Abstract
Rationale
Psychotomimetic N-methyl-d-aspartate/glutamate receptor antagonists, such as phencyclidine (PCP), have been shown to produce a spectrum of behavioral, neurochemical and anatomical changes in rats that are relevant to aspects of schizophrenia, including impairments of working memory and visual attention. The alpha2 noradrenergic receptor agonist clonidine prevents some of the behavioral effects of NMDA antagonists, suggesting that monoaminergic systems mediate some aspects of these deficits.
Objectives
We sought to determine the ability of clonidine to modify the PCP-induced deficits of visual attention and spatial working memory in rats.
Results
In a lateralized reaction time task, a lower dose of clonidine (10 μg/kg) ameliorated the impairment of choice accuracy produced by PCP (2.5 mg/kg, IP), while the higher dose of clonidine (50 μg/kg) slowed response times and induced a deficit of choice accuracy on its own. The high dose of clonidine effectively prevented the motor impulsivity produced by PCP. In addition, clonidine (10 μg/kg) prevented PCP-induced performance deficits in a delayed non-match to sample task.
Conclusions
These data indicate that clonidine may attenuate deficits of attention and working memory produced by PCP, perhaps in part by preventing some of the downstream neurochemical and anatomical effects of this psychotomimetic drug.
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References
Andrews GD, Nogueira L, Lavin A (2003) Characterization of noradrenergic effects on pyramidal neurons: In vivo and in vitro studies. Society for Neuroscience, p 461.4
Aoki C, Venkatesan C, Go CG, Forman R, Kurose H (1998) Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons. Cereb Cortex 8:269–277
Arnsten AF, Goldman-Rakic PS (1985) Alpha2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276
Brozoski TJ, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–932
Bushnell PJ, Oshiro WM, Padnos BK (1997) Detection of visual signals by rats: effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention. Psychopharmacology 134:230–241
Carli M, Evenden JL, Robbins TW (1985) Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention. Nature 313:679–682
Chergui K, Akaoka H, Brunet JL, Charlety PJ, Saunier CF, Buda M, Privat A, Vignon J, Kamenka JM, Chouvet G (1992) Inhibition of locus coeruleus neurons by the phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine: evidence for potent indirect adrenoceptor agonist properties. Eur J Pharmacol 219:169–172
Coan EJ, Collingridge GL (1987) Effects of phencyclidine, SKF 10,047 and related psychotomimetic agents on N-methyl-d-aspartate receptor mediated synaptic responses in rat hippocampal slices. Br J Pharmacol 91:547–556
Coull JT (1994) Pharmacological manipulations of the alpha2-noradrenergic system. Effects on cognition. Drugs Aging 5:116–126
Deutch AY, Tam SY, Freeman AS, Bowers MB, Jr., Roth RH (1987) Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response. Eur J Pharmacol 134:257–264
Duncan EJ, Madonick SH, Parwani A, Angrist B, Rajan R, Chakravorty S, Efferen TR, Szilagyi S, Stephanides M, Chappell PB, Gonzenbach S, Ko GN, Rotrosen JP (2001) Clinical and sensorimotor gating effects of ketamine in normals. Neuropsychopharmacology 25:72–83
Farber NB, Foster J, Duhan NL, Olney JW (1995) Alpha2 adrenergic agonists prevent MK-801 neurotoxicity. Neuropsychopharmacology 12:347–349
Fields RB, Van Kammen DP, Peters JL, Rosen J, Van Kammen WB, Nugent A, Stipetic M, Linnoila M (1988) Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res 1:417–423
Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, White L, Parrella M, Davis KL (2001) Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology 25:402–409
Greene R (2001) Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 11:569–577
Gresch PJ, Sved AF, Zigmond MJ, Finlay JM (1995) Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex. J Neurochem 65:111–116
Grottick AJ, Higgins GA (2000) Effect of subtype selective nicotinic compounds on attention as assessed by the five-choice serial reaction time task. Behav Brain Res 117:197–208
Guillermain Y, Micallef J, Possamai C, Blin O, Hasbroucq T (2001) N-Methyl-d-aspartate receptors and information processing: human choice reaction time under a subanaesthetic dose of ketamine. Neurosci Lett 303:29–32
Gutnikov SA, Barnes JC, Rawlins JN (1994) Working memory tasks in five-choice operant chambers: use of relative and absolute spatial memories. Behav Neurosci 108:899–910
Harkin A, Morris K, Kelly JP, O’Donnell JM, Leonard BE (2001) Modulation of MK-801-induced behaviour by noradrenergic agents in mice. Psychopharmacology 154:177–188
Hertel P, Nomikos GG, Schilstrom B, Arborelius L, Svensson TH (1997) Risperidone dose-dependently increases extracellular concentrations of serotonin in the rat frontal cortex: role of alpha2-adrenoceptor antagonism. Neuropsychopharmacology 17:44–55
Jakala P, Riekkinen M, Sirvio J, Koivisto E, Riekkinen P, Jr. (1999) Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers. Neuropsychopharmacology 21:495–502
Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308
Jentsch JD (2003) Genetic vasopressin deficiency facilitates performance of a lateralized reaction time task: altered attention and motor processes. J Neurosci 23:1066–1071
Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20:201–225
Jentsch JD, Taylor JR (2003) Sex differences in visuospatial divided attention and motor impulsivity in rats. Behav Neurosci 117:76–83
Jentsch JD, Wise A, Katz Z, Roth RH (1998) Alpha-noradrenergic receptor modulation of the phencyclidine- and delta9-tetrahydrocannabinol-induced increases in dopamine utilization in rat prefrontal cortex. Synapse 28:21–26
Jin J, Yamamoto T, Watanabe S (1997) The involvement of sigma receptors in the choice reaction performance deficits induced by phencyclidine. Eur J Pharmacol 319:147–152
Kim SH, Price MT, Olney JW, Farber NB (1999) Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and alpha2-adrenergic agonists. Mol Psychiatry 4:344–352
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214
Krystal JH, Anand A, Moghaddam B (2002) Effects of NMDA receptor antagonists: implications for the pathophysiology of schizophrenia. Arch Gen Psychiatry 59:663–664
Kubota T, Hirota K, Yoshida H, Takahashi S, Anzawa N, Ohkawa H, Kushikata T, Matsuki A (1999a) Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats. Psychopharmacology 146:335–338
Kubota T, Hirota K, Yoshida H, Takahashi S, Ohkawa H, Anzawa N, Kushikata T, Matsuki A (1999b) Inhibitory effect of clonidine on ketamine-induced norepinephrine release from the medial prefrontal cortex in rats. Br J Anaesth 83:945–947
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A (1996) NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 14:301–307
McCann DJ, Rabin RA, Winter JC (1987) Interactions of clonidine with phencyclidine and ketamine: studies of radial maze performance and righting reflex in rats. Pharmacol Biochem Behav 26:23–28
Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352
Murase S, Nisell M, Grenhoff J, Svensson TH (1992) Decreased sensory responsiveness of noradrenergic neurons in the rat locus coeruleus following phencyclidine or dizocilpine (MK-801): role of NMDA antagonism. Psychopharmacology 109:271–276
Newcomer JW, Krystal JH (2001) NMDA receptor regulation of memory and behavior in humans. Hippocampus 11:529–542
Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106–118
Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33:523–533
Oranje B, van Berckel BN, Kemner C, van Ree JM, Kahn RS, Verbaten MN (2000) The effects of a sub-anaesthetic dose of ketamine on human selective attention. Neuropsychopharmacology 22:293–302
Presburger G, Robinson JK (1999) Spatial signal detection in rats is differentially disrupted by delta-9-tetrahydrocannabinol, scopolamine, and MK-801. Behav Brain Res 99:27–34
Sams-Dodd F (1999) Phencyclidine in the social interaction test: an animal model of schizophrenia with face and predictive validity. Rev Neurosci 10:59–90
Stefani MR, Moghaddam B (2002) Effects of repeated treatment with amphetamine or phencyclidine on working memory in the rat. Behav Brain Res 134:267–274
Tamminga CA (1998) Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12:21–36
Tang AH, Franklin SR (1983) Disruption of brightness discrimination in a shock avoidance task by phencyclidine and its antagonism in rats. J Pharmacol Exp Ther 225:503–508
Terry AV Jr, Risbrough VB, Buccafusco JJ, Menzaghi F (2002) Effects of (±)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a selective ligand for nicotinic acetylcholine receptors, in tests of visual attention and distractibility in rats and monkeys. J Pharmacol Exp Ther 301:284–292
Tsai G, Coyle JT (2002) Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42:165–179
Varvel SA, Hamm RJ, Martin BR, Lichtman AH (2001) Differential effects of delta 9-THC on spatial reference and working memory in mice. Psychopharmacology 157:142–150
Witte EA, Marrocco RT (1997) Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting. Psychopharmacology 132:315–323
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Jentsch, J.D., Anzivino, L.A. A low dose of the alpha2 agonist clonidine ameliorates the visual attention and spatial working memory deficits produced by phencyclidine administration to rats. Psychopharmacology 175, 76–83 (2004). https://doi.org/10.1007/s00213-004-1772-3
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DOI: https://doi.org/10.1007/s00213-004-1772-3