McLean Hospital, Belmont, MA

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Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

McLean Hospital, Belmont, MA

JACK H. MENDELSON - Primate Testing - 2006

Grant Number: 5P01DA014528-050004
Project Title: BIOLOGIC APPROACHES TO COCAINE ABUSE TREATMENT
PI Information: PROFESSOR JACK H. MENDELSON, jmendel@mclean.harvard.edu 

Abstract: Project V:
Biologic Approaches to Cocaine Abuse Treatment is part of a new application for a NIDA Program Project (P-01) entitled Cocaine and Polydrug Abuse: New Medication Strategies. Two series of studies are proposed to test the hypothesis that endocrine and neuroendocrine systems may be useful targets for the development of novel medication strategies for cocaine abuse. The first series of studies is based on our discovery that administration of synthetic luteinizing hormone releasing hormone (LHRH) not only increased plasma levels of luteinizing hormone (LH), but also dose-dependently decreased peak plasma levels of free (unbound) cocaine in both rhesus monkeys and humans following i.v. cocaine injection. he LH glycoprotein molecule shares structural features with other cocaine binding substrates including the dopamine transporter, and plasma levels of circulating glycoproteins (e.g., alpha- acid glycoprotein) are known to bind to cocaine and influence levels of free cocaine in plasma. In pharmacokinetic studies in rats, we will assess the ability of synthetic LHRH injections to alter plasma and brain levels of cocaine after i.v. administration. In complementary behavioral studies, we will evaluate the effects of synthetic LHRH on both cocaine discrimination and cocaine self-administration in rhesus monkeys. If our hypothesis is correct, increased LHRH levels will reduce brain levels of cocaine in rats and cocaine's abuse-related effects in monkeys. Such findings would encourage further studies to identify the relevant subunit of the LH glycoprotein that binds to cocaine, and may provide a new approach to the development of anti-cocaine medications. A second series of studies is based on our recent findings that acute administration of cocaine stimulates an immediate release of adrenocorticotropin hormone (ACTH) from the anterior pituitary and a subsequent release of cortisol from the adrenal gland in rhesus monkeys and in humans (Projects III and IV). Clinical reports of a significant temporal concordance between increased plasma cocaine levels, cocaine- induced increases in ACTH and subjective reports of cocaine-induced "high" further suggest that the hypothalamic-pituitary adrenal (HPA) axis may contribute to cocaine's abuse-related effects. Using newly available systematically-active CRF antagonists, we will test the hypothesis that activation of HPA systems contributes to cocaine's discriminative stimulus and reinforcing effects in rats and monkeys. Additional studies in rats will compare peptidic and non-peptidic CRF antagonists after central and systemic administration to assess pharmacokinetics and to identify brain and/or pituitary regions involved in the putative anti-cocaine effects of CRF antagonists. In these basic neurobiological and pharmacological studies, experimental designs (e.g., doses and time course of cocaine, LHRH and CRF antagonists) will be based, in par, on findings from Projects II-IV. Collectively, these studies will complement findings from other inter- related projects on cocaine's influence on endocrine function and will address the question of whether endocrine and/or neuroendocrine systems may be manipulated to attenuate cocaine's abuse-related effects and/or strengthen anti-cocaine effects of other candidate treatment medications.

Thesaurus Terms:
cocaine, drug abuse, drug abuse chemotherapy, drug addiction antagonist, nonhuman therapy evaluation
corticotropin releasing factor, gonadotropin releasing factor, hypothalamic pituitary adrenal axis, luteinizing hormone, neuropharmacology, neurotransmitter antagonist, pharmacokinetics, self medication, substance abuse related behavior
Macaca mulatta, behavioral /social science research tag, catheterization, intravenous administration, laboratory rat

Institution: MC LEAN HOSPITAL (BELMONT, MA)
115 MILL ST
BELMONT, MA 02478
Fiscal Year: 2006
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: NIDA

Vol. 281, Issue 1, 70-83, 1997

The Effects of Chronic Cocaine Self-Administration on the Menstrual Cycle in Rhesus Monkeys

Nancy K. Mello, Jack H. Mendelson, Maureen Kelly, Nicolas Diaz-Migoyo and J. Wallis Sholar

Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, 115 Mill Street, Belmont, MA 02178

Operant Behavioral Procedures and Apparatus
Monkeys lived in a well-ventilated stainless steel chamber equipped with an operant panel, a banana pellet feeder and a water dispenser. Drug injections were delivered by a syringe pump in a single pulse that dispensed 0.1 ml of fluid over 0.9 sec. The operation of the syringe pump (Model 981210, Harvard Apparatus, Inc., South Natick, MA) was audible to the monkey. Schedules of reinforcement were programmed by custom-designed software and run on Apple II GS computers.
Monkeys worked at an operant task for food and for i.v. cocaine injections on a second-order schedule of reinforcement (FR2 [VR:16S]) that required an average of 32 responses for each food pellet or cocaine injection. Food availability and cocaine availability conditions were associated with different colored stimulus lights (S+) projected on a translucent Plexiglas response key (2-in. diameter) in the center of the operant panel. The key was dark during time-out periods when responses had no programmed consequences. When a food pellet or drug injection was delivered, the appropriate colored stimulus light (S+) (red or green) was illuminated for 1 sec on one of the three circles (3/4-in. diameter) located in a vertical column below the response key. Flashes of the 1-sec colored stimulus lights (S+) also signaled the completion of each successive VR component of a second-order schedule response requirement. When cocaine was not available because of catheter loss, the response key was dark except during food sessions.
Each experimental day consisted of four food availability and four drug availability sessions. Food sessions began at 11 A.M., 3 P.M., 7 P.M. and 7 A.M. each day, and drug sessions began 1 hr later at 12 noon, 4 P.M., 8 P.M. and 8 A.M. Consecutive food and drug sessions were separated by time-out periods 2 hr (1-3 P.M., 5-7 P.M. and 9-11 A.M.) or 10 hr in duration (9 P.M.-7 A.M.). The response key was dark during time-out periods, and responses had no programmed consequences. Each food or drug session lasted 1 hr or until 100 banana pellets (1 gm) or 20 cocaine injections (0.10 mg/kg/injection) were delivered. Cocaine injections were limited to 80 per day (8 mg/kg/day) to minimize the possibility of adverse drug effects.

Surgical Procedures
After operant performance for food was stable on the final schedule of reinforcement and there was evidence of normal ovulatory base-line menstrual cycles, each monkey was surgically implanted with an i.v. double lumen silicon catheter (I.D. 0.028 in., O.D. 0.080 in.) under aseptic conditions. Monkeys were sedated with ketamine (5 mg/kg s.c.), and anesthesia was induced with sodium thiopental (10 mg/kg i.v.). Atropine (0.05 mg/kg) was given to reduce salivation. After insertion of an intratracheal tube, a surgical level of anesthesia was maintained with halothane (1-1.5% in oxygen). Catheters were implanted in the jugular or femoral vein and exited in the mid-scapular region. After surgery, monkeys were given 200,000 units of Combiotic Dihydrostreptomycin and Penicillin G i.m. on alternate days for a total of 5 injections. The i.v. catheter was protected by a tether system consisting of a custom-fitted nylon vest connected to a flexible stainless steel cable and fluid swivel (Spaulding Medical Products, Birmingham, AL), which permitted monkeys to move freely. Catheter patency was maintained by i.v. cocaine administration and a saline flush. Fluid swivel and catheter patency were checked manually each day. A short-acting barbiturate, methohexital sodium (3 mg/kg i.v.), was used to evaluate catheter patency, if necessary. The catheter was considered to be patent if i.v. administration of methohexital produced a loss of righting within 10 sec of its administration.

Please email: JACK H. MENDELSON, jmendel@mclean.harvard.edu to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: saen@saenonline.org

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.

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