Abstract
Rationale
The cognitive functions of the prefrontal cortex (PFC) are profoundly impaired in schizophrenic patients. Although dopamine has been the major focus of schizophrenia research, norepinephrine (NE) also has marked influences on PFC cognitive functioning.
Objective
This review aims to identify the adrenergic receptors which may be appropriate targets for therapeutic actions in schizophrenia.
Methods
Studies of adrenergic mechanisms influencing PFC function in animals and humans were reviewed.
Results
Modest levels of NE engage postsynaptic α2A-adrenergic receptors and strengthen working memory. These beneficial effects have been observed at both the behavioral and cellular levels in animals, and have translated to the clinic in patients with PFC impairments. Thus, the α2A-adrenergic receptor is a proven molecular target. In contrast, high levels of NE released during stress impair PFC cognitive function via activation of protein kinase C intracellular signaling, a pathway increasingly associated with the etiology of schizophrenia. Blockade of α1 adrenoceptors or inhibition of protein kinase C helps to protect PFC cognitive function in animals, and may have similar therapeutic actions in humans. Blockade of the α2C receptor may also be helpful in enhancing catecholamine release while blocking detrimental DA actions in striatum.
Conclusion
Highly selective adrenergic agents may be useful for enhancing PFC function in schizophrenic patients
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References
Aoki C, Go C-G, Venkatesan C, Kurose H (1994) Perikaryal and synaptic localization of alpha2A-adrenergic receptor-like immunoreactivity. Brain Res 650:181–204
Aoki C, Venkatesan C, Go C-G, 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 AFT (1997) Catecholamine regulation of the prefrontal cortex. J Psychopharmacol 11:151–162
Arnsten AFT (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cognit Sci 2:436–447
Arnsten AFT, Cai JX (1993) Postsynaptic alpha-2 receptor stimulation improves working memory in aged monkeys: indirect effects of yohimbine vs. direct effects of clonidine. Neurobiol Aging 14:597–603
Arnsten AFT, Contant TA (1992) Alpha-2 adrenergic agonists decrease distractability in aged monkeys performing a delayed response task. Psychopharmacology 108:159–169
Arnsten AFT, Goldman-Rakic PS (1985) Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276
Arnsten AFT, Goldman-Rakic PS (1986) Reversal of stress-induced delayed response deficits in rhesus monkeys by clonidine and naloxone. Soc Neurosci Abstr 12:1464
Arnsten AFT, Goldman-Rakic PS (1998) Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 55:362–369
Arnsten AFT, Robbins TW (2002) Neurochemical modulation of prefrontal cortical function in humans and animals. In: Stuss DT, Knight RT (eds) Principles of frontal lobe function. Oxford University Press, New York, pp 51–84
Arnsten AFT, Cai JX, Goldman-Rakic PS (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects. J Neurosci 8:4287–4298
Arnsten AFT, Steere JC, Hunt RD (1996) The contribution of alpha-2 noradrenergic mechanisms to prefrontal cortical cognitive function: potential significance to attention deficit hyperactivity disorder. Arch Gen Psychiatry 53:448–455
Arnsten AFT, Mathew R, Ubriani R, Taylor JR, Li B-M (1999) Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function. Biol Psychiatry 45:26–31
Baldessarini RJ, Huston-Lyons D, Campbell A, Marsh E, Cohen BM (1992) Do central antiadrenergic actions contribute to the atypical properties of clozapine? Br J Psychiatry 160:12–16
Birnbaum SG, Gobeske KT, Auerbach J, Taylor JR, Arnsten AFT (1999) A role for norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in prefrontal cortex. Biol Psychiatry 46:1266–1274
Brozoski T, Brown RM, Rosvold HE, Goldman PS (1979) Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 205:929–931
Cai JX, Arnsten AFT (1997) Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 282:1–7
Cai JX, Ma Y, Xu L, Hu X (1993) Reserpine impairs spatial working memory performance in monkeys: reversal by the alpha-2 adrenergic agonist clonidine. Brain Res 614:191–196
Carlson S, Tanila H, Rama P, Mecke E, Pertovaara A (1992) Effects of medetomidine, an alpha-2 adrenoceptor agonist, and atipamezole, an alpha-2 antagonist, on spatial memory performance in adult and aged rats. Behav Neural Biol 58:113–119
Cedarbaum JM, Aghajanian GK (1977) Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Eur J Pharmacol 44:375–385
Cohen BM, Lipinski JF (1986) In vivo potencies of antipsychotic drugs in blocking alpha-1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci 39:2571–2580
Coull JT (1994) Pharmacological manipulations of the a-2 noradrenergic system: effects on cognition. Drugs Aging 5:116–126
Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995) Contrasting effects of clonidine and diazepam on tests of working memory and planning. Psychopharmacology 120:311–321
Coull JT, Frith CD, Dolan RJ, Frackowiak RS, Grasby PM (1997) The neural correlates of the noradrenergic modulation of human attention, arousal and learning. Eur J Neurosci 9:589–598
Darracq L, Blanc G, Glowinski J, Tassin J-P (1998) Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of d-amphetamine. J Neurosci 18:2729–2739
Duman RS, Nestler EJ (1995) Signal transduction pathways for catecholamine receptors. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven Press, N.Y., pp 303–320
Ferry B, Roozendaal B, McGaugh JL (1999) Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between beta- and alpha-1-adrenoceptors. J Neurosci 19:5119–5123
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. Schizophr Res 1:417–423
Franowicz JCS, Arnsten AFT (1998) The alpha2A noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136:8–14
Franowicz JS, Kessler L, Dailey-Borja CM, Kobilka BK, Limbird LE, Arnsten AFT (2002) Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci 22:8771–8777
Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, White L, Parrella M, Davis KL (2001) Guanfacine treatment of cognitive impairment in schizophrenia: a pilot study. Neuropsychopharmacology (in press)
Funahashi S, Bruce CJ, Goldman-Rakic PS (1989) Mnemonic coding of visual space in the monkey’s dorsolateral prefrontal cortex. J Neurophysiol 61:331–349
Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW (2000) Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 20:1208–1215
Haroutunian V, Kanof PD, Tsuboyama G, Davis KL (1990) Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats. Brain Res 507:261–266
Hertel P, Fagerquist MV, Svensson TH (1999) Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade. Science 286:105–107
Hunt RD, Mindera RB, Cohen DJ (1985) Clonidine benefits children with attention deficit disorder and hyperactivity: reports of a double-blind placebo-crossover therapeutic trial. J Am Acad Child Psychiatry 24:617–629
Jackson WJ, Buccafusco JJ (1991) Clonidine enhances delayed matching-to-sample performance by young and aged monkeys. Pharmacol Biochem Behav 39:79–84
Jakala P, Riekkinen M, Sirvio J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen PJ (1999a) Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20:460–470
Jakala P, Sirvio J, Riekkinen M, Koivisto E, Kejonen K, Vanhanen M, Riekkinen PJ (1999b) Guanfacine and clonidine, alpha-2 agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropsychopharmacology 20:119–130
Koh PO, Bergson C, Undie AS, Goldman-Rakic PS, Lidow MS (2003) Up-regulation of the D1 dopamine receptor-interacting protein, calcyon, in patients with schizophrenia. Arch Gen Psychiatry 60:311–319
Lezcano N, Mrzljak L, Eubanks S, Levenson R, Goldman-Rakic PS, Bergson C (2000) Dual signaling regulated by calcyon, a D1 dopamine receptor interacting protein. Science 287:1660–1664
Li B-M, Mei Z-T (1994) Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol 62:134–139
Li B-M, Mao Z-M, Wang M, Mei Z-T (1999) Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys. Neuropsychopharmacology 21:601–610
Lidow MS (2003) Calcium signaling dysfunction in schizophrenia: a unifying approach. Brain Res Rev (in press)
MacDonald E, Kobilka BK, Scheinin M (1997) Gene targeting—homing in on alpha-2-adrenoceptor subtype function. Trends Pharmacol Sci 18:211–219
Mair RG, McEntree WJ (1986) Cognitive enhancement in Korsakoff’s psychosis by clonidine: a comparison with 1-dopa and ephedrine. Psychopharmacology 88:374–380
Manji HK, Lenox RH (1999) Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry 46:1328–1351
Manji HK, Lenox RH (2000) Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry 48:518–30
Manji HK et al. (2004) Psychopharmacology (in press)
Mao Z-M, Arnsten AFT, Li B-M (1999) Local infusion of alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol Psychiatry 46:1259–1265
Marek GJ, Aghajanian GK (1998) 5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by mu-opiate receptor activation. Neuroscience 86:485–497
Marek GJ, Aghajanian GK (1999) 5-HT2A receptor or alpha1-adrenoceptor activation induces EPSCs in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206
Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100:6186–6191
Mazure CM (1995) Does stress cause psychiatric illness? In: Spiegel D (ed) Progress in psychiatry. American Psychiatric Press, Washington, D.C., p 270
Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P (2001) Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 6:293–301
Moffoot A, O’Carroll RE, Murray C, Dougall N, Ebmeier K, Goodwin GM (1994) Clonidine infusion increases uptake of Tc-exametazime in anterior cingulate cortex in Korsakoff’s psychosis. Psychol Med 24:53–61
Murphy BL, Arnsten AFT, Goldman-Rakic PS, Roth RH (1996) Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci USA 93:1325–1329
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:106–118
Rama P, Linnankoski I, Tanila H, Pertovaara A, Carlson S (1996) Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys. Pharmacol Biochem Behav 54:1–7
Riekkinen P, Riekkinen M (1999) THA improves word priming and clonidine enhances fluency and working memory in Alzheimer’s disease. Neuropsychopharmacology 20:357–364
Sawaguchi T (1998) Attenuation of delay-period activity of monkey prefrontal cortical neurons by an alpha-2 adrenergic antagonist during an oculomotor delayed-response task. J Neurophysiol 80:2200–2205
Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950
Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, Arnsten AFT, Cohen DJ, Leckman JF (2001) Guanfacine in the treatment of children with tic disorders and ADHD: a placebo-controlled study. Am J Psychiatry 158:1067–1074
Tanila H, Rama P, Carlson S (1996) The effects of prefrontal intracortical microinjections of an alpha-2 agonist, alpha-2 antagonist and lidocaine on the delayed alternation performance of aged rats. Brain Res Bull 40:117–119
Taylor FB, Russo J (2001) Comparing guanfacine and dextroamphetamine for the treatment of adult attention deficit-hyperactivity disorder. J Clin Psychopharmacol 21:223–228
van Kammen DP, Kelley M (1991) Dopamine and norepinephrine activity in schizophrenia. An integrative perspective. Schizophr Res 4:173–191
Williams GV, Goldman-Rakic PS (1995) Blockade of dopamine D1 receptors enhances memory fields of prefrontal neurons in primate cerebral cortex. Nature 376:572–575
Zahrt J, Taylor JR, Mathew RG, Arnsten AFT (1997) Supranormal stimulation of dopamine D1 receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci 17:8528–8535
Acknowledgements
This research was supported by MERIT Award AG06036 and P50mH068789.
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Arnsten, A.F.T. Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology 174, 25–31 (2004). https://doi.org/10.1007/s00213-003-1724-3
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DOI: https://doi.org/10.1007/s00213-003-1724-3