation /irritant; dosage; pharmacokinetics; drug adverse effect; drug withdrawal; nitrous oxide; toluene; avoidance behavior;

The purpose of the research proposed in this request for an ADAMHA RSDA (Level II) is to advance the behavioral pharmacology and toxicology of inhalants. The scientific content of the proposal grows from a NIDA grant in progress for fourteen years that has just been moved to the NYU Medical Center. Except for the opportunities to gain new competencies and to profit from the unique research potential of my new environment, the specific aims of the research program remains the same: The development of models of inhalant abuse will provide techniques that: (1) permit assessment of the relative abuse potential of solvents and anesthetics; (2) permit specification of nontoxic levels of solvent exposure and the recommendation of industrial exposure limit values; (3) permit comparison of the strength of inhalant-maintained drug-seeking behavior with the strength of behavior maintained by other drugs of abuse. The proposed program will proceed in parallel phases: 1) Solvent self-administration by the monkey. Concentration- and duration-effect curves will be determined for inhalants such as alkyl benzenes (e.g. toluene), ketones, and aliphatic alcohols. Schedules of reinforcement will be examined to determine the effectiveness of these agents as reinforcers. Inhalant blood levels will be determined. 2) Aversive properties of inhaled substances. We will generate performances maintained by the termination of noxious inhalants. Initial aversiveness may play an important role in determining abuse potential. Techniques to make volatile materials aversive are of paramount importance, and could bear directly on product formulation. 3) Effects of organic solvents on performance. Inhaled materials induce behavioral toxicity that can be measured by using schedule-controlled behavior. Concentration- effect curves of several agents will be obtained to determine how concentrations that maintain self-administration are related to those that affect other performances. This helps characterize their pharmacologic profiles and, with both self-administration and pharmacokinetic data, helps us understand the determinants of inhalant abuse.

cocaine; psychopharmacology; aerosols; inhalation drug abuse; heart rate; drug addiction; chemical stimulation; pharmacology; inhalation drug administration; analytical chemistry; Macaca;

Smoking is one of the predominant routes of administration of abused drugs such as heroin, phencyclidine, marihuana, tobacco and cocaine base ("crack"). Uptake is more rapid by inhalation than by the intranasal route, and the abuse potential of crack is at least as great as intravenously administered cocaine hydrochloride, if not greater, judging from clinical experience and the limited human literature. Unfortunately, there is a very limited animal literature on self-administration of cocaine base by inhalation, on its pharmacokinetics, or on repetitive use. We have developed technologies for generating aerosol atmospheres of cocaine which are repeatable and are appropriate for quinea pig and monkey. The refinement and of use of this exposure technology with these species will enable the characterization of cocaine self-administration and the pharmacology and toxicity unique to this route of self-administration. These techniques should facilitate subsequent laboratory investigations of cocaine and other drugs subject to abuse by this route, e.g., metham- phetamine hydrochloride. The goals for the next four years of this project include: 1) completing experiments on the aerosol physics of smoked drugs; 2) describing the abuse potential of cocaine base in self-administration sessions of limited duration in laboratory primates, with special attention to tolerance phenomena, and to concentration- and particle-size dependence of the behavior; 3) characterizing the effects of acute inhalation on conditioned behavior and on physiologic indices including: minute ventilation, pulmonary conductance (bronchodilation/constriction), arterial, pulmonary, and pulmonary wedge pressures, and heart rate in laboratory primates; 4) the description of acute and chronic toxicity syndromes, especially those expressed in pulmonary function and respiratory system structure. This will be done by characterizing the effects of acute inhalation on the cardiopulmonary function of guinea pigs: minute ventilation, pulmonary compliance, arterial pressures, heart rate, carbon monoxide diffusing capacity, and enzyme assays on pulmonary lavage fluids that are indicative of lung injury; 5) describing the pharmacokinetics of the agent following acute administration and brief (within--day) regimes of repeated administration. Arterial/venous differences will be described, as will the concentration-dependency of achieved levels by the inhalation and intravenous routes. 6) demonstration of the feasibility of applying these techniques to methamphetamine HCI smoking.

[unreadable] DESCRIPTION (provided by applicant): Aging men manifest Benign Prostatic Hyperplasia (BPH) that can result in lower urinary tract symptoms (LUTS), decreased flow, prolonged voiding, detrusor instability (Dl), nocturia, retention, and hydronephrosis. Preclinical models mimic this by suddenly tightening a ligature around the urethra, resulting in onset of Dl in a few weeks; instant onset of urethral constriction is likely to differ importantly from partial outlet obstruction that takes five or more decades to develop in humans and months in mice. After developing methods to measure uroflow and void duration in the awake mouse, we turned our attention to several transgenic mouse strains (TRAMP, TRAMP-FVB, MPAKT and PbPRL) known to develop urinary obstruction associated with probasin-driven expression systems. Changes in voiding function typical of outlet obstruction have occurred in two strains to date. Automated image capture confirmed prolonged pulsatile voiding, not overflow incontinence. Histologic study confirmed neoplasia, suburethral gland enlargement, and other changes consistent with obstruction. The MPAKT mouse is documented to obstruct at >400 days in the absence of invasive cancer. The PbPRL mouse also obstructs associated with prolactin-induced benign hyperplasia. These transgenic mice show promise as nonsurgical models of slow-onset bladder outlet obstruction. We will monitor the development of voiding dysfunction, and measure prostate size noninvasively using soft tissue conebeam computed tomographic methods (conebeam CT). Contrast studies offer detection of the onset of ureterohydronephrosis, bladder vesiculation, and increased bladder wall thickness in vivo. Histopathology will be used to confirm imaging findings, and to describe potential bladder hypertrophy and fibrosis. Pharmacologic challenges with medications used for clinical management of BPH will be administered across their lifespan to reveal functionally silent compensatory changes in voiding function, and to demonstrate therapeutic enhancement of impaired voiding function. We expect to describe three stages of BPH in the mouse, i.e. asymptomatic, dysfunctional, and hydronephrotic, and to observe compensatory and decompensation processes. Development of mouse models of the lower urinary tract symptoms seen in benign prostatic hypertrophy and other bladder diseases are expected to generate increased understanding of the underlying disease process, and eventually to help predict how the disease will progress in individual patients. Many medications are developed by studying effects in normal animals, because true models of the disease do not exist. Valid animal models of disease should respond similarly to patients treated with prescription medications. Such models help identify new types of medications as well as their likelihood of side effects. [unreadable] [unreadable] [unreadable]

Address; Anatomic; Anatomical Sciences; Anatomy; Animals; Automobile Driving; Biochemistry; Biophysics; CRISP; Chemistry, Biological; Clinical; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Data; Data Set; Dataset; Disease; Disorder; Drivings, Automobile; Female; Funding; Genetic Alteration; Genetic Change; Genetic defect; Genitourinary; Genitourinary system; Grant; Hearing; Image; Institution; Investigation; Investigators; Label; Lower urinary tract; Mammals, Mice; Medical Specialities; Mice; Microscopy; Missouri; Modeling; Murine; Mus; Mutation; NIH; National Institutes of Health; National Institutes of Health (U.S.); Oregon; Organ; Pathologist; Pathology; Pelvic; Pelvic Region; Pelvis; Procidentia; Prolapse; Ptosis; Publishing; Purpose; Research; Research Personnel; Research Resources; Research Specimen; Researchers; Resolution; Resources; Science of Anatomy; Source; Specialties, Medical; Specialty; Specimen; Students; Talents; Thinking; Thinking, function; Tissue Sample; United States National Institutes of Health; Urogenital; Urogenital System; Work; anatomy; disease/disorder; driving; experience; genome mutation; hearing perception; imaging; interest; male; medical specialties; sound perception; tool; urogenital system (urinary part)