Laboratory of Behavioral Neuroscience

Current Projects

Cognitive Aspects of Addiction –Related Behavior (DA 11716)

The initial aims of this project were three-fold. The first aim was to identify sites within different memory systems capable of mediating specific associative learning processes that may have relevance for regulating different aspects of cocaine addiction. To identify these sites, we made use of a variety of dissociable cognitive tasks in an eight-arm radial maze and evaluated changes in associative learning functions after lidocaine inactivation. The second aim was to use lidocaine inactivation of these cognitively identified sites to examine how different associative learning processes might regulate cocaine-seeking and cocaine-taking behavior studied in a newly developed maintenance/reinstatement model. Once the role of these learning processes in regulating cocaine seeking and cocaine-taking behaviors were revealed, the third aim assessed the effects of persistent cocaine self-administration on cognitive task performance. The results from the first two aims demonstrated that unique cognitive functions and unique influences on addiction-related behavior were found for each the four memory systems we are studying (amygdalar, hippocampal, dorsal striatal and prefrontal cortical). Currently, we are studying the interactions among these memory systems for regulating addiction-related behavior by making use of the asymmetric lidocaine inactivation procedure and Fos protein expression measurement. Together, these studies advance our understanding of how neurocognitive substrates might regulate drug use and relapse. By studying memory system functions and their interactions during different phases of the cocaine addiction process, insight into the complex challenges that face successful treatment of cocaine-addicted individuals will surface and perhaps guide medications development.

Publications and recent abstracts related to this project

Kantak. K.M., Green-Jordan, K., Valencia, E., Kremin, T. and Eichenbaum, H.B. Cognitive task performance following lidocaine-induced inactivation of different sites within the basolateral amygdala and dorsal striatum. Behavioral Neuroscience, 115: 589-601, 2001

Kantak, K.M., Black, Y., Valencia, E., Green-Jordan, K. and Eichenbaum, H.B. Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats. Journal of Neuroscience, 22:1126-1136, 2002

Kantak, K.M., Black, Y., Valencia, E., Green-Jordan, K. and Eichenbaum, H.B. Stimulus-response functions of the lateral dorsal striatum and regulation of behavior studied in a cocaine maintenance/cue reinstatement model in rats. Psychopharmacology, 161: 278-287, 2002

Black, Y., Green-Jordan, K., Eichenbaum, H.B. and Kantak, K.M. Hippocampal memory system function and the regulation of cocaine self-administration behavior in rats. Behavioural Brain Research (in press).

Black, Y., Eichenbaum, H.B. and Kantak, K.M. Dysregulation of drug-seeking behavior following lidocaine inactivation of the lateral prefrontal cortex. College on Problems of Drug Dependence, Quebec City, Canada, June 2002

Di Pietro, N.C., Black, Y.D., Green-Jordan, K., Eichenbaum, H.B. and Kantak, K.M. Validation of a radial-arm maze task to study lateral prefrontal cortex functions. Society for Neuroscience, Orlando, FL, November 2002

Udo, T., Ugalde, F.A., DiPietro, N.C., Eichenbaum, H.B. and Kantak, K.M. Effects of Persistent Cocaine Self-Administration on Amygdala-Dependent and Dorsal Striatum-Dependent Learning in Rats. Psychopharmacology (in press).

Developing Theoretical and Computational Models of Drug Abuse (DA11716-S2)

Neurocomputational modeling is done using the Catacomb2 modeling environment, developed by Robert C. Cannon (Cannon et al., 2002) in accordance with our specific modeling needs. In Catacomb, we model both physical interaction with the environment and the biological details of neuronal circuitry, an approach that closes the loop between the output of the behaving system and its consequent realistic input. A variety of controls can be added to implement experimental protocols, such as the dispensing of food in response to a pressed lever or the scheduled activation of lights and sound. The Hasselmo Lab has previously used Catacomb to successfully model the memory functions of entorhinal and hippocampal networks in spatial navigation experiments for food-seeking behavior (Hasselmo et al, 2002). The neuronal circuitry in the present model of drug-seeking behavior developed by Mike Hasselmo and Randal Koene consists of integrate-and-fire neurons with some additional physiological detail, such as the characteristic after-hyperpolarization after a spike and the modulation of synaptic transmission. Learning, in terms of long-term potentiation at synapses, is modeled with Hebbian processes at the synapses of specific fibers between cell populations.

The current version of the model uses the following connectivity: 1) the hippocampus provides input to the nucleus accumbens and prefrontal cortex; 2) the amygdala provides fast as well as sustained delayed input to the nucleus accumbens; and 3) the prefrontal cortex provides input to the nucleus accumbens. The activity in the simulation is started by a single exploratory lever press and all output is a result of network computations based on assumptions about the strength of synaptic connections and the intrinsic time constants of neurons. Our choices about these parameters were guided by knowledge about standard physiological properties of individual neurons in cortical and subcortical structures. These properties were then tuned to provide output-firing rates that mediate the realistic effects of lesions on behavioral output of the model. These assumptions may differ from some physiological properties of the real circuit, but the construction of this model provides a useful starting point for understanding the physiological substrates mediating these behaviors. This model is currently being used to make predictions on how memory systems may interact to regulate addiction-related behavior.

New Method for Studying Drug Self-Administration in Mice (DA 13590)

The Trans-NIH Mouse Initiative is now underway for developing new, cost-effective, high throughput phenotyping techniques to assess specific components of central nervous system function in inbred strains of laboratory mice. One purpose for developing such techniques is to apply this technology to mutant mice, with the expectation that the genetic analysis of complex traits will be facilitated and that basic brain processes and diseases of the central nervous system will be better understood and treated. Numerous mouse "knockouts" now exist, but little is known regarding the functional significance of their altered genetics. There are many complex behaviors of interest in the Trans-NIH Mouse Initiative; among them are cognition, learning and memory, and the taking and seeking of drugs of abuse. The goal of this research is to establish a reliable method of drug self-administration that can be used long-term in inbred and genetic knockout strains of mice to simulate the full array of human behaviors or experiences associated with drug addiction. These include the acquisition, maintenance, extinction and reinstatement of drug-seeking and drug-taking behavior. In the present project, we are developing inhalation methods of drug self-administration (cocaine smoke or alcohol vapor), thus avoiding many of the technical limitations imposed by previous methods.

Past Projects

Antibody Intervention in Cocaine Addiction (DA08979) and A Therapeutic Cocaine Vaccine (DA10946)

Cocaine, being a haptenic molecule, cannot produce an immune response. However, if conjugated with an immunogenic carrier molecule, administration of the conjugate would induce the immune system to produce antibodies against cocaine. The cocaine vaccine developed by Barbara Fox and colleagues at ImmuLogic Pharmaceutical Corporation used a synthetic derivative of norcocaine conjugated to an immunogenic carrier protein. In mice immunized with three tri-weekly 50 mg injections of the vaccine, antibody titers rose to over 100,000 three weeks after the last boost and remained at these levels for up to four months. With periodic administration of a booster, antibody titers were maintained for more than a year. Following intravenous administration of cocaine, significant changes in the distribution of cocaine are observed in immunized animals that favor its therapeutic use (increase in plasma, decrease in brain and heart). In active-immunization experiments in rats, antagonism of cocaine self-administration across a range of doses is observed after immunization with the cocaine vaccine as long as antibody levels are of a sufficient concentration. Based on these pre-clinical findings, clinical trials have begun and its safety and immunogenicity in people have been demonstrated (Kosten et al., 2002).

Publications related to these projects

Fox B.S., K.M. Kantak, M.A. Edwards, K.M. Black, B.K. Bollinger, A.J. Botka, T.L. French, T.L. Thompson, V.C. Schad, J.L. Greenstein, M.L.Gefter, M.A. Exley, P.A. Swain and T.J. Briner. Efficacy of a therapeutic vaccine in rodent models. Nature and Medicine, 2:1129-1132, 1996

Kantak, K.M., Collins, S.L., Lipman, E.G., Bond, J., Giovanoni, K. and Fox, B.S. Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model. Psychopharmacology 148: 251-262, 2000

Kantak, K.M., Collins, S.L., Bond, J. and Fox, B.S. Time course of changes in cocaine self-administration behavior during immunization with the cocaine vaccine IPC-1010. Psychopharmacology 153: 334-340, 2001

Kantak, K.M. Vaccines Against Drugs of Abuse: A Viable Treatment Option? Drugs 63:341-352, 2003

Kantak, K.M. Anti-Cocaine Vaccines: Antibody Protection Against Relapse. Expert Opinion in Pharmacotherapy 4: 213-218, 2003

Kantak, K.M. Preclinical and Clinical Studies with the Cocaine Vaccine TA-CD (IPC-1010). In: Neuroscience and Addiction: a WHO Report Initiative, in press

Cocaine Abuse: Nutritional Aspects (DA04325)

In 1982 we began studies with magnesium and aggression because of my interest in how nutrients would influence this behavior. As work progressed, we noted how similar the behavioral effects of magnesium were to psychomotor stimulants like cocaine and amphetamine. More studies were then conducted to look at the interactions of magnesium and cocaine in mouse aggression. The findings from these studies compelled me to look at the effects of magnesium in drug abuse models. We began with conditioned place preference studies in mice and demonstrated that magnesium maintained cocaine-induced place preference in the same way that amphetamine did and could also induce its own place preference that could be maintained by cocaine. The significance of this work was that magnesium appeared to have reinforcing effects that overlapped with psychomotor stimulants. Self-administration work seemed warranted.

In 1987, NIDA funded a grant to conduct self-administration studies with cocaine and magnesium. This work demonstrated that magnesium substituted for cocaine under a wide range of experimental conditions, suggesting that in cocaine-trained rats, magnesium has reinforcing effects. Other studies demonstrated that magnesium would not be self-administered in drug-naive rats, and so, magnesium would have a low potential for abuse, but a high potential for reducing the intake of cocaine if given as a therapeutic.

In 1991, we began incorporating drug discrimination methods into our studies on magnesium and cocaine, since it was known that drugs of abuse have both reinforcing stimulus effects and discriminative stimulus effects and both types of stimulus effects contribute to cocaine's abuse potential. As knowledge of the magnesium-binding site associated with the NMDA receptor complex surfaced, we expanded our research to include not only magnesium (an NMDA antagonist), but also other NMDA antagonists and a number of drugs having common effects with cocaine (dopamine agonists and dopamine uptake inhibitors). These findings confirmed that magnesium had stimulus effects in common with cocaine, which may be related to it's binding to the magnesium site in the NMDA receptor complex. The NMDA receptor complex in turn has been shown to regulate the amount of dopamine release, which is important for the behavioral and addictive effects of cocaine. Work was also done in collaboration with Roger Spealman to examine the effects of magnesium and other NMDA antagonists in squirrel monkey trained to discriminate high training doses of cocaine.

We were subsequently interested in knowing if magnesium itself would have discriminative stimulus effects and if cocaine and other more selective monoamine uptake inhibitors as well as other NMDA antagonists would substitute for magnesium. The results demonstrated substitution by a low dose of cocaine for magnesium, but also substitution by all the selective monoamine uptake inhibitors. These findings suggest that magnesium interacts not only with dopamine, but also with serotonin and norepinephrine neurotransmitter systems, which are the same three neurotransmitter systems affected by cocaine. These findings may explain the high degree of overlap between magnesium and cocaine that has been observed in ours studies since the 1980's. Other NMDA antagonists only poorly substituted for the discriminative stimulus effects of magnesium indicating that magnesium is acting at a site distinct from the other NMDA antagonists. These data also suggest that the action of magnesium in the brain is more complex than we previously thought and its mechanism may include direct interactions with dopamine, norepinephrine and serotonin receptors in addition to its action at the magnesium binding site in the NMDA receptor complex.

More recently, we have examined the effects of nitric oxide synthase inhibitors on the discriminative and reinforcing effects of cocaine in rats. Nitric oxide is a gas neuromodulator that is formed post-synaptically in response to glutamate stimulation of the NMDA receptor. The effects of NOS inhibitors would therefore be expected to resemble the effects of NMDA antagonists. The results demonstrated that the two types of drugs had different profiles of effects. Noteworthy are the findings showing that NOS inhibitors enhanced the discriminative and reinforcing effects of cocaine and other stimulant drugs, without themselves being cocaine-like. An idea generated from this work was that brain specific NOS inhibitors might be useful to administer along with cocaine substitute-type medications so that substitute medication dose could be reduced to eliminate and likely side effects.

In collaboration with Art Margolin, the first clinical trial with magnesium for drug addiction treatment was conducted in 2001 in outpatient methadone maintained individuals exhibiting ongoing illicit opiates and cocaine. With moderate maintenance doses of magnesium, the prevalence of illicit opiate-positive urines was less in individuals who were compliant with the outpatient magnesium treatment (16%) vs. individuals who were compliant with the outpatient placebo control treatment (48%) in the 12-week double blind study. There were also significant decreases in ratings of cocaine craving in magnesium treated individuals, but not in the percent of cocaine positive urines (84% placebo vs. 71% magnesium). The findings suggest that higher maintenance doses of magnesium might be necessary to reduce cocaine use, as suggested by the pre-clinical animal studies.

Publications and abstracts related to this project

Izenwasser, S. E., K. Garcia-Valdez, and K. M. Kantak. Stimulant-like effects of magnesium on aggression in mice. Pharmacology Biochemistry & Behavior 25: 1195‑1199, 1986

Kantak, K.M. Magnesium deficiency alters aggressive behavior and catecholamine function. Behavioral Neuroscience 102:304-311, 1988

Kantak, K.M. Magnesium alters the potency of cocaine and haloperidol on mouse aggression. Psychopharmacology, 99: 181-188, 1989

Lawley, S.I. and K. M. Kantak. Post-conditioning effects of magnesium on cocaine induced place preference in mice. Pharmacology Biochemistry & Behavior 36: 531-538,1990

Lawley, S.I. and K.M. Kantak. Magnesium induced place preference in mice. Pharmacology Biochemistry & Behavior 36: 539-545, 1990

Kantak, K.M. and L.K. Adlerstein. Enhancement of apomorphine and l-amphetamine induced behaviors by magnesium. Pharmacology Biochemistry & Behavior 36: 29-33, 1990

Kantak, K.M., J.F. Bourg and S.I. Lawley. Failure of magnesium to maintain self-administration in cocaine-naive rats. Pharmacology Biochemistry & Behavior 36: 9-12, 1990

Kantak, K.M., S.I. Lawley, S.J. Wasserman, and J.F. Bourg. Magnesium-maintained self-administration responding in cocaine-trained rats. Psychopharmacology 104: 527-535, 1991

Kantak, K.M. Attenuation of the rate-altering effects of cocaine by magnesium chloride in squirrel monkeys. Behavioural Pharmacology 2:97-104, 1991

Spealman, R.D. and K.M. Kantak. Dizocilpine (MK801) modulated discriminative stimulus effects of cocaine in rats but not squirrel monkeys. Presented at the FASEB annual meeting, Anaheim, CA, April 1992.

Kantak, K.M. and R.D. Spealman. Partial cocaine mimetic effects of magnesium chloride in rats and squirrel monkeys. Presented at the annual meeting of the College on Problems of Drug Dependence, Keystone, CO, June 1992

Kantak, K.M. Effects of magnesium on cocaine-reinforced responding in mice, rats and squirrel monkeys. In: NIDA Research Monographs, Problems of Drug Dependence 1991, edited by the Superintendent of Documents, Washington, D.C.: U.S. Government Printing Office, 1992, 195-199.

Kantak, K.M., S.J. Wasserman, S.I. Lawley, and T. O'Connor. Acute and multiple injection effects of MgCl₂ on responding maintained by cocaine, extinction from cocaine, glucose + saccharin, and food. Pharmacology Biochemistry & Behavior 41: 415-423, 1992

Kantak, K.M., M.A. Edwards and R.D. Spealman. Effects of N-methyl-D-aspartate antagonists in rats discriminating different doses of cocaine: comparison with direct and indirect dopamine agonists. Journal of Pharmacology and Experimental Therapeutics 27:657-665, 1995

Kantak, K.M., M.A. Edwards, K.M. Wilcox and E. Kitchel. Discriminative stimulus effects of magnesium chloride: substitution studies with monoamine uptake inhibitors and N-methyl-D aspartate antagonists. Journal of Pharmacology and Experimental Therapeutics 283: 200-206, 1997

Kantak K.M., M.A. Edwards and T.P. O'Connor. Modulation of the discriminative stimulus and rate-altering effects of cocaine by competitive and noncompetitive NMDA antagonists. Pharmacology Biochemistry & Behavior 59: 159-169, 1998

Collins, S.L. Edwards, MA and Kantak, K.M. Effects of the nitric oxide synthase inhibitors on the discriminative stimulus effects of cocaine in rats. Psychopharmacology 154: 261-273, 2001

Collins, S.L. and Kantak, K.M. The nitric oxide synthase inhibitor 7-nitroindazole alters the reinforcing effects of self-administered cocaine, Psychopharmacology 159:361-369,2002

Margolin, A., Kantak, K., Copenhaver, M. and Avants, S.K. A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. Journal of Addictive Diseases, in press

Cocaine-Opioid Interactions

The growing abuse of cocaine combined with morphine-like opiates ("speedballs") in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. The subjective ratings of “drug liking” and “high” frequently have been found to be greater when cocaine and a µ opioid agonist are administered in combination than when either drug is given alone. Drug discrimination procedures in animals may provide a preclinical model of these subjective effects reported by people (Spealman 1992). Studies of this type have begun to characterize cocaine–opioid interactions and to elucidate the roles of different opioid receptor subtypes in mediating their combined discriminative stimulus effects. One objective of our studies was to examine the degree to which a relatively high versus a relatively low cocaine-training dose influenced the interactions between the discriminative stimulus effects of cocaine and either the mu opioid agonist morphine or the kappa opioid agonist U50,488. The results demonstrated that cocaine-opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of mu and kappa opioid receptors in modifying the discriminative stimulus effects of cocaine. Another objective of our studies was to determine if variations in opioid pretreatment time would affect how mu opioid agonists interact with cocaine. The results reflect the complexity of morphine-cocaine interactions. The mechanisms underlying morphine enhancement of cocaine’s discriminative stimulus effects at 1 hr may be related to the development of acute morphine tolerance, while the mechanisms underlying morphine attenuation of cocaine’s discriminative stimulus effects at 4 hr may be related to the development of acute morphine dependence.

From a clinical perspective, understanding the behavioral effects of cocaine under conditions of acute opioid tolerance or dependence is relevant because the two drugs may be co-abused, but at different times. A well-known pattern of circumstances leading to speedball abuse, or simultaneous abuse of cocaine and opioid, is the heroin addict, who periodically adds cocaine for either its pleasurable effects or as an additive to relieve physiological stress associated with heroin withdrawal during detoxification. Thus, temporal parameters are important because motivational changes possibly related to opioid dependence and withdrawal may play a role in altering sensitivity to the subjective state produced by a second centrally active drug, such as cocaine. Elucidation of the mechanisms underlying morphine-cocaine interactions is far from complete and further studies are needed to clarify the interaction of CNS cellular and molecular mechanisms related to cocaine and opioid abuse.

Publications related to this project

Kantak K.M., A. Riberdy and R.D. Spealman. Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine. Psychopharmacology, 147:257-265,1999

Green-Jordan, K., Warren, L. and Kantak, K.M. Temporal factors affecting cocaine-opioid interactions: a cocaine drug discrimination study. Psychopharmacology, 156: 427-34, 2001

Facilities

Current Projects

Past Projects