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Stress impairs prefrontal cortical function in rats and monkeys: role of dopamine D1 and norepinephrine α-1 receptor mechanisms
H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.G.P. Feenstra and C.M.A. Pennartz Progress in Brain Research,Vo1126 © 2000 Elsevier Science BV. All rights reserved.
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Stress impairs prefrontal cortical function in rats and monkeys: role of dopamine D 1 and norepinephrine oL-1 receptor mechanisms Amy ET. Arnsten Sect. Neurobiology, Yale Medical School, 333 Cedar St., New Haven, CT 06520-8001, USA
Introduction The prefrontal cortex (PFC) is critical for guiding behavior using working memory (Goldman-Rakic, 1987); working memory is constantly updated; these memories may be called up from long-term storage or from recent buffers. The PFC uses this representational knowledge to guide behavior effectively, freeing the organism from its dependence on the environment, inhibiting inappropriate responses or distractions and allowing us to plan and organize our behavior (Robbins, 1996). Animals or humans with lesions to the PFC can exhibit poor attention regulation, disorganized or perseverative behavior, hyperactivity and impulsivity (Stuss et al., 1994). PFC functions are impaired by uncontrollable stress in humans and animals Studies in humans, monkeys and rats have shown that acute exposure to mild uncontrollable stress impairs cognitive functions associated with the PFC. The original work of Broadbent, Hockey and others showed that exposing human subjects to loud noise stress improved reaction time on wellrehearsed or simple tasks, but impaired performance of more complex tasks (Broadbent, Corresponding author: Tel.: 203-785-4431; Fax: 203-785-5263; e-mail: [email protected]
1971), especially when the subjects experienced themselves as having no control over the stressor (Glass et al., 1971). Loud noise stress impaired the ability to sustain attention (Hockey, 1970), or to inhibit prepotent, inappropriate responses on the Stroop interference test (Hartley and Adams, 1974), functions associated with the PFC (Perret, 1974; Wilkins et al., 1987; Coull et al., 1998; Peterson et al., 1999). Monkeys exposed to the same stressor used in the human studies, loud noise (110 dB), are significantly impaired on performance of the spatial delayed response task (Arnsten and GoldmanRakic, 1998), a test of working memory dependent upon the dorsolateral PFC surrounding the principal sulcus (Goldman and Rosvold, 1970). Stress-exposed monkeys show no impairment following '0' sec delay control trials, but are impaired when performance depended upon working memory (Arnsten and Goldman-Rakic, 1998). Similar results are observed when monkeys are administered a pharmacological stressor, the benzodiazepine inverse agonist FG7142 (Murphy et al., 1996). Administration of FG7142 also impairs spatial working memory performance in rats, as measured by the delayed alternation task in a T maze (Murphy et al., 1996; Birnbaum et al., 1999a). In contrast to these PFC tasks, stress exposure has little effect, or actually improves performance of tasks dependent upon the inferior
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temporal cortex (Arnsten and Goldman-Rakic, 1998), parietal cortex (Murphy et al., 1996), or cerebellum (Shors et al., 1992). Thus, the working memory and attention functions of the PFC appear to be particularly vulnerable to the effects of uncontrollable stress. As discussed later, it may be adaptive to have the PFC go 'off-line' during some types of dangerous situations in which it is helpful to react rapidly and reflexively, without PFC guidance. It has long been appreciated that catecholamine turnover is increased in the PFC during exposure to stress e.g. (Thierry et al., 1976; Deutch and Roth, 1990; Finlay et al., 1995; Goldstein et al., 1996). The following briefly reviews the evidence suggesting that high levels of DA acting at D 1 receptors, and high levels of NE acting at c~-i receptors, contribute to stress-induced deficits in working memory function (Fig. 1).
The role of DA in stress-induced working memory deficits: D1 receptors and cAMP/ protein ldnase A intraeellular signalling pathways Low to moderate levels of DA activity are necessary for PFC working memory (Brozoski et al., 1979; Simon, 1981; Bubser and Schmidt, 1990) and attention (Robbins et al., 1998) functions, and activation of D1 receptors appears particularly important in this regard (Sawaguchi et al., 1988; Sawaguchi and Goldman-Rakic, 1991; Seamans et al., 1998, but see Broersen et al., 1994). However, accumulating evidence indicates that high levels of DA receptor stimulation in the PFC impairs working memory function. The working memory deficits induced by stress exposure in rats or monkeys can be blocked by pretreatment with DA receptor antagonists, including the D1 receptor antagonist, SCH23390 (Fig. 2A; Arnsten and Goldman-Rakic, 1990; Murphy et al., 1996; Arnsten and Goldman-Rakic, 1998). Stress-induced working memory deficits correlate with the rise in DA turnover in PFC (Murphy et al., 1996). Conversely, stress-induced working memory deficits can be mimicked by the administration of a D1 receptor agonist. Infusion of a full D 1 agonist (0.1 p~g/0.5 Ixl SKF81297) directly into the PFC in rats impairs working memory performance and pro-
duces a mildly perseverative pattern of response, much as is seen in stressed rats (Zahrt et al., 1997). These deficits can be reversed by pretreatment with a D1 receptor antagonist, consistent with actions at D1 receptors (ibid). Electrophysiological studies of PFC neurons have also shown that high levels of D1 receptor stimulation can erode neuronal function. For example, the iontophoresis of low concentrations of D1 receptor antagonists can increase memory-related neuronal responses in monkeys performing a challenging working memory task (Williams and Goldman-Rakic, 1995). Conversely, intracellular recordings of pyramidal cells from rodent PFC slices have shown that D1 receptor stimulation decreases the n and p calcium currents that convey
IMPAIRED PFC FUNCTION
PKC
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PP1
J PKA ~cAMP
p~ho-
adenylyl
(x'l o I
j D2
~
high levelsof release e.g. duringstress ~/~
Fig. 1. Highly schematized illustration of the receptor mechanisms and intracellular pathways contributing to impaired PFC function during stress. Evidence to date suggest that high levels of DA impair working memory through actions at D1/D5 receptors coupled to Gs/PKA pathways. DA may also impair through actions at D2/D4 receptors (not shown) which may be concentrated on interneurons. High levels of NE appear to impair working memory through actions at et-1 receptors coupled to Gq/PKC pathways.
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signals from dendrite to soma (Yang and Seamans, 1996). Optimal levels of D1 receptor stimulation appear to focus signal transmission, conveying only large or temporally-coincident signals to the cell body (Yang and Seamans, 1996). However, higher concentrations of dopamine or a D 1 agonist abolish calcium currents, effectively preventing informaA,
DA D1 ANTAGONIST BLOCKS STRESS -INDUCED WORKING MEMORY IMPAIRMENT
~1~I
tion transfer from dendrite to soma (Yang and Seamans, 1996; Zahrt et al., 1997; schematically represented in Fig, 2C and Fig. 2D). This interruption of information transfer may underlie the working memory impairment seen at high levels of D1 receptor stimulation; animals' behavior may become perseverative, as no new spatial informa-
C.S CA1 D. IMPAIRED SIGNAL TRANSFER TO SOMA
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2
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.
~
DA AJ FROk S.
NE al ANTAGONIST BLOCKS 8TRESS -INDUCED WORKING MEMORY IMPAIRMENT ~100I t
VEH VEH URA URA VEH STR VEH STR ~$
cue cleby response OF QIELIkY-I~I.ATEDACTIVITY
Fig. 2. Hypothetical model of how DA D1 and NE (x-1 receptor actions may impair PFC function during stress by interrupting signal transmission from the dendrite to the soma. (A) Stress-induced working memory deficits in monkeys are blocked by pretreatment with the DA D1 receptor antagonist, SCH23390. Monkeys were exposed to loud noise stress (about 105 dB white noise) or normal levels of background noise (about 70dB) following injection of saline vehicle or SCH23390 (0.01-0.1 mg/kg, i.m.). Results represent mean per cent correct _+S.E.M. on the spatial delayed response task. Adapted from Arnsten and Goldman-Rakic, 1998. A similar response is observed in rats (Murphy et al., 1996). VEH=vehicle, CON=control noise conditions, STR=noise stress conditions, SCH = SCH23390, *significantly different than vehicle control, significantly different than vehicle stress. (B) Stress-induced working memory deficits in rats are blocked by intra-PFC infusions of the NE c~-1 receptor antagonist, urapidil. Rats were injected with vehicle or the pharmacological stressor, FG7142 (30 mg/kg, i.p.) prior to intra-PFC infusion of vehicle or urapidil (0.1 p,g/0.5 txl). Results represent mean per cent correct _+S.E.M. on the spatial delayed alternation task. Adapted from Bimbaum et al., 1999. VEH = vehicle, STR=stress, URA=urapidil, *significantly different from vehicle/vehicle, tsignificantly different from stress/vehicle. (C) Hypothetical model depicting how DA D1/D5 and NE et-1 receptor actions may impair PFC function during stress by interupting signal transmission from the dendrite to the soma. Catecholamine levels may rise near the primary dendritic shaft during stress due to increased catecholamine release and blockade of extraneuronal catecholamine transporters (ECT) by circulating steroids (Grundemann et al., 1998). High levels of DA may stimulate D5 receptors on the dendritic shaft, activating PKA (Surmeier et al., 1995) and reducing the high threshold calcium currents which normally convey signals to the soma (Yang and Seamans, 1996). High levels of NE may increase 'noise' in the proximal dendritic stem by evoking glutamate release, which in turn increases sodium entry into the proximal dendritic stem (Marek and Aghajanian, 1999). This mechanism is likely mediated by PKC. (D) Hypothetical changes in signal transmission from the dendritic tree to the soma. (1) a signal enters the primary dendritic shaft for conveyance to the soma; (2) the signal is reduced by D1/D5 receptor stimulation due to closing of n and p calcium channels that normally convey signals to the soma; (3) 'noise' is increased in the proximal dendritic stem due to NE et-1 excitation of non-specific glutamate release; (4) due to reduced signal and/or increased noise no new information is able to reach the soma, thus preventing the relative increase in delayrelated activity which would normally guide behavior thoughtfully. Without new information to guide responses, the animal may respond in a perseverative manner.
186 tion can access the soma to change response patterns (Figure 2D4). The work of Surrneier et al., (1995) indicates that DA D1 receptor stimulation can decrease n and p calcium currents through activation of a cAMPprotein kinase A (PKA) intracellular signalling pathway. Ongoing studies in our lab suggest that the deficits in delayed alternation performance induced by D1 agonist infusion may also involve activation of a cAMP-PKA intracellular pathway (Fig. 1). Thus, intra-PFC infusion of the PKA activator, Sp-cAMPS, produces a dose-dependent impairment in delayed alternation performance that mimics the effects of a D1 agonist or stress (Taylor et al., 1999). The impairment induced by SpcAMPS is reversed by co-infusion of the PKA inhibitor, Rp-cAMPS, which has no effect on its own (ibid). This response profile is consistent with drug actions on PKA activity. Further studies are in progress to determine whether infusion of the PKA inhibitor, Rp-cAMPS, can reverse the effects of stress. There has been less research on the role of the D2 receptor family in the regulation of the stress response in PFC. Neuroleptics with potent D2 and D4 receptor blocking actions such as haloperidol (Murphy et al., 1996; Arnsten and Goldman-Rakic, 1998) and clozapine (Murphy et al., 1997) are effective in preventing stress-induced cognitive deficits in rats and monkeys, but these agents are not selective. Recent evidence suggests that a selective D4 receptor antagonist can protect cognitive performance from the effects of stress in monkeys but not rats (Arnsten et al., 2000), and that infusion of a D2 agonist into the rat PFC can induce working memory deficits (Druzin et al., 1999), but more research is needed in this area. It is likely that D2/D4 agents can have powerful effects on PFC function through their actions on interneurons, on which these receptors are concentrated (Mrzljak et al, 1996).
The role of NE in stress-induced working memory deficits: ~t-1 adrenoceptors and phosphotidyl inositol/protein kinase C intracellular signalling pathways More recently, we have focused on the contribution of elevated NE levels (Finlay et ai., 1995; Goldstein
et al., 1996) to the stress response in the PFC. Extensive evidence indicates that low levels of NE enhance the working memory and attention functions of the PFC through actions at post-synaptic oL-2A receptors (reviewed in Arnsten et al., 1996; Arnsten, 1998b). Thus, stimulation of tx-2 receptors in the PFC is essential for working memory as measured by cognitive performance (Arnsten and Goldman-Rakic, 1985; Li and Mei, 1994; Tanila et al., 1996; Mao et al., 1999) and delay-related firing (Sawaguchi and Kikuchi, 1998; Li et al., 1999). These beneficial effects result from actions at postsynaptic receptors (Arnsten and Goldman-Rakic, 1985; Cai et al., 1993) with an tx-2A receptor subtype pharmacology (Arnsten et al., 1988; Franowicz et al., 1998; Tanila et al., 1999). tx-2A receptors have been localized on the post-synaptic membrane of dendritic spines on pyramidal cells in monkey cortex (Aoki et al., 1994; Arnsten et al., 1996), and it is possible that some of these beneficial actions occur at these sites (schematically represented in Figure 2C). et-2 agonists have been shown to improve working memory and other PFC functions in mice (Franowicz et al., 1998; Tanila et al., 1999), rats (Carlson et al., 1992; Tanila et al., 1996), monkeys (Rama et al., 1996; Franowicz and Arnsten, 1998), and humans (Jakala et al., 1999a; 1999b). In humans, ~-2 agonists such as guanfacine are being used to treat patients with prominent symptoms of PFC dysfunction such as Attention Deficit Hyperactivity Disorder (Chappell et al., 1995; Horrigan and Barnhill, 1995; Hunt et al., 1995). or-2 agonists are especially potent in patients with NE depletion (McEntee and Mair, 1990). However, in contrast to the beneficial effects of o~-2A receptor stimulation, high levels of NE release may impair PFC function through actions at e~-I adrenoceptors. High levels of NE release may occur during stress or when the subject is agitated and spontaneous activity of the NE cells is high (Rajkowski et al, 1998). For example, working memory deficits due to stress exposure can be reversed by intra-PFC infusion of the NE oL-1 antagonist, urapidil (Fig. 2B; Birnbaum et al., 1999a). Interestingly, urapidil reversed the cognitive deficits, but not the non-cognitive aspects (e.g. freezing) of the stress response (ibid), suggesting
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that other components of the stress response are mediated by different brain regions (e.g. the PAG). Stress-induced working memory deficits can be mimicked by intra-PFC infusions of the et-1 agonist, phenylephrine, which like stress and D1 agonists induces a mildly perseverative pattern of response (Arnsten et al., 1999). Delayed alternation deficits induced by phenylephrine can be blocked by co-infusion of urapidil, consistent with actions at ~-l-adrenoceptors (ibid). Similar effects are observed in the non-human primate, where infusions of phenylephrine into the dorsolateral PFC surrounding the caudal two-thirds of the principal sulcus produce a marked, delay-related impairment in spatial working memory performance (Mao et al., 1999). Ablations of this same cortical region produce profound impairments in spatial working memory performance (Goldman and Rosvold, 1970). Phenylephrine infusions outside this cortical region are ineffective, demonstrating regional specificity for the drug effect (Mao et al., 1999). Working memory deficits in monkeys can also be produced by systemic administration of the ~-1 adrenoceptor agonist, cirazoline, a non-selective agonist which crosses the blood brain barrier (Arnsten and Jentsch, 1997). These results may explain why decongestants with ~-1 agonist properties such as pseudoephedrine can produce cognitive impairment in some individuals. Preliminary evidence suggests that the impairment induced by ct-1 adrenoceptor stimulation results from activation of the Gq-phosholipase Cprotein kinase C (PKC) intracellular pathway, the signalling pathway most commonly coupled to oL1-adrenoceptors (Fig. 1). For example, working memory deficits induced by intra-PFC phenylephrine infusions in rats can be blocked by pretreatment with a dose of lithium known to suppress turnover of this pathway (Arnsten et al., 1999). The phenylephrine response also appears to be reversed by co-infusion of the selective PKC inhibitor, chelerythrine (Birnbaum et al., 1999b). These results suggest that NE-induced PFC dysfunction results from activation of the Gq-PKC signalling pathway. NE oL-1 stimulation may impair PFC function by further eroding signal transfer from dendrite to soma (Fig. 2C). Marek and Aghajanian (1999) have
shown that NE et-1 stimulation increases excitatory post-synaptic currents in the dendritic stem by increasing glutamate release, thus adding 'noise' (Fig. 2D3). Thus, high levels of DA and NE may have additive or synergistic effects on information processing in PFC, reducing signals and increasing noise, respectively. We have speculated that high levels of both catecholamines may build in the extrasynaptic space during stress when extraneuronal catecholamine transporters which normally take up large concentrations of catecholamines are blocked by circulating steroids (schematically represented in Fig. 2C). Subjects with loss of dendritic spines (e.g. the elderly (Feldman and Dowd, 1975) or schizophrenic patients (Glantz and Lewis, 1995; Glantz and Lewis, 1997; Selemon et al., 1995)) may be particularly vulnerable to the detrimental effects of catecholamines due to a relative imbalance of these actions on dendritic shafts. The amygdala controls the 'catecholamine switch' during stress Although PFC cognitive functions are often essential for successful organization of high order behavior, there may be some conditions, e.g. acute danger, when it may be adaptive to 'shut down' these complex, reflective operations and to allow more automatic or habitual responses dependent on posterior cortical and subcortical structures to control our behavior (Arnsten, 1998a). The amygdala may play a critical role in shifting control of behavior from the PFC to posterior cortical and subcortical structures (schematically represented in Fig. 3), and it may accomplish this 'switch' of control, at least in part, by increasing catecholamine levels throughout the brain. This increase in catecholamine levels may enhance the functioning of subcortical and posterior cortical structures, but impair the functioning of the PFC. The importance of the amygdala for this function is underscored by the finding that stress-induced increases in catecholamine turnover are not observed in rats with lesions of the amygdala (Goldstein et al., 1996). The amygdala is thought to increase catecholamine turnover through its projec-
188
tions to DA and NE cell bodies (reviewed in Goldstein et al., 1996). The amygdala may also increase extrasynaptic catecholamine levels through hypothalamic projections which facilitate the release of steroids, which in turn block extraneuronal catecholamine transporters (Fig. 2C).
Activation of the amygdala may enhance associative learning and long term memory consolidation at the same time that it impairs working memory functions. Evidence from both animals and humans indicates that enhanced long term memory consolidation can be initiated by increased NE [3 receptor stimulation in the amyg-
NONSTRESS
STRESS
Fig. 3. Schematic illustration of the possible role of the amygdala in orchestrating cognitive changes in response to mild to moderate stress. During non-stress conditions (top picture), the PFC often controls behavior, inhibiting inappropriate processing and responding through its extensive connections to posterior cortical and subcortical structure. During uncontroUable stress (bottom picture), the amygdala may enhance the functioning of areas such as the amygdala and hippocampus (Packard and Teather, 1998), while impairing the functioning of the PFC by producing high levels of catecholamine release. The amygdala appears to be a critical structure for stimulating increased catecholamine turnover in the PFC during stress, as amygdala lesions prevent this response (Goldstein et al., 1996). The amygdala may increase catecholamine levels by directly exciting NE and DA neurons, and indirectly by increasing steroid release through its projections to hypothalamus. Steroids block the extraneuronai catecholamine transporters which normal take up high levels of catecholamines from the extrasynaptic space (Fig. 2C). The amygdala may be especially important for evoking these mechanisms during conditioned or psychological stressors (Davis, 1992; Schafe et al., 1999).
189 dala (Cahill et al., 1994; Cahill and McGaugh, 1996). Increased catecholamine release in the amygdala also has been shown to enhance the associative memory functions of the hippocampus and the habit memory functions of the slriatum (Packard and Teather, 1998). These mechanisms may enhance our long-term memory of the aversive event so that we might better avoid it in the future; (however, more severe stressors appear to impair hippocampal function and may produce amnesia (Kim and Yoon, 1998)). Increased catecholamine release in the sensory cortices might also alter attentional regulation, allowing attention to be 'captured' by prominent stimuli in the environment by increasing [3 and/or a-1 receptor enhancement of signal processing in sensory cortices (Foote et ai., 1975; Waterhouse et al., 1998). This hypothesis is consistent with the findings of Hockey (1970) who showed that stress narrows the focus of attention onto salient signals. Hockey also demonstrated that loud noise stress makes attention more labile (i.e. impairs the ability to sustain attention), and this change in attentional regulation may occur via or- 1 receptor impairment of PFC function. This hypothesis is consistent with the affinity of NE for the adrenergic receptors. NE has higher affinity for a-2A receptors (O'Rourke et al., 1994) than for ct-1 receptors (Mohell et al., 1983) or [3 receptors (Pepper1 and Regan, 1994). Functional studies also indicate that NE is more potent at e~-2 receptors than at ~-1 or [3 receptors (e.g. Atkinson and Minneman, 1991). Thus lower levels of NE release (e.g. during normal waking) may engage o~2A receptors and enhance PFC regulation of behavior. However, during stress, higher levels of NE would be released, engaging or-1 receptors and impairing PFC function, while enhancing the abilities of the posterior cortices and subcortical structures through actions at [3 and/or or-1 receptors. This neurochemical 'switch' may be helpful under many conditions, e.g. during dangerous circumstances that require rapid responding to stimuli in the environment, but may be problematic when PFC regulation of behavior is required, e.g. in a classroom setting. The discovery of neurochemical mechanisms which actively impair PFC function may help to explain why deficits in PFC function are prevalent in most neuropsychiatric
disorders, and why these disorders are often precipitated or exacerbated by exposure to stress (Mazure~ 1995).
Acknowledgement Much of the work in this chapter was supported by PHS MERIT Award AG06036 to AFTA.
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191 Jakala, P., Riekkinen, M., Sirvio, J., Koivisto, E., Kejonen, K., Vanhanen, M. and Riekkinen, EJ. (1999a) Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology, 20: 460-470. Jakala, E, Sirvio, J., Riekkinen, M., Koivisto, E., Kejonen, K., Vanhanen, M. and Riekkinen, EJ. (1999b) Guanfacine and clonidine, a-2 agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropsychopharmacology, 20:119-130. Kim, J.J. and Yoon, K.S. (1998) Stress: Metaplastic effects in the hippocampus. Trends Neurosci., 21: 505-509. Li, B.-M., Mao, Z.-M., Wang, M. and Mei, Z.-T. (1999) ct-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys. Neuropsychopharmacology, 21: 601-610. Li, B.-M. and Mei, Z.-T. (1994) Delayed response deficit induced by local injection of the et-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav. Neural. Biol., 62: 134-139. Mao, Z.-M., Arnsten, A.ET. and Li, B.-M. (1999) Local infusion of ct-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol. Psychiatry, 46: 1259-1265. Marek, G.J. and Aghajanian, G.K. (1999) 5-HT2A receptor or et-l-adrenoceptor activation induces EPSCs in layer V pyramidal cells of the medial prefrontal cortex. Eur. J. Pharmacol., 367: 197-206. Mazure, C.M. (1995) Does stress cause psychiatric illness? In: D. Spiegel (Ed.), Progress in Psychiatry Vol. 46, pp. 270. American Psychiatric Press: Washington, D.C. McEntee, W.J. and Mair, R.G. (1990) The Korsakoff syndrome: a neurochemical perspective. Trends Neurosci., 13: 340-344. Mohell, N., Svartengren, J. and Cannon, B. (1983) Identification of [3H]prazosin binding sites in crude membranes and isolated cells of brown adipose tissue as et-1 adrenergic receptors. Eur. J. Pharmacol., 92: 15-25. Mrzljak, L., Bergson, C., Pappy, M., Levenson, R., Huff, R., Goldman-Rakic, ES. (1996) Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature, 381: 245-248. Murphy, B., Roth, R. and Arnsten, A.ET. (1997) Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys. Neuropsychopharmacology, 16: 433-437. Murphy, B.L., Arnsten, A.ET., Goldman-Rakic, ES. and Roth, R.H. (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. O'Rourke, M.E, Blaxall, H.S., Iversen, L.J. and Bylund, D.B. (1994) Characterization of [3H]RX821002 binding to et-2 adrenergic receptor subtypes. J. Pharmacol. Exp. Ther., 268: 1362-1367. Packard, M.G. and Teather, L.A. (1998)Amygdala modulation of multiple memory systems: hippocampus and caudateputamen. Neurobiol. Learn. Mem., 69: 163-203.
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192 D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons, Neuron, 14: 385-397. Tanila, H., Mustonen, K., Sallinen, J., Scheinin, M. and Riekkinen, P. (1999) Role of et-2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the ~t-2C-adrenoceptor gene, Eur. J. Neurosci., 11: 599-603. Tanila, H., Rama, P. and Carlson, S. (1996) The effects of prefrontal intracortical microinjections of an or-2 agonist, ct-2 antagonist and lidocaine on the delayed alternation performance of aged rats. Brain Res. BulL, 40:117-119. Taylor, J.R., Birnbaum, S.G., Ubriani, R. and Arnsten, A.ET. (1999) Activation of protein kinase A in prefrontal cortex impairs working memory performance. J. Neurosci. (Online) 19: RC23. Thierry, A.M., Tassin, J.P., Blanc, G. and Glowinski, J. (1976) Selective activation of the mesocortical DA system by stress. Nature, 263: 242-244.
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CHAPTER
12
Stress impairs prefrontal cortical function in rats and monkeys: role of dopamine D 1 and norepinephrine oL-1 receptor mechanisms Amy ET. Arnsten Sect. Neurobiology, Yale Medical School, 333 Cedar St., New Haven, CT 06520-8001, USA
Introduction The prefrontal cortex (PFC) is critical for guiding behavior using working memory (Goldman-Rakic, 1987); working memory is constantly updated; these memories may be called up from long-term storage or from recent buffers. The PFC uses this representational knowledge to guide behavior effectively, freeing the organism from its dependence on the environment, inhibiting inappropriate responses or distractions and allowing us to plan and organize our behavior (Robbins, 1996). Animals or humans with lesions to the PFC can exhibit poor attention regulation, disorganized or perseverative behavior, hyperactivity and impulsivity (Stuss et al., 1994). PFC functions are impaired by uncontrollable stress in humans and animals Studies in humans, monkeys and rats have shown that acute exposure to mild uncontrollable stress impairs cognitive functions associated with the PFC. The original work of Broadbent, Hockey and others showed that exposing human subjects to loud noise stress improved reaction time on wellrehearsed or simple tasks, but impaired performance of more complex tasks (Broadbent, Corresponding author: Tel.: 203-785-4431; Fax: 203-785-5263; e-mail: [email protected]
1971), especially when the subjects experienced themselves as having no control over the stressor (Glass et al., 1971). Loud noise stress impaired the ability to sustain attention (Hockey, 1970), or to inhibit prepotent, inappropriate responses on the Stroop interference test (Hartley and Adams, 1974), functions associated with the PFC (Perret, 1974; Wilkins et al., 1987; Coull et al., 1998; Peterson et al., 1999). Monkeys exposed to the same stressor used in the human studies, loud noise (110 dB), are significantly impaired on performance of the spatial delayed response task (Arnsten and GoldmanRakic, 1998), a test of working memory dependent upon the dorsolateral PFC surrounding the principal sulcus (Goldman and Rosvold, 1970). Stress-exposed monkeys show no impairment following '0' sec delay control trials, but are impaired when performance depended upon working memory (Arnsten and Goldman-Rakic, 1998). Similar results are observed when monkeys are administered a pharmacological stressor, the benzodiazepine inverse agonist FG7142 (Murphy et al., 1996). Administration of FG7142 also impairs spatial working memory performance in rats, as measured by the delayed alternation task in a T maze (Murphy et al., 1996; Birnbaum et al., 1999a). In contrast to these PFC tasks, stress exposure has little effect, or actually improves performance of tasks dependent upon the inferior
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temporal cortex (Arnsten and Goldman-Rakic, 1998), parietal cortex (Murphy et al., 1996), or cerebellum (Shors et al., 1992). Thus, the working memory and attention functions of the PFC appear to be particularly vulnerable to the effects of uncontrollable stress. As discussed later, it may be adaptive to have the PFC go 'off-line' during some types of dangerous situations in which it is helpful to react rapidly and reflexively, without PFC guidance. It has long been appreciated that catecholamine turnover is increased in the PFC during exposure to stress e.g. (Thierry et al., 1976; Deutch and Roth, 1990; Finlay et al., 1995; Goldstein et al., 1996). The following briefly reviews the evidence suggesting that high levels of DA acting at D 1 receptors, and high levels of NE acting at c~-i receptors, contribute to stress-induced deficits in working memory function (Fig. 1).
The role of DA in stress-induced working memory deficits: D1 receptors and cAMP/ protein ldnase A intraeellular signalling pathways Low to moderate levels of DA activity are necessary for PFC working memory (Brozoski et al., 1979; Simon, 1981; Bubser and Schmidt, 1990) and attention (Robbins et al., 1998) functions, and activation of D1 receptors appears particularly important in this regard (Sawaguchi et al., 1988; Sawaguchi and Goldman-Rakic, 1991; Seamans et al., 1998, but see Broersen et al., 1994). However, accumulating evidence indicates that high levels of DA receptor stimulation in the PFC impairs working memory function. The working memory deficits induced by stress exposure in rats or monkeys can be blocked by pretreatment with DA receptor antagonists, including the D1 receptor antagonist, SCH23390 (Fig. 2A; Arnsten and Goldman-Rakic, 1990; Murphy et al., 1996; Arnsten and Goldman-Rakic, 1998). Stress-induced working memory deficits correlate with the rise in DA turnover in PFC (Murphy et al., 1996). Conversely, stress-induced working memory deficits can be mimicked by the administration of a D1 receptor agonist. Infusion of a full D 1 agonist (0.1 p~g/0.5 Ixl SKF81297) directly into the PFC in rats impairs working memory performance and pro-
duces a mildly perseverative pattern of response, much as is seen in stressed rats (Zahrt et al., 1997). These deficits can be reversed by pretreatment with a D1 receptor antagonist, consistent with actions at D1 receptors (ibid). Electrophysiological studies of PFC neurons have also shown that high levels of D1 receptor stimulation can erode neuronal function. For example, the iontophoresis of low concentrations of D1 receptor antagonists can increase memory-related neuronal responses in monkeys performing a challenging working memory task (Williams and Goldman-Rakic, 1995). Conversely, intracellular recordings of pyramidal cells from rodent PFC slices have shown that D1 receptor stimulation decreases the n and p calcium currents that convey
IMPAIRED PFC FUNCTION
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Fig. 1. Highly schematized illustration of the receptor mechanisms and intracellular pathways contributing to impaired PFC function during stress. Evidence to date suggest that high levels of DA impair working memory through actions at D1/D5 receptors coupled to Gs/PKA pathways. DA may also impair through actions at D2/D4 receptors (not shown) which may be concentrated on interneurons. High levels of NE appear to impair working memory through actions at et-1 receptors coupled to Gq/PKC pathways.
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signals from dendrite to soma (Yang and Seamans, 1996). Optimal levels of D1 receptor stimulation appear to focus signal transmission, conveying only large or temporally-coincident signals to the cell body (Yang and Seamans, 1996). However, higher concentrations of dopamine or a D 1 agonist abolish calcium currents, effectively preventing informaA,
DA D1 ANTAGONIST BLOCKS STRESS -INDUCED WORKING MEMORY IMPAIRMENT
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tion transfer from dendrite to soma (Yang and Seamans, 1996; Zahrt et al., 1997; schematically represented in Fig, 2C and Fig. 2D). This interruption of information transfer may underlie the working memory impairment seen at high levels of D1 receptor stimulation; animals' behavior may become perseverative, as no new spatial informa-
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Fig. 2. Hypothetical model of how DA D1 and NE (x-1 receptor actions may impair PFC function during stress by interrupting signal transmission from the dendrite to the soma. (A) Stress-induced working memory deficits in monkeys are blocked by pretreatment with the DA D1 receptor antagonist, SCH23390. Monkeys were exposed to loud noise stress (about 105 dB white noise) or normal levels of background noise (about 70dB) following injection of saline vehicle or SCH23390 (0.01-0.1 mg/kg, i.m.). Results represent mean per cent correct _+S.E.M. on the spatial delayed response task. Adapted from Arnsten and Goldman-Rakic, 1998. A similar response is observed in rats (Murphy et al., 1996). VEH=vehicle, CON=control noise conditions, STR=noise stress conditions, SCH = SCH23390, *significantly different than vehicle control, significantly different than vehicle stress. (B) Stress-induced working memory deficits in rats are blocked by intra-PFC infusions of the NE c~-1 receptor antagonist, urapidil. Rats were injected with vehicle or the pharmacological stressor, FG7142 (30 mg/kg, i.p.) prior to intra-PFC infusion of vehicle or urapidil (0.1 p,g/0.5 txl). Results represent mean per cent correct _+S.E.M. on the spatial delayed alternation task. Adapted from Bimbaum et al., 1999. VEH = vehicle, STR=stress, URA=urapidil, *significantly different from vehicle/vehicle, tsignificantly different from stress/vehicle. (C) Hypothetical model depicting how DA D1/D5 and NE et-1 receptor actions may impair PFC function during stress by interupting signal transmission from the dendrite to the soma. Catecholamine levels may rise near the primary dendritic shaft during stress due to increased catecholamine release and blockade of extraneuronal catecholamine transporters (ECT) by circulating steroids (Grundemann et al., 1998). High levels of DA may stimulate D5 receptors on the dendritic shaft, activating PKA (Surmeier et al., 1995) and reducing the high threshold calcium currents which normally convey signals to the soma (Yang and Seamans, 1996). High levels of NE may increase 'noise' in the proximal dendritic stem by evoking glutamate release, which in turn increases sodium entry into the proximal dendritic stem (Marek and Aghajanian, 1999). This mechanism is likely mediated by PKC. (D) Hypothetical changes in signal transmission from the dendritic tree to the soma. (1) a signal enters the primary dendritic shaft for conveyance to the soma; (2) the signal is reduced by D1/D5 receptor stimulation due to closing of n and p calcium channels that normally convey signals to the soma; (3) 'noise' is increased in the proximal dendritic stem due to NE et-1 excitation of non-specific glutamate release; (4) due to reduced signal and/or increased noise no new information is able to reach the soma, thus preventing the relative increase in delayrelated activity which would normally guide behavior thoughtfully. Without new information to guide responses, the animal may respond in a perseverative manner.
186 tion can access the soma to change response patterns (Figure 2D4). The work of Surrneier et al., (1995) indicates that DA D1 receptor stimulation can decrease n and p calcium currents through activation of a cAMPprotein kinase A (PKA) intracellular signalling pathway. Ongoing studies in our lab suggest that the deficits in delayed alternation performance induced by D1 agonist infusion may also involve activation of a cAMP-PKA intracellular pathway (Fig. 1). Thus, intra-PFC infusion of the PKA activator, Sp-cAMPS, produces a dose-dependent impairment in delayed alternation performance that mimics the effects of a D1 agonist or stress (Taylor et al., 1999). The impairment induced by SpcAMPS is reversed by co-infusion of the PKA inhibitor, Rp-cAMPS, which has no effect on its own (ibid). This response profile is consistent with drug actions on PKA activity. Further studies are in progress to determine whether infusion of the PKA inhibitor, Rp-cAMPS, can reverse the effects of stress. There has been less research on the role of the D2 receptor family in the regulation of the stress response in PFC. Neuroleptics with potent D2 and D4 receptor blocking actions such as haloperidol (Murphy et al., 1996; Arnsten and Goldman-Rakic, 1998) and clozapine (Murphy et al., 1997) are effective in preventing stress-induced cognitive deficits in rats and monkeys, but these agents are not selective. Recent evidence suggests that a selective D4 receptor antagonist can protect cognitive performance from the effects of stress in monkeys but not rats (Arnsten et al., 2000), and that infusion of a D2 agonist into the rat PFC can induce working memory deficits (Druzin et al., 1999), but more research is needed in this area. It is likely that D2/D4 agents can have powerful effects on PFC function through their actions on interneurons, on which these receptors are concentrated (Mrzljak et al, 1996).
The role of NE in stress-induced working memory deficits: ~t-1 adrenoceptors and phosphotidyl inositol/protein kinase C intracellular signalling pathways More recently, we have focused on the contribution of elevated NE levels (Finlay et ai., 1995; Goldstein
et al., 1996) to the stress response in the PFC. Extensive evidence indicates that low levels of NE enhance the working memory and attention functions of the PFC through actions at post-synaptic oL-2A receptors (reviewed in Arnsten et al., 1996; Arnsten, 1998b). Thus, stimulation of tx-2 receptors in the PFC is essential for working memory as measured by cognitive performance (Arnsten and Goldman-Rakic, 1985; Li and Mei, 1994; Tanila et al., 1996; Mao et al., 1999) and delay-related firing (Sawaguchi and Kikuchi, 1998; Li et al., 1999). These beneficial effects result from actions at postsynaptic receptors (Arnsten and Goldman-Rakic, 1985; Cai et al., 1993) with an tx-2A receptor subtype pharmacology (Arnsten et al., 1988; Franowicz et al., 1998; Tanila et al., 1999). tx-2A receptors have been localized on the post-synaptic membrane of dendritic spines on pyramidal cells in monkey cortex (Aoki et al., 1994; Arnsten et al., 1996), and it is possible that some of these beneficial actions occur at these sites (schematically represented in Figure 2C). et-2 agonists have been shown to improve working memory and other PFC functions in mice (Franowicz et al., 1998; Tanila et al., 1999), rats (Carlson et al., 1992; Tanila et al., 1996), monkeys (Rama et al., 1996; Franowicz and Arnsten, 1998), and humans (Jakala et al., 1999a; 1999b). In humans, ~-2 agonists such as guanfacine are being used to treat patients with prominent symptoms of PFC dysfunction such as Attention Deficit Hyperactivity Disorder (Chappell et al., 1995; Horrigan and Barnhill, 1995; Hunt et al., 1995). or-2 agonists are especially potent in patients with NE depletion (McEntee and Mair, 1990). However, in contrast to the beneficial effects of o~-2A receptor stimulation, high levels of NE release may impair PFC function through actions at e~-I adrenoceptors. High levels of NE release may occur during stress or when the subject is agitated and spontaneous activity of the NE cells is high (Rajkowski et al, 1998). For example, working memory deficits due to stress exposure can be reversed by intra-PFC infusion of the NE oL-1 antagonist, urapidil (Fig. 2B; Birnbaum et al., 1999a). Interestingly, urapidil reversed the cognitive deficits, but not the non-cognitive aspects (e.g. freezing) of the stress response (ibid), suggesting
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that other components of the stress response are mediated by different brain regions (e.g. the PAG). Stress-induced working memory deficits can be mimicked by intra-PFC infusions of the et-1 agonist, phenylephrine, which like stress and D1 agonists induces a mildly perseverative pattern of response (Arnsten et al., 1999). Delayed alternation deficits induced by phenylephrine can be blocked by co-infusion of urapidil, consistent with actions at ~-l-adrenoceptors (ibid). Similar effects are observed in the non-human primate, where infusions of phenylephrine into the dorsolateral PFC surrounding the caudal two-thirds of the principal sulcus produce a marked, delay-related impairment in spatial working memory performance (Mao et al., 1999). Ablations of this same cortical region produce profound impairments in spatial working memory performance (Goldman and Rosvold, 1970). Phenylephrine infusions outside this cortical region are ineffective, demonstrating regional specificity for the drug effect (Mao et al., 1999). Working memory deficits in monkeys can also be produced by systemic administration of the ~-1 adrenoceptor agonist, cirazoline, a non-selective agonist which crosses the blood brain barrier (Arnsten and Jentsch, 1997). These results may explain why decongestants with ~-1 agonist properties such as pseudoephedrine can produce cognitive impairment in some individuals. Preliminary evidence suggests that the impairment induced by ct-1 adrenoceptor stimulation results from activation of the Gq-phosholipase Cprotein kinase C (PKC) intracellular pathway, the signalling pathway most commonly coupled to oL1-adrenoceptors (Fig. 1). For example, working memory deficits induced by intra-PFC phenylephrine infusions in rats can be blocked by pretreatment with a dose of lithium known to suppress turnover of this pathway (Arnsten et al., 1999). The phenylephrine response also appears to be reversed by co-infusion of the selective PKC inhibitor, chelerythrine (Birnbaum et al., 1999b). These results suggest that NE-induced PFC dysfunction results from activation of the Gq-PKC signalling pathway. NE oL-1 stimulation may impair PFC function by further eroding signal transfer from dendrite to soma (Fig. 2C). Marek and Aghajanian (1999) have
shown that NE et-1 stimulation increases excitatory post-synaptic currents in the dendritic stem by increasing glutamate release, thus adding 'noise' (Fig. 2D3). Thus, high levels of DA and NE may have additive or synergistic effects on information processing in PFC, reducing signals and increasing noise, respectively. We have speculated that high levels of both catecholamines may build in the extrasynaptic space during stress when extraneuronal catecholamine transporters which normally take up large concentrations of catecholamines are blocked by circulating steroids (schematically represented in Fig. 2C). Subjects with loss of dendritic spines (e.g. the elderly (Feldman and Dowd, 1975) or schizophrenic patients (Glantz and Lewis, 1995; Glantz and Lewis, 1997; Selemon et al., 1995)) may be particularly vulnerable to the detrimental effects of catecholamines due to a relative imbalance of these actions on dendritic shafts. The amygdala controls the 'catecholamine switch' during stress Although PFC cognitive functions are often essential for successful organization of high order behavior, there may be some conditions, e.g. acute danger, when it may be adaptive to 'shut down' these complex, reflective operations and to allow more automatic or habitual responses dependent on posterior cortical and subcortical structures to control our behavior (Arnsten, 1998a). The amygdala may play a critical role in shifting control of behavior from the PFC to posterior cortical and subcortical structures (schematically represented in Fig. 3), and it may accomplish this 'switch' of control, at least in part, by increasing catecholamine levels throughout the brain. This increase in catecholamine levels may enhance the functioning of subcortical and posterior cortical structures, but impair the functioning of the PFC. The importance of the amygdala for this function is underscored by the finding that stress-induced increases in catecholamine turnover are not observed in rats with lesions of the amygdala (Goldstein et al., 1996). The amygdala is thought to increase catecholamine turnover through its projec-
188
tions to DA and NE cell bodies (reviewed in Goldstein et al., 1996). The amygdala may also increase extrasynaptic catecholamine levels through hypothalamic projections which facilitate the release of steroids, which in turn block extraneuronal catecholamine transporters (Fig. 2C).
Activation of the amygdala may enhance associative learning and long term memory consolidation at the same time that it impairs working memory functions. Evidence from both animals and humans indicates that enhanced long term memory consolidation can be initiated by increased NE [3 receptor stimulation in the amyg-
NONSTRESS
STRESS
Fig. 3. Schematic illustration of the possible role of the amygdala in orchestrating cognitive changes in response to mild to moderate stress. During non-stress conditions (top picture), the PFC often controls behavior, inhibiting inappropriate processing and responding through its extensive connections to posterior cortical and subcortical structure. During uncontroUable stress (bottom picture), the amygdala may enhance the functioning of areas such as the amygdala and hippocampus (Packard and Teather, 1998), while impairing the functioning of the PFC by producing high levels of catecholamine release. The amygdala appears to be a critical structure for stimulating increased catecholamine turnover in the PFC during stress, as amygdala lesions prevent this response (Goldstein et al., 1996). The amygdala may increase catecholamine levels by directly exciting NE and DA neurons, and indirectly by increasing steroid release through its projections to hypothalamus. Steroids block the extraneuronai catecholamine transporters which normal take up high levels of catecholamines from the extrasynaptic space (Fig. 2C). The amygdala may be especially important for evoking these mechanisms during conditioned or psychological stressors (Davis, 1992; Schafe et al., 1999).
189 dala (Cahill et al., 1994; Cahill and McGaugh, 1996). Increased catecholamine release in the amygdala also has been shown to enhance the associative memory functions of the hippocampus and the habit memory functions of the slriatum (Packard and Teather, 1998). These mechanisms may enhance our long-term memory of the aversive event so that we might better avoid it in the future; (however, more severe stressors appear to impair hippocampal function and may produce amnesia (Kim and Yoon, 1998)). Increased catecholamine release in the sensory cortices might also alter attentional regulation, allowing attention to be 'captured' by prominent stimuli in the environment by increasing [3 and/or a-1 receptor enhancement of signal processing in sensory cortices (Foote et ai., 1975; Waterhouse et al., 1998). This hypothesis is consistent with the findings of Hockey (1970) who showed that stress narrows the focus of attention onto salient signals. Hockey also demonstrated that loud noise stress makes attention more labile (i.e. impairs the ability to sustain attention), and this change in attentional regulation may occur via or- 1 receptor impairment of PFC function. This hypothesis is consistent with the affinity of NE for the adrenergic receptors. NE has higher affinity for a-2A receptors (O'Rourke et al., 1994) than for ct-1 receptors (Mohell et al., 1983) or [3 receptors (Pepper1 and Regan, 1994). Functional studies also indicate that NE is more potent at e~-2 receptors than at ~-1 or [3 receptors (e.g. Atkinson and Minneman, 1991). Thus lower levels of NE release (e.g. during normal waking) may engage o~2A receptors and enhance PFC regulation of behavior. However, during stress, higher levels of NE would be released, engaging or-1 receptors and impairing PFC function, while enhancing the abilities of the posterior cortices and subcortical structures through actions at [3 and/or or-1 receptors. This neurochemical 'switch' may be helpful under many conditions, e.g. during dangerous circumstances that require rapid responding to stimuli in the environment, but may be problematic when PFC regulation of behavior is required, e.g. in a classroom setting. The discovery of neurochemical mechanisms which actively impair PFC function may help to explain why deficits in PFC function are prevalent in most neuropsychiatric
disorders, and why these disorders are often precipitated or exacerbated by exposure to stress (Mazure~ 1995).
Acknowledgement Much of the work in this chapter was supported by PHS MERIT Award AG06036 to AFTA.
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