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Background: Stress exacerbates many neuropsychiatric disorders associated with prefrontal cortical (PFC) dysfunction. Stress also impairs the working memory functions of the PFC. Although stress research has focused on dopaminergic mechanisms, stress also increases norepinephrine (NE) release in PFC, and intra-PFC infusions of NE α-1-adrenoceptor agonists impair working memory. The current study examined whether NE α-1-adrenoceptor actions in PFC contribute to stress-induced deficits in working memory performance.
Methods: Rats were treated with a pharmacological stressor, FG7142 (30 mg/kg) or vehicle 30 min before testing on a test of spatial working memory, delayed alternation. The α-1-adrenoceptor antagonist, urapidil (0.1 μg/0.5 μL), or saline vehicle, was infused into the PFC 15 min before delayed alternation testing.
Results: As observed previously, FG7142 significantly impaired the accuracy of delayed alternation performance, and induced a perseverative pattern of responding consistent with PFC dysfunction. FG7142 also slowed motor response times. Infusion of urapidil into the PFC completely reversed the FG7142-induced impairment in delayed alternation performance, but did not alter the slowed motor responding.
Conclusions: These findings indicate that α-1-adrenoceptor stimulation in the PFC contributes to stress-induced impairments in PFC cognitive functions. These neurochemical actions may contribute to symptoms of working memory impairment, poor attention regulation, or disinhibited behaviors in neuropsychiatric disorders sensitive to stress exposure.
Research on the biological basis of mental illness has revealed the relevance of prefrontal cortex (PFC) dysfunction in many neuropsychiatric disorders. The PFC uses working memory to regulate behavior and attention, allowing individuals to inhibit inappropriate responses and thoughts. Symptoms such as poor concentration, impaired sensory gating, and impulsivity, common in mental illness, are thought to reflect PFC dysfunction. Researchers have also appreciated that many neuropsychiatric disorders are influenced by exposure to stress. For example, schizophrenia and affective disorder are often exacerbated or precipitated by stress exposure (reviewed in
). Thus, understanding the mechanisms by which stress alters brain function is of increasing interest in psychiatry.
It is well established that stress exposure releases catecholamines in both the peripheral and central nervous systems. Furthermore, disorders such as schizophrenia (
) are associated with increased catecholamine transmission. Thus, the effects of catecholamines on PFC function are particularly relevant to neuropsychiatry.
Extensive research has demonstrated that the catecholamine inputs to the PFC are necessary for the working memory functions of this region. For example, either experimental depletion of dopamine (DA) and norepinephrine (NE) in the PFC (
) produces marked deficits on working memory tasks. Indeed, catecholamine depletion produces deficits as severe as those observed after ablation of the PFC (
Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys.
) into the PFC impair performance of working memory tasks, showing that endogenous stimulation of these receptors is essential to PFC function. In contrast, infusion of the α-1-adrenoceptor antagonist, prazosin, into the monkey PFC had no effect on working memory performance (
Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys.
). Thus, it has been assumed that activation of D1 and α-2 receptors, but not α-1 receptors, are necessary for normal PFC function.
In contrast, recent research has suggested that high levels of catecholamines released during stress exposure may impair PFC function. Neurochemical studies in rats have shown that even mild stress increases monoamine release in PFC (e.g.,
). Behavioral studies have shown that exposure to mild stress induces deficits in working memory tasks, but not in control discrimination tasks with similar motor and motivational demands (
). These studies have focused on the role of DA mechanisms in working memory deficits. The stress-induced DA turnover in the PFC of rats was correlated with the level of impairment on a delayed alternation task (
) suggesting that excessive DA in the PFC impairs cognitive performance. The role of DA in mediating the stress-induced PFC impairment is supported by the study in which direct infusion of a D1 agonists into the PFC of rats impaired performance on a delayed alternation task (
). Stress-induced cognitive impairments can be reversed by the nonspecific DA antagonists, haloperidol and clozapine, as well as the specific D1 receptor antagonist, SCH23390 (
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.
). Together, these data suggest that either insufficient or excessive DA receptor stimulation impairs normal PFC function.
Although most research has focused on the role of PFC DA mechanisms during stress, the role of NE mechanisms in the stress response also deserves examination. Biochemical studies have shown enhanced release of NE as well as DA in the PFC during stress exposure (
). Furthermore, two of the dopamine receptor antagonists (haloperidol and clozapine) that were effective in reversing stress-induced cognitive impairments in rats and monkeys also have affinity for NE α-1-adrenoceptors (
). Thus, it is possible that enhanced NE release during stress may play a role in the subsequent cognitive impairment. This idea is supported by recent studies examining the effects of α-1-adrenoceptor agonists on PFC function. Systemic administration of the imidazoline/α-1 agonist, cirazoline, impairs delayed response performance in aged monkeys (
). This impairment was reversed by co-infusion of the α-1 antagonist, urapidil, consistent with actions at α-1-adrenoceptors. These data suggest that, in addition to excessive DA receptor stimulation, high levels of α-1-adrenoceptor stimulation in the PFC might contribute to PFC dysfunction during stress. The current study addressed this question by examining whether infusions of the α-1-adrenoceptor antagonist, urapidil, into the PFC of rats performing a delayed alternation task would reverse the cognitive deficits induced by the pharmacological stressor, FG7142.
Methods and materials
Subjects
Male Sprague-Dawley rats (n = 7) from Taconic weighing 240–280 g (approximately 2 mos old) were pair-housed in filter frame cages. The rats were kept on a 12 hr light-dark cycle and the experiments were conducted during the light phase. The animals were fed a diet of Purina rat chow (16 g/rat/day) immediately after behavioral testing. Water was available ad libitum. Rats grew to weights of about 400–450 g by the end of the study (approximately 8 mos). Food rewards during cognitive testing were highly palatable miniature chocolate chips, thus minimizing the need for dietary regulation. Rats were assigned a single experimenter who handled them extensively before behavioral testing.
Cognitive training and testing
Rats were pretrained on the delayed alternation task in a T-maze, using the methods described in
. Rats were initially habituated to the T-maze (dimensions 90 cm × 65 cm) for several days until they were readily eating chocolate chips from the experimenter’s hand. After habituation, rats were trained on the delayed alternation task. On the first trial, animals were rewarded for entering either arm. Thereafter, for a total of 10 trials per session, rats were rewarded only if they entered the maze arm that was not previously chosen. Response times were measured on each trial. Between trials the choice point was wiped with alcohol to remove any olfactory clues. The delay between trials initially was “0” sec, i.e., the rat was retained in the start box of the maze for less than 2 sec. It is important to note that true 0 sec delays are not possible in a delayed alternation task performed in a T-maze. The minimum time to replace the animal in the start box and have the animal traverse the stem of the T-maze is at least 2–3 sec. Delays were raised as needed to maintain a stable baseline performance of 60%–80% correct on the delayed alternation task. This baseline level of performance allowed for the detection of either improvement or impairment after drug administration. Delays were increased from “0” sec to a mean of 33.6 ± 8.9 sec by the end of the study to maintain performance at 60–80% correct. There was no relationship between delay and drug efficacy. Rats were scored for accuracy of response, arm selected (for qualitative analysis of perseverative responding), and response time. Perseverative responding was defined as the greatest number of consecutive entries into a single arm. Response times for each trial were measured from the time the gate was lifted from the start box until the animal made its choice.
Cannula implantation
After training, guide cannulae were implanted bilaterally above the medial PFC. Surgery was performed under ketamine (80 mg/kg) + xylazine (10 mg/kg) anesthesia using aseptic methods. Guide cannulae consisted of 9.0 mm of 23 g stainless steel (Plastics One) directed immediately dorsal to the medial PFC (Figure 1); prelimbic and infralimbic PFC; stereotaxic coordinates: AP: +3.2 mm, ML: ±0.75 mm DV: either −1.7 or −3.0 mm). Cannulae were affixed to the skull using dental cement secured with sterile stainless steel screws. A stylette was placed into each guide cannula to prevent occlusion. Stylettes were checked on a regular basis to maintain patency. Great care was taken to minimize pain and infection postoperatively, reducing stress to the animal. Rats were treated with Buprenex (0.01 mg/kg) to decrease pain immediately after surgery, and were monitored on a daily basis for signs of distress or infection. After surgery, rats were housed singly to minimize tampering with implants. Testing on the delayed alternation task was resumed approximately 1 week postsurgery.
Figure 1Location of the guide cannulae tips in the rat medial PFC. As cannulae were implanted at either −1.7 or −3.0 DV, the length of the infusion cannulae were adjusted such that all infusions occurred at −4.5 DV. Coronal slices indicate distance (mm) anterior from Bregma. Infusions (0.5 μl) were bilateral.
Rats were gently restrained while the stylettes were removed and replaced with 30 g infusion cannulae that extended below the guide cannulae to a point −4.5 mm DV from the skull (i.e., 2.8 mm below the guide cannulae placed at DV −1.7 mm, and 1.5 mm below the guide cannulae placed at DV −3.0 mm). The rats received bilateral infusions of drug or vehicle driven by a Harvard Apparatus syringe pump set at a flow rate of 0.25 μL/min for 2 min using two 25 μL Hamilton syringes. Infusion cannulae were left in place for 2 min after the completion of the infusion. Stylettes were inserted back into the cannulae. Behavioral testing began 15 min after the infusion procedure. Rats were adapted to mock infusions to accustom them to the procedure before the actual infusions.
Drug treatments
FG7142 (30 mg/kg, i.p., Tocris-Cookson, Ballwin, MO) was suspended in vehicle by sonicating 18 mg FG7142 in a sterile vehicle containing 0.1 mL ethanol, 0.2 mL low pH saline (pH = 3), and 0.9 mL hydroxybetacyclodextrin (HBC) solution (HBC from Research Biochemicals Inc., Natick, MA). The HBC solution was made by dissolving 1.5 g HBC in 1 mL Tween 80 and 7.4 mL low pH saline overnight. FG7142 or vehicle was injected 30 min before testing using a 22 g needle. Fifteen minutes after the i.p. injection, urapidil (0.1 μg/0.5 μL; Research Biochemicals, Inc., Natick, MA), or saline vehicle was infused into the medial PFC. The effective dose of urapidil (0.1 μg) had been previously determined in a pilot study.
Rats were initially adapted to i.p. injections of saline and the mock infusions. After achieving stable baseline performance for 2 consecutive days, rats (n = 7) received 1 of 4 different drug treatments: vehicle i.p./intra-PFC saline; vehicle i.p./intra-PFC urapidil; FG7142 i.p./intra-PFC saline; or FG7142 i.p./intra-PFC urapidil. The 4 treatments were administered in a counter-balanced order with at least 1 week between treatments. Two of the 7 rats lost their implants over the course of the study and thus were unable to finish all treatments. One rat was unable to receive vehicle i.p./intra-PFC urapidil or FG7142 i.p./intra-PFC saline; the second rat was unable to receive FG7142 i.p./intra-PFC urapidil. The 5 remaining rats completed all 4 treatments. The experimenter testing the animal was blind to the drug treatment conditions.
Histology
At the completion of the experiment, rats were sacrificed by overdose with barbiturate. Brains were stored in formalin, sectioned (40 μm), and cannulae placement was verified visually.
Data analysis
Data were analyzed using a two way analysis of variance with repeated measures (2-ANOVA-R) with factors of systemic drug administration (vehicle or FG7142) and intra-PFC infusion (vehicle or urapidil). The 3 empty data cells (1 each for vehicle/urapidil, FG7142/saline, and FG7142/urapidil) were filled with the mean score from the other rats. Planned comparisons (user defined contrasts) were performed to examine whether 1) vehicle/saline significantly differed from FG7142/saline; 2) vehicle/saline significantly differed from vehicle/urapidil; and 3) FG7142/saline significantly differed from FG7142/urapidil. Statistics were performed on a Power Macintosh using Systat software.
Results
The results of the histological analysis are shown in Figure 1. All animals had cannulae correctly localized dorsal to, or in the dorsal portion of, the medial PFC.
The results of this study for accuracy of responding, perseverative responding and response time are shown in Figure 2.
Figure 2The effects of the α-1-adrenoceptor antagonist, urapidil, and the pharmacological stressor, FG7142, on delayed alternation performance. A) The effects of drug treatments on accuracy of delayed alternation performance. Results represent mean percent correct ± SEM on the delayed alternation task (n = 7). B) The effects of drug treatments on the perseverative quality of the response. Perseveration was defined as the greatest number of consecutive entries into a single arm. Results represent mean number of consecutive entries ± SEM (n = 7). C) The effects of drug treatments on total response time. Results represent mean time (sec) ± SEM from the time the start gate is lifted until the animal makes its choice for all 10 trials (n = 7). For all graphs, ∗ indicates significant difference from vehicle/vehicle treatment; † indicates significant difference from FG7142/vehicle treatment. VEH = vehicle, FG = FG7142 (30 mg/kg, i.p.), URA = urapidil (0.1 μg/0.5 μl, intra-PFC infusion).
Statistical analysis of the accuracy data showed a significant main effect of systemic drug (vehicle or FG7142) administration: F(1,6) = 12.02, p = .013; no main effect of intra-PFC infusion (vehicle or urapidil): F(1,6) = 3.59, p = .11; and a significant interaction between systemic drug treatment (vehicle or FG7142) and intra-PFC infusion (vehicle or urapidil): urapidil × FG7142 interaction F(1,6) = 25.34, p = .002. Planned comparisons showed that FG7142 (30 mg/kg, i.p.) significantly impaired accuracy of responding compared to vehicle control when animals received intra-PFC infusions of vehicle [Figure 2A; vehicle/vehicle vs. FG7142/vehicle F(1,6) = 105.12, p < .0001]. Intra-PFC infusion of urapidil significantly reversed the impairment induced by FG7142 [Figure 2A; FG7142/vehicle vs. FG7142/urapidil F(1,6) = 29.28, p = .002]. Infusion of urapidil in vehicle-injected animals had no effect on accuracy of performance [Figure 2A; vehicle/vehicle vs. vehicle/urapidil F(1,6) = 0.79, p = .41].
Perseveration
Perseverative responses were assessed by the greatest number of consecutive entries into 1 arm. Statistical analysis showed no main effect of systemic drug (vehicle or FG7142) administration: F(1,6) = 4.16, p = .087; no main effect of intra-PFC infusion (vehicle or urapidil): F(1,6) = 2.1, p = .2; and a significant interaction between systemic drug treatment (vehicle or FG7142) and intra-PFC infusion (vehicle or urapidil): urapidil × FG7142 interaction F(1,6) = 7.21, p = .036. Planned comparisons showed that FG7142 significantly increased perseverative responding compared to vehicle control when animals received intra-PFC infusions of vehicle [Figure 2B; vehicle/vehicle vs. FG7142/vehicle F(1,6) = 13.95, p = .01]. A perseverative response pattern is consistent with PFC dysfunction. Intra-PFC infusion of urapidil significantly reversed the perseverative pattern of response induced by FG7142 [Figure 2B; FG7142/vehicle vs. FG7142/urapidil F(1,6) = 7.94, p = .03]. Infusion of urapidil in vehicle-injected animals had no effect on the perseverative pattern of performance [Figure 2B; vehicle/vehicle vs. vehicle/urapidil F(1,6) = 0.55, p = .49].
Response time
Response times for each trial began when the gate was lifted from the start box and ended when the animal made its choice. Total response times for the 10 trials that made up each test session are shown in Figure 2C. Statistical analysis showed a main effect of systemic drug (vehicle or FG7142) administration: F(1,6) = 106.64, p < .0001; no main effect of intra-PFC infusion (vehicle or urapidil): F(1,6) = 4.91, p = .07; and no interaction between systemic drug treatment (vehicle or FG7142) and intra-PFC infusion (vehicle or urapidil): urapidil × FG7142 interaction F(1,6) = 0.99, p = .36. Planned comparisons showed that FG7142 significantly increased response time compared to vehicle control when animals received intra-PFC infusions of vehicle [Figure 2C; vehicle/vehicle vs. FG7142/vehicle F(1,6) = 52.7, p < .0001]. In contrast to the accuracy and perseveration data, intra-PFC infusion of urapidil had no effect on the increased response time induced by FG7142 [Figure 2C; FG7142/vehicle vs. FG7142/urapidil F(1,6) = 3.3, p = .12; vehicle/vehicle vs. FG7142/urapidil F(1,6) = 27.9, p = .002]. Thus, the improved accuracy produced by urapidil infusions in FG7142-treated animals can not be accounted for by a reduction in response time. This is particularly important in a delayed alternation task where response times influence the delay over which information must be remembered. Infusion of urapidil in vehicle-injected animals had no effect on response time [Figure 2C; vehicle/vehicle vs. vehicle/urapidil F(1,6) = 2.3, p = .18].
Discussion
The current study examined the hypothesis that α-1-adrenoceptor stimulation in PFC contributes to stress-induced PFC deficits. The results showed that infusion of the α-1-adrenoceptor antagonist, urapidil (0.1 μg/0.5 μL), into the PFC was highly effective in reversing the effects of the pharmacological stressor, FG7142 (30 mg/kg), on response accuracy. As urapidil had little effect on performance when administered under nonstress conditions, the amelioration of the FG7142 response could not be explained by additive effects of the 2 treatments. Instead, the most parsimonious interpretation would be that the accuracy of delayed alternation performance was restored by α-1-adrenoceptor blockade in the PFC. These results are consistent with recent studies showing that α-1-adrenoceptor stimulation in the PFC of rats (
Mao Z-M, Arnsten AFT, Li B-M (1999): Local infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol Psychiatry 46:1259–1265.
this volume) markedly impairs spatial working memory performance. The latter study demonstrated a delay-dependent effect of phenylephrine, consistent with effects on working memory processes mediated by the PFC (ibid). In the current study, urapidil infusions restored accuracy of response after FG7142 treatment, but did not ameliorate the slowed motor responses induced by FG7142. These results suggest that urapidil infusions into the PFC altered the cognitive component, but not other aspects of the stress response that may be mediated by other brain regions. For example, freezing responses to stress are likely mediated by interactions between structures such as the amygdala and periaqueductal gray (
The finding that urapidil had little effect on performance under nonstress conditions is consistent with a previous literature indicating that infusions of the α-1-adrenoceptor antagonist, prazosin, into the monkey PFC, similarly had no effect on spatial working memory performance under nonstress conditions (
Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys.
). It is possible that infusions of higher doses of α-1-adrenoceptor antagonists into the PFC might impair performance. The current results support previous suggestions that α-1-adrenoceptors may not be significantly engaged in PFC under basal conditions.
To our knowledge, all α-1-adrenoceptor antagonists have affinity for other receptors (e.g., prazosin has high affinity for α-2B/C-adrenoceptors). Urapidil can have partial agonist actions at serotonergic 5HT1A receptors in addition to its α-1-adrenoceptor-blocking activities (
Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for alpha-1-adrenoceptor binding sites.
), the ramifications of serotonergic mechanisms to PFC cognitive changes during stress are unknown. Thus, future studies are needed to determine whether partial stimulation of 5HT1A receptors in PFC could help to ameliorate FG7142-induced deficits in delayed alternation performance.
Regulation of catecholamine levels in PFC during stress
Research suggests that the amygdala may play a critical role in orchestrating the stress response in PFC, as amygdala lesions abolish the rise in PFC monoamine levels during stress (
Roozendaal B, Koolhaas JM, Bohus B (1991): Attenuated cardiovascular, endocrine and behavioral response after a single footshock in central amygdaloid lesioned male rats. Physiol Behav 50:771–775.
). Steroids potently (corticosterone ki = 120 nM) block extra neuronal catecholamine transporters (ECT) that normally function to remove higher concentrations of catecholamines from the synaptic/extra synaptic space (
). A schematic illustration of ECT effects on extra synaptic catecholamine levels in PFC is shown in Figure 3. Under normal conditions (Figure 3A), ECTs on glia “mop up” excess catecholamines that may have escaped uptake from high affinity neuronal transporters on catecholamine terminals. During stress (Figure 3B), steroids block the ECTs and allow catecholamine levels to rise in the extra synaptic space. Thus, either endogenous steroids released during stress, or exogenously administered steroids, could serve to increase extra synaptic catecholamine levels in PFC. This mechanism may permit stimulation of catecholamine receptors far from catecholamine axons that may receive little endogenous stimulation under basal conditions (e.g., D5 receptors on the primary dendritic stem).
Figure 3Highly schematized representation of stress effects at α-1-adrenoceptors and dopamine receptors in the PFC of an animal performing a working memory task. See text for more complete description. A) Under optimal conditions, signals are conveyed from the dendritic tree to the soma via calcium currents along the dendritic stem (1–3 = hypothetical intracellular recordings). Catecholamine release is moderate, and extraneuronal catecholamine transporters (ECT) on glia remove excess catecholamines in the extra synaptic space. It is hypothesized that DA may act at D1 receptors and NE at α-2-adrenoceptors on dendritic spines to enhance signal integration on the dendritic tree. There would be little DA or NE actions on the dendritic stem under these conditions. Thus the signals would be conveyed to the soma, where enhanced firing during the delay period (4 = hypothetical extracellular recording) can be used to guide responses effectively in working memory tasks such as delayed alternation or delayed response. B) During stress exposure, catecholamine release is increased in the PFC. We speculate that steroid blockade of ECT on glia may also contribute to the rise in extra synaptic catecholamine levels during stress. DA may engage the D5 receptors concentrated on the dendritic stem and decrease calcium currents through n or p calcium channels, thus reducing signal transfer (1–2) (Yang and Seamans 1996). NE may engage α-1-adrenoceptors, inducing glutamate release and sodium entry into the dendritic stem (Marek and Aghajanian 1999). This increase in “noise” would further obscure signal transfer to the cell body (3). Loss of information would weaken delay-related firing (4); thus, there would be no new information to effectively guide behavioral responses.
A model of stress effects on PFC neuronal function
Figure 3 proposes a model summarizing our current ideas of how catecholamines may alter PFC function during stress. The top figure (Figure 3A) depicts a PFC pyramidal cell under normal conditions, when low to moderate levels of catecholamine release optimize function through actions on dendritic spines. The lower figure (Figure 3B) depicts the cell under stressful conditions, when high levels of NE and DA release impair PFC function by interfering with signal transfer along the dendritic stem to the cell body. It is well-documented that there are large increases in monoamine (
) release in the PFC during stress exposure. Intracellular recordings from rodent PFC slices suggest that the dendritic stem may be an important site of action for both DA D1/D5 and NE α-1-adrenoceptor actions (
Marek GJ, Aghajanian GK (1999): 5-HT2A receptor or alpha 1-adrenoceptor activation induces EPSCs in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206.
). The dendritic stem is a critical site for transfer of signals from the dendritic tree to the cell body, and thus catecholamine modulation of this process may have significant effects on information transfer.
Under optimal conditions (Figure 3A; low to moderate catecholamine release), it is likely that signals are conveyed from the dendritic tree to the soma via high threshold calcium currents that arise through n and p calcium channels on the dendritic stem (
). Under conditions of normal catecholamine release, we hypothesize that norepinephrine and dopamine have little effect on information transfer on the dendritic stem, but may enhance signal processing on more distal dendritic spines through actions at α-2 (
The contribution of a-2 noradrenergic mechanisms to prefrontal cortical cognitive function Potential significance to Attention Deficit Hyperactivity Disorder.
), respectively (Figure 3A). Under these conditions, well-defined signals would be transmitted down the dendritic stem to the soma (Figure 3A, 1–3). Thus recordings from PFC pyramidal cells in animals performing spatial working memory tasks under these conditions would show well-defined delay-related activity (Figure 3A, 4), that is thought to be the cellular basis for working memory. α-2-Adrenoceptor stimulation (
Li B-M, Mei Z-T (1994): Alpha-2 adrenergic modulation of prefrontal neuronal activity related to working memory in monkeys. Abstracts of the 3rd Congress of Federation of Asian and Oceanian Physiological Societies 96.
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.
) both enhance delay-related activity and spatial working memory performance in monkeys.
In contrast, we hypothesize that during stress exposure (Figure 3B), increased levels of norepinephrine and dopamine would act on the dendritic stem to erode signal transfer.
have shown that dopamine acting at D1/D5 receptors can decrease high threshold calcium currents that normally convey signals to the soma by closing n and p calcium channels. This reduction in signal is illustrated in Figure 3B, 1–2. Furthermore, the work of
Marek GJ, Aghajanian GK (1999): 5-HT2A receptor or alpha 1-adrenoceptor activation induces EPSCs in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206.
suggests that NE may erode signal transfer by increasing noise in the dendritic stem. These studies have shown that NE acts at α-1-adrenoceptors to increase glutamate release, that in turn increases excitatory post-synaptic sodium currents in the proximal stem. This increase in background noise (illustrated in Figure 3B, 3), would further obscure signal transmission by decreasing the signal/noise ratio of cell response. This erosion in signal transfer thus would decrease the delay-related activity needed to guide behavior during working memory tasks (Figure 3B, 4). Note that this model suggests that NE and DA actions may be additive or synergistic, and that the signal may be able to survive either modest reduction by DA, or modest noise by NE, but could not survive both. This hypothesis is supported by the finding that either a D1/D5 (
) or an α-1-adrenoceptor antagonist (present study) can protect performance from the detrimental effects of stress. The model further predicts that a reduction in glutamate release might similarly be beneficial in reversing the stress response.
It is understood that this model is simplistic, and that numerous actions likely contribute to stress-induced impairments in PFC function. For example, serotoninergic and opioid mechanisms may also contribute to the stress response.
have shown that 5HT2A receptor stimulation in the PFC, like α-1 adrenoceptor stimulation, can increase glutamate release and excitatory post-synaptic potentials in the dendritic stem. It is also likely that actions on other parts of the pyramidal cell, and on interneurons, contribute to the overall response.
Advances in our basic understanding of stress effects on higher cortical function are essential to our understanding of neuropsychiatric disorders. The present study expands our focus beyond DA actions to provide a more integrative view of mechanisms influencing PFC function during stress.
The contribution of a-2 noradrenergic mechanisms to prefrontal cortical cognitive function Potential significance to Attention Deficit Hyperactivity Disorder.
This work was supported by U.S. Public Health Service grant (MERIT Award) AG06036 to AFTA. We would like to thank L. Ciavarella and T. White for their expert technical assistance.
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Li B-M, Mei Z-T (1994): Alpha-2 adrenergic modulation of prefrontal neuronal activity related to working memory in monkeys. Abstracts of the 3rd Congress of Federation of Asian and Oceanian Physiological Societies 96.
Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys.
Mao Z-M, Arnsten AFT, Li B-M (1999): Local infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys. Biol Psychiatry 46:1259–1265.
Marek GJ, Aghajanian GK (1999): 5-HT2A receptor or alpha 1-adrenoceptor activation induces EPSCs in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206.
Roozendaal B, Koolhaas JM, Bohus B (1991): Attenuated cardiovascular, endocrine and behavioral response after a single footshock in central amygdaloid lesioned male rats. Physiol Behav 50:771–775.
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.
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