Howell Lab - Yerkes National Primate Research Center

Jump to:...... Behavioral Pharmacology ...... Neurochemistry ...... Neuroimaging

..........................Behavioral Pharmacology..........................

A major focus of the laboratory is on the behavioral pharmacology of cocaine and related psychomotor stimulants. Operant conditioning techniques are used to characterize drug effects on learned behavior. Emphasis is on intravenous drug self-administration behavior in order to study the reinforcing properties of these drugs of abuse. Drug interaction studies are used to understand better the neurochemical basis of cocaine use in nonhuman primates. Drug self-administration is a very powerful approach in drug abuse research because it provides a basis for testing the abuse liability of drugs as well as medication effectiveness in reducing drug use. In addition, drug effects on schedule-controlled behavior allow for the determination of dose-effect curves to quantify the range of doses that are behaviorally active, and for the determination of drug time course to quantify onset and duration of drug action. Collectively, these behavioral studies provide the foundation for our medications development research.

Select Publications (2000 - present)

Kimmel, H.L., O'Connor, J.A., Carroll, F.I., Howell, L.L. Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys. Pharmacology Biochemistry and Behavior, 86: 45-54, 2007 PDF.

Howell, L.L., Carroll, F.I., Votaw, J.R., Goodman, M.M., Kimmel, H.L. Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics, 320: 757-765, 2007 PDF.

Carroll, F.I., Howard, J.L., Howell, L.L., Fox, B.S., Kuhar, M.J. Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse. American Association of Pharmaceutical Scientists Journal, 8: E196-203, 2006 PDF.

Howell, L.L., Wilcox, K.M., Lindsey, K.P., Kimmel, H.L. Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys. Neuropsychopharmacology, 31: 585-593, 2006 PDF.

Wilcox, K.M., Kimmel, H.L., Lindsey, K.P., Votaw, J.R., Goodman, M.M., Howell, L.L. In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys. Synapse, 58: 220-228, 2005. PDF.

Ginsburg, B.C., Kimmel, H.L., Carroll, F.I., Goodman, M.M., Howell, L.L. Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys. Pharmacology Biochemistry and Behavior, 80: 481-491, 2005. PDF.

Czoty, P.W., Ginsburg, B.C. and Howell, L.L. Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys. Journal of Pharmacology and Experimental Therapeutics, 300: 831-7, 2002. PDF.

Howell, L.L. and Wilcox, K.M. The dopamine transporter and cocaine medication development: Drug self-administration in nonhuman primates. Journal of Pharmacology and Experimental Therapeutics, 298: 1-6, 2001. PDF.

Howell, L.L. and Wilcox, K.M. Intravenous drug self-administration in nonhuman primates. In: Methods of Behavior Analysis in Neuroscience, J.J. Buccafusco, Ed. CRC Press: Boca Raton, FL, pp. 91-110, 2001.

Howell, L.L., Czoty, P.W., Kuhar, M.J. and Carroll, F.I. Comparative behavioral pharmacology of cocaine and the selective dopamine uptake inhibitor, RTI-113, in the squirrel monkey. Journal of Pharmacology and Experimental Therapeutics, 292: 521-529, 2000. PDF.

Czoty, P.W. and Howell, L.L. Behavioral effects of AMI-193, a 5-HT_2A- and dopamine D2-receptor antagonist, in the squirrel monkey. Pharmacology, Biochemistry and Behavior, 67: 257-264, 2000.

..........................Hallucinogens..........................

In addition to psychomotor stimulants, we are interested in the behavioral pharmacology of hallucinogenic compounds. We are interested in these compounds because they engender profound and unusual effects in people and relatively little in known about their receptor and behavioral pharmacology. Furthermore, these compounds attained significant notoriety in our society in the 1950's and 60's and abuse of these drugs has continued at significant levels ever since. Although intravenous drug self-administration is a powerful approach to studying behavioral pharmacolgy, its use cannot be extended to studying hallucinogens as these drugs do not function as positive reinforcers. With that in mind, we have approached studying these compounds with other well characterized behavioral assays. In particular, we use the rodent head twitch assay and the drug discrimination assay. The rodent head twitch assay has utility because drug induced increases in head twitches in rodents is highly predictive of hallucinogenic effect in people. Drug discrimination is an important assay because is one of the few, if not only, assay in which an animal can be trained to report the interoceptive state induced by a drug. Furthermore, we work in collaboration with medicinal chemists to establish stucture activity relationships for these compounds both in terms of receptor and behavioral pharmacology.

Select Publications (2000 - present)

Yarosh, H.L., Katz, E.B., Coop, A., Fantegrossi, W.E.MDMA-like behavioral effects of N-substituted piperazines in the mouse. Pharmacology Biochemistry and Behavior, 2007.

Fantegrossi, W.E., Harrington, A.W., Kiessel, C.L., Eckler, J.R., Rabin, R.A., Winter, J.C., Coop, A., Rice, K.C., Woods, J.H. Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Pharmacology Biochemistry and Behavior, 83: 122-9, 2006 PDF.

...................Neurochemistry...................

In vivo microdialysis protocols have been developed to identify the neurochemical mechanisms that mediate drug effects on behavior. Microdialysis is a sampling technique used to determine direct changes in neurochemistry that occur in response to drug administration. The neurochemical basis of cocaine's addictive properties can be documented by characterizing the profile of neurochemical effects that occur during cocaine self-administration. In drug interaction studies, these neurochemical measures help identify relevant mechanisms that underlie medication effectiveness in reducing cocaine use. The information obtained will identify specific neurochemical targets and direct medication development efforts. A unique aspect of our research program is the ability to conduct in vivo microdialysis in awake, behaving nonhuman primates.

Select Publications (2000 - present)

Howell, L.L., Wilcox, K.M., Lindsey, K.P., Kimmel, H.L. Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys. Neuropsychopharmacology, 31: 585-593, 2006 PDF.

Kimmel, H.L., Ginsburg, B.C., Howell, L.L. Changes in extracellular dopamine during cocaine self-administration in squirrel monkeys. Synapse, 56: 129-134, 2005. PDF.

Czoty, P.W., Justice, J.B, Jr. and Howell, L.L. Cocaine-induced changes in extracellular dopamine determined by microdialysis in awake squirrel monkeys. Psychopharmacology, 148: 299-306, 2000. PDF.

..........................Neuroimaging..........................

Our laboratory has established a strong collaboration with the Emory University Center for Positron Emission Tomography (PET). Functional neuroimaging with PET is used to characterize drug interactions with molecular targets in vivo. In addition, brain activation studies identify specific neuroanatomical structures and circuits that are influenced by cocaine administration. Related studies document changes in brain activity influenced by drug-related environmental stimuli as a model of cocaine craving. The pattern of brain activation induced by cocaine or drug-related stimuli can be used to access medication effectiveness. Currently, protocols are being developed to conduct brain activation studies with functional magnetic resonance imaging (fMRI). These noninvasive neuroimaging procedures can be extended directly into human studies of drug addiction. We are one of the few research programs in the world to conduct functional imaging in awake, behaving nonhuman primates.

Select Publications (2000 - present)

Plisson, C., Jarkas, N., McConathy, J., Voll, R.J., Votaw, J., Williams, L., Howell, L.L., Kilts, C.D., Goodman, M.M. Evaluation of carbon-11-labeled 2beta-carbomethoxy-3beta-[4'-((Z)-2-iodoethenyl)phenyl]nortropane as a potential radioligand for imaging the serotonin transporter by PET. Journal of Medicinal Chemistry, 49: 942-6, 2006 PDF.

Lindsey, K.P., Wilcox, K.M., Votaw, J.R., Goodman, M.M., Plisson, C., Carroll, F.I., Rice, K.C., Howell, L.L. Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging. Journal of Pharmacology and Experimental Therapeutics, 309: 959-969, 2004. PDF.

Votaw, J.R., Howell, L.L., Martarello, L., Hoffman, J.M., Kilts, C.D., Lindsey, K.P., Goodman, M.M. Measurement of dopamine transporter occupancy for multiple injections of cocaine using a single injection of [F-18]FECNT. Synapse, 44: 203-210, 2002. PDF.

Howell, L.L., Wilcox, K.M. Functional imaging and neurochemical correlates of stimulant self-administration in primates. Psychopharmacology, 163: 352-61, 2002. PDF.

Wilcox, K.M., Lindsey, K.P., Votaw, J.R., Goodman, M.M., Martarello, L., Carroll, F.I. and Howell, L.L. Self-administration of cocaine and the cocaine analog RTI-113: Relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys. Synapse, 43: 78-85, 2002. PDF.

Howell, L.L., Hoffman, J. M., Votaw, J.R., Landrum, A.M., Wilcox, K.M. and Lindsey, K.P. Cocaine-induced brain activation determined by positron emission tomography (PET) neuroimaging in conscious rhesus monkeys. Psychopharmacology, 159: 154-160, 2002. PDF.

Howell, L.L., Hoffman, J.M., Votaw, J.R., Landrum, A.M. and Jordan, J.F. An apparatus and behavioral training protocol to conduct positron emission tomography (PET) neuroimaging in conscious rhesus monkeys. Journal of Neuroscience Methods, 106: 161-169, 2001. PDF.

Last updated 31 Jul 07