David R. Helton
Eli Lilly and Company
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Featured researches published by David R. Helton.
Neuropharmacology | 1997
David R. Helton; Joseph P. Tizzano; James A. Monn; Darryle D. Schoepp
LY354740 is a conformationally constrained analog of glutamate with high selectivity and nanomolar agonist activity at Group II metabotropic glutamate receptors (mGluRs). This orally active compound is a new drug candidate which is being developed for the treatment of anxiety. In this study, LY354740 was investigated in a model of nicotine withdrawal using the acoustic startle reflex (sensorimotor reactivity) in rats. Nicotine (6 mg/kg/day) was administered for 12 days subcutaneously by osmotic minipumps. After 12 days the pumps were removed and the animals were allowed to go through spontaneous withdrawal. Cessation of chronic nicotine exposure led to increased startle responding for 4 days following withdrawal. Treatment with LY354740 (0.0001-0.1 mg/kg, i.p.; 0.03-3 mg/kg, oral) produced a dose-dependent attenuation of the enhanced auditory startle responding following withdrawal of nicotine with intraperitoneal and oral ED50 values of 0.003 mg/kg and 0.7 mg/kg, respectively. These effects were stereoselective since the (-)-enantiomer of LY354740, LY366563, was without effect in this model. LY354740 produced no changes in the sensorimotor reactivity of rats not exposed to nicotine at oral doses up to 10 mg/kg. These data support the functional role of mGluR agonists in nicotine withdrawal and indicate that LY354740 may be efficacious in reducing the symptoms associated with nicotine withdrawal during smoking cessation in humans.
Psychopharmacology | 1993
David R. Helton; Deah Modlin; Joseph P. Tizzano; Kurt Rasmussen
Three different behavioral measures were used to assess the effects of abrupt cessation of chronic nicotine treatment. Nicotine (0, 3, or 6 mg/kg per day) was continuously administered for 12 days in rats by surgically implanting Alzet osmotic mini-pumps subcutaneously. Experiment 1 employed a light/dark discrimination task. There were no significant effects on number of responses or percent correct responding either during nicotine administration, or following cessation of nicotine. Experiment 2 examined ambulatory (locomotor) and nonambulatory activity. Chronic nicotine administration produced significant dose-dependent increases in both ambulatory and nonambulatory activity during the first 3 days of exposure. However, no significant alterations were seen in activity levels following nicotine cessation. Experiment 3 examined sensorimotor reactivity using the auditory startle response. During nicotine withdrawal, significant increases were seen in startle amplitude in both nicotine groups for 4 days. Nicotine (0.4 mg/kg, IP) administered before startle testing during the withdrawal phase attenuated the increased reactivity seen during nicotine cessation. These studies indicate that 1) rats display increased sensorimotor reactivity after cessation of chronic nicotine exposure, and 2) the expression of nicotine dependence and withdrawal is dependent on the behavioral task employed.
Neuroscience Letters | 1993
Joseph P. Tizzano; Kelly I. Griffey; J.Allen Johnson; Andrew S. Fix; David R. Helton; Darryle D. Schoepp
The functional role of metabotropic glutamate receptor (mGluR) activation was investigated following intracerebral administration of 1S,3R-ACPD in mice. Injections of 1S,3R-ACPD (50-800 nmol in 5 microliters) into the thalamus produced a dose-dependent increase in limbic seizures. These effects were stereoselective since 1R,3S-ACPD, did not elicit seizure activity. Pharmacologically, limbic seizures were attenuated by the mGluR partial agonist/antagonist L-2-amino-3-phosphonopropionate (L-AP3) and dantrolene, an inhibitor of intracellular calcium mobilization, but not by D-AP3 or ionotropic glutamate receptor antagonists (MK-801 or GYKI-52466). Thus, activation of mGluRs by 1S,3R-ACPD in mice, induces limbic seizures that may involve the mobilization of intracellular calcium stores.
Synapse | 1997
Kurt Rasmussen; David R. Helton
Withdrawal from the chronic administration of nicotine has previously been shown to lead to an enhanced auditory startle response in rats. In order to explore the neuropharmacology and neurophysiology underlying this phenomenon, we examined the effects of various 5‐hydroxytryptamine (5‐HT)‐1A antagonists and agonists on the nicotine‐withdrawal‐enhanced auditory startle response in male rats. Animals were treated with nicotine (6 mg/kg/day nicotine base, via subcutaneously implanted osmotic minipumps) for 12 days. After 12 days the pumps were removed and the animals allowed to undergo spontaneous withdrawal for several days. In agreement with previous results, nicotine withdrawal led to a significant elevation of the auditory startle response. Pretreatment with the 5‐HT‐1A agonists (+)8‐OH‐DPAT (0.001–0.1 mg/kg) and LY274600 (0.3–3.0 mg/kg) either had no affect or exacerbated the nicotine‐withdrawal‐enhanced startle response. Pretreatment with the 5‐HT‐1A antagonists NAN‐190 (1–3 mg/kg), LY206130 (1–10 mg/kg), or WAY‐100635 (0.1–1.0 mg/kg) blocked the increase in the startle response caused by nicotine withdrawal at doses that had no effect on baseline startle responses. These data indicate that 5‐HT‐1A receptors play a role in the neurophysiology of nicotine withdrawal. In addition, 5‐HT‐1A antagonists may be able to relieve some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation. Synapse 27:145–152, 1997.
Neuroreport | 1993
Kurt Rasmussen; David R. Helton; James E. Berger; Elizabeth Scearce
In order to explore the potential clinical utility of CCK-B antagonists for the treatment of benzodiazepine withdrawal symptoms, the auditory startle reflex was examined in rats undergoing withdrawal from the chronic administration of diazepam. Animals were exposed to diazepam continuously for 12 days (20 mg kg-1 per day) via osmotic minipumps. After 12 days the pumps were removed and the animals were allowed to go through spontaneous withdrawal for 4 days. Acute pretreatment with either diazepam or the selective CCK-B antagonist LY288513 dose-dependently blocked withdrawal-induced increases in the auditory startle response. These results support the hypothesis that the selective CCK-B antagonist LY288513 may be an effective treatment for alleviating at least some benzodiazepine withdrawal symptoms in man.
Pharmacology, Biochemistry and Behavior | 1996
David R. Helton; James E. Berger; Janet F. Czachura; Kurt Rasmussen
The activity of LY288513, an investigational cholecystokinin (CCK)B antagonist, was evaluated in a wide range of pharmacological tests in mice and rats. The anxiolytic benzodiazepine, diazepam, served as a reference standard for LY288513 in many of the tests. In the elevated plus-maze, LY288513 (3, 10 mg/kg, IP; 10, 30 mg/kg, PO) produced an anxiolytic-like action in mice with a magnitude of effect similar to that of diazepam. However, unlike diazepam, LY288513 produced no overt clinical signs and did not affect muscle tone, neuromuscular coordination, or sensorimotor reactivity. Also, in contrast to diazepam, LY288513 did not produce changes in the thresholds for electroshock- or pentylenetetrazol-induced convulsions. High doses of LY288513 (1000 mg/kg, PO) were required to reduce spontaneous activity levels, decrease body temperature, or potentiate the CNS-depressant effects of hexobarbital. LY288513 had no analgesic activity in mouse writhing or tail-flick tests. Electrophysiological studies in anesthetized rats showed that acute administration of LY288513 decreased the number of spontaneously active dopamine neurons in the substantia nigra and ventral tegmental area. However, LY288513 did not produce catalepsy. These data indicate that LY288513 possess both anxiolytic and antipsychotic potential.
Neuroreport | 1996
Kurt Rasmussen; Janet F. Czachura; David R. Helton
IN order to explore the potential clinical utility of CCK-B antagonists for the treatment of nicotine withdrawal symptoms, the auditory startle reflex was examined in rats undergoing withdrawal from the chronic administration of nicotine. Rats were exposed to nicotine continuously for 12 days (6 mg kg−1 day−1) via osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal for several days. Acute treatment with the CCK-B antagonist LY288513, at doses that have no effect on startle responses in naive rats, blocked the nicotine withdrawal-induced increase in the acoustic startle reflex. These results indicate that CCK-B antagonists may be an efficacious treatment for some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation.
Journal of Pharmacy and Pharmacology | 1994
David R. Helton; Walter E. Colbert
Abstract— The effects of single and multiple (5, 10, or 15 days) administration of the 5‐HT1A agonist 8‐hydroxy‐2‐(di‐N‐propylamino) tetralin (8‐OH‐DPAT) (3 mg kg−1, i.p.) or 5‐HT (3 mg kg−1, i.p.) in‐vivo on the response of selected isolated smooth muscles to 5‐HT in‐vitro were investigated. Single dosing with 8‐OH‐DPAT did not alter the responses of the isolated tissues (rat aorta, uterus or fundus, or guinea‐pig trachea) to 5‐HT, while multiple dosing with 8‐OH‐DPAT produced rightward shifts and a suppression of the maximum response of all these tissues to 5‐HT, with the exception of the rat stomach fundus. Multiple administration of 5‐HT had no effect on the in‐vitro response of the tissues to 5‐HT. These data indicate that multiple administration of 8‐OH‐DPAT desensitizes or down‐regulates the peripheral 5‐HT2 receptors found on the rat aorta and uterus, and guinea‐pig trachea.
Journal of Medicinal Chemistry | 1997
James A. Monn; Matthew John Valli; Steven Marc Massey; Rebecca A. Wright; Craig R. Salhoff; Bryan G. Johnson; Trevor J. Howe; Charles A. Alt; Gary A. Rhodes; Roger L. Robey; Kelly R. Griffey; Joseph P. Tizzano; David R. Helton; Darryle D. Schoepp
Journal of Pharmacology and Experimental Therapeutics | 1998
David R. Helton; Joseph P. Tizzano; James A. Monn; Darryle D. Schoepp