Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats. 2014

Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
Department of Psychology, Virginia Commonwealth University, PO Box 842018, 806 West Franklin Street, Richmond, 23284, VA, USA.

BACKGROUND The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern. OBJECTIVE This study examined abuse-related effects of ketamine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison. METHODS Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency-rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2-10.0 mg/kg) and MK-801 (0.032-0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2-20.0 mg/kg/day) and acute cocaine (10.0 mg/kg). RESULTS Following acute administration, ketamine (3.2-10 mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032-0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS. CONCLUSIONS The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.

UI MeSH Term Description Entries
D007649 Ketamine A cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (RECEPTORS, N-METHYL-D-ASPARTATE) and may interact with sigma receptors. 2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone,CI-581,Calipsol,Calypsol,Kalipsol,Ketalar,Ketamine Hydrochloride,Ketanest,Ketaset,CI 581,CI581
D008297 Male Males
D008474 Medial Forebrain Bundle A complex group of fibers arising from the basal olfactory regions, the periamygdaloid region, and the septal nuclei, and passing to the lateral hypothalamus. Some fibers continue into the tegmentum. Median Forebrain Bundle,Bundle, Medial Forebrain,Bundle, Median Forebrain,Bundles, Medial Forebrain,Bundles, Median Forebrain,Forebrain Bundle, Medial,Forebrain Bundle, Median,Forebrain Bundles, Medial,Forebrain Bundles, Median,Medial Forebrain Bundles,Median Forebrain Bundles
D003042 Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Cocaine HCl,Cocaine Hydrochloride,HCl, Cocaine,Hydrochloride, Cocaine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D000778 Anesthetics, Dissociative Intravenous anesthetics that induce a state of sedation, immobility, amnesia, and marked analgesia. Subjects may experience a strong feeling of dissociation from the environment. The condition produced is similar to NEUROLEPTANALGESIA, but is brought about by the administration of a single drug. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Dissociative Anesthetics
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012653 Self Stimulation The act or process of inducing or increasing the level of arousal in oneself. It can be observed in various situations; for example, infants who are understimulated may explore their surroundings or babble to themselves.(https://dictionary.apa.org/self-stimulation accessed 12/30/2020) ICSS Intracranial Self-Stimulation,Intracranial Self Stimulation,Self-Stimulation,Intracranial Self Stimulations,Self Stimulation, Intracranial,Self Stimulations,Self Stimulations, Intracranial,Self-Stimulations,Stimulation, Self,Stimulations, Self
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor
D016194 Receptors, N-Methyl-D-Aspartate A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity. N-Methyl-D-Aspartate Receptor,N-Methyl-D-Aspartate Receptors,NMDA Receptor,NMDA Receptor-Ionophore Complex,NMDA Receptors,Receptors, NMDA,N-Methylaspartate Receptors,Receptors, N-Methylaspartate,N Methyl D Aspartate Receptor,N Methyl D Aspartate Receptors,N Methylaspartate Receptors,NMDA Receptor Ionophore Complex,Receptor, N-Methyl-D-Aspartate,Receptor, NMDA,Receptors, N Methyl D Aspartate,Receptors, N Methylaspartate

Related Publications

Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
September 2016, European journal of pain (London, England),
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
January 1991, European journal of pharmacology,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
October 2001, Neuropharmacology,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
October 1992, Pharmacology, biochemistry, and behavior,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
September 1996, Pharmacology, biochemistry, and behavior,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
January 2001, Developmental neuroscience,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
June 1990, The Japanese journal of psychiatry and neurology,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
May 1997, European journal of pharmacology,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
April 1990, Pharmacology, biochemistry, and behavior,
Todd M Hillhouse, and Joseph H Porter, and S Stevens Negus
December 1994, Biophysical journal,
Copied contents to your clipboard!