Progress in Neuro-Psychopharmacology and Biological Psychiatry
Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by α1-adrenergic receptors in medial prefrontal cortex
Introduction
Cognitive impairments associated with prefrontal cortical dysfunction are major components of depression, anxiety disorders and other stress-related psychiatric illnesses (Anisman and Matheson, 2005, Beck, 1976, Beck et al., 1987, Fossati et al., 1999). The medial prefrontal cortex (mPFC) is particularly important in cognitive set-shifting and flexibility, i.e., using feedback from the environment to modify established behavioral patterns in an appropriate manner (Dalley et al., 2004, Ragozzino et al., 1999). Depressed patients exhibit cognitive flexibility deficits and mPFC hypoactivity (Austin et al., 2001, Beats et al., 1996, Davidson et al., 2002, Rogers et al., 2004). The attentional set-shifting test (AST) was developed to assess such prefrontal cortical executive capabilities in rats (Birrell and Brown, 2000). Lesions of rat mPFC specifically impaired cognitive set-shifting on the AST, confirming a function analogous to that of mPFC in humans and non-human primates (Dalley et al., 2004, Dias et al., 1996, Owen et al., 1991, Ragozzino et al., 1999).
The brain noradrenergic (NA) system modulates cognitive function in contexts such as arousal, attention, learning and memory (Berridge et al., 1993, Cole and Robbins, 1992, Devauges and Sara, 1990). We have previously shown that enhancing NA tone by acute systemic administration of the α2-adrenergic autoreceptor antagonist, atipamezole, can improve cognitive set-shifting on the AST, and that this effect was blocked by microinjections of the α1-adrenergic receptor antagonist, benoxathian, directly into mPFC (Lapiz and Morilak, 2006). Norepinephrine (NE) also plays an important role in the physiological and behavioral responses to stress (Aston-Jones et al., 1991, Morilak et al., 2005). Thus, dysregulation of NE has been implicated in the stress-related etiology of depression and anxiety disorders (Ressler and Nemeroff, 2000, Schatzberg and Schildkraut, 1995), and NE reuptake blockers are beneficial in their treatment (see Morilak and Frazer, 2004).
Unpredictable stress has greater negative impact than predictable stress (see Anisman and Matheson, 2005, Willner and Mitchell, 2002). Thus, to study possible mechanisms underlying stress-induced cognitive dysfunction in rats, we have employed a chronic unpredictable stress (CUS) model (Lu et al., 2006, Willner and Mitchell, 2002). CUS was shown to induce cognitive set-shifting deficits that were prevented by chronic treatment with the selective NE reuptake blocker, desipramine (DMI) (Bondi et al., 2008b). However, the mechanisms underlying the beneficial effects of DMI are not known, nor is it known if the CUS-induced cognitive deficit is associated with a loss of noradrenergic modulatory capability in mPFC. Thus, the purpose of Experiment 1 was first to determine if CUS compromised noradrenergic modulatory function in mPFC, specifically whether the CUS-induced cognitive deficit was associated with a change in NE release evoked in mPFC, and whether acute pharmacological elevation of NE in mPFC is still capable of enhancing cognitive function after CUS. If noradrenergic facilitation of cognitive flexibility in mPFC remains intact after chronic stress, then this may serve a neuroadaptive function, helping to overcome the detrimental effects of chronic stress. Additionally, it may represent a substrate by which antidepressant drugs that block NE reuptake can exert their beneficial effects on cognition. Thus, to further examine potential mechanisms underlying antidepressant drug effects, Experiment 2 tested the hypothesis that post-synaptic α1-adrenergic receptors in mPFC are responsible for the beneficial effects on cognition of chronic NE reuptake blockade during CUS. Portions of this work have been presented in abstract form (Bondi et al., 2008a).
Section snippets
Animals
A total of 124 adult male Sprague–Dawley rats (Harlan, Indianapolis, IN, USA), weighing 200–250 g upon arrival, were used. They were initially housed in groups of three in 25 × 45 × 15 cm plastic cages, and maintained on a 12/12 h light/dark cycle (lights on at 0700 h), with food and water available ad libitum. Rats were acclimated to the housing facility for at least 4 days prior to any experimental procedures. For the social defeat procedure, male Long–Evans rats (Harlan, Indianapolis, IN, USA),
Results
Experiment 1 Effect of elevating NE neurotransmission by acute systemic administration of the α2-autoreceptor antagonist, atipamezole, on the cognitive deficit seen after CUS.
The first experiment assessed whether acutely elevating NE release by systemic administration of the α2-autoreceptor antagonist, atipamezole, was able to reverse the detrimental effects of CUS on attentional set-shifting performance. A comparison between rats implanted with microdialysis cannulae versus those that were not revealed no
Discussion
The purpose of this study was to investigate whether chronic stress may compromise noradrenergic modulation of cognitive processes in prefrontal cortex, and to elucidate potential mechanisms by which chronic antidepressant drug treatment might exert beneficial effects against stress-induced cognitive dysfunction. We provide evidence that the capacity for noradrenergic facilitation of cognitive flexibility in medial prefrontal cortex is preserved after chronic stress, thus potentially
Conclusion
Understanding the mechanisms by which chronic stress alters activity of the mPFC, or the noradrenergic modulation of that activity, may provide important clues to the mechanisms underlying stress-related psychopathology and its treatment. The fact that the noradrenergic system is still capable of exerting a facilitating influence in mPFC after cognitive capabilities have been compromised by chronic stress provides a viable substrate by which antidepressant drugs that block NE reuptake may exert
Acknowledgements
We thank Ms. Ashley Furr for outstanding technical assistance. We also thank Dr. Jim Mintz, Departments of Psychiatry and Epidemiology and Biostatistics, UTHSCSA for his insight and advice with the statistical analyses. This work was supported by research grants from the National Institute of Mental Health (MH053851 and MH072672) and by the San Antonio Neuroscience Alliance. The authors have no conflicts of interest to report, nor any involvement to disclose, financial or otherwise, that may
References (74)
- et al.
Stress, depression, and anhedonia: caveats concerning animal models
Neurosci Biobehav Revs
(2005) - et al.
Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions
Biol Psychiatry
(2005) - et al.
α-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function
Biol Psychiatry
(1999) - et al.
Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance
Prog Brain Res
(1991) - et al.
Role of locus coeruleus in attention and behavioral flexibility
Biol Psychiatry
(1999) - et al.
Effects of locus coeruleus inactivation on electroencephalographic activity in neocortex and hippocampus
Neuroscience
(1993) - et al.
Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats
Pharm Biochem Behav
(2000) - et al.
Current advances and trends in the treatment of depression
Trends Pharmacol Sci
(1994) - et al.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder
Neuropsychopharmacology
(2002) - et al.
Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress
Neuroscience
(2002)
Prefrontal cognitive and executive functions in rodents: neural and neurochemical substrates
Neurosci Biobehav Revs
Activation of the noradrenergic system facilitates an attentional shift in the rat
Behav Brain Res
Executive functioning and verbal memory in young patients with unipolar depression and schizophrenia
Psychiatry Res
Facilitation of cognitive functions by a specific [alpha]2-adrenoceptor antagonist, atipamezole
Eur J Pharmacol
Effects of antidepressant drugs on different receptors in the brain
Eur J Pharmacol
Single-unit and physiological analyses of brain norepinephrine function in behaving animals
Prog Brain Res
Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability
Neuroscience
Local infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys
Biol Psychiatry
Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat
Behav Brain Res
Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting
Neuroscience
Role of brain norepinephrine in the behavioral response to stress
Prog Neuropsychopharmacol Biol Psychiatr
Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalohippocampectomy
Neuropsychologia
Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex
Neuroscience
Effect of sympathomimetic amines on the synaptosomal transport of noradrenaline, dopamine and 5-hydroxytryptamine
Eur J Pharmacol
Atipamezole, an alpha 2 antagonist, stabilizes age-related high-voltage spindle and passive avoidance defects
Pharm Biochem Behav
Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence
Neurosci Res
Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat
Psychoneuroendocrinology
Locus coeruleus-evoked responses in behaving rats: a clue to the role of noradrenaline in memory
Brain Res Bull
Regional concentrations of noradrenaline and dopamine in the frontal cortex of the rat: dopaminergic innervation of the prefrontal subareas and lateralization of prefrontal dopamine
Brain Res
Reversal of phenylpropanolamine anorexia in rats by the alpha-1 receptor antagonist benoxathian
Pharmacol Biochem Behav
Scales and statistics: parametric and nonparametric
Psychol Bull
Cognitive deficits in depression: possible implications for functional neuropathology
Brit J Psychiatry
Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed
Psychol Med
Cognitive therapy and the emotional disorders
Differentiating anxiety and depression: a test of the cognitive content-specificity hypothesis
J Abnormal Psychol
The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling
Mol Psychiatry
Medial frontal cortex mediates perceptual attentional set shifting in the rat
J Neurosci
Cited by (82)
The acute exercise-cognition interaction: From the catecholamines hypothesis to an interoception model
2021, International Journal of PsychophysiologyA combined therapeutic regimen of citalopram and environmental enrichment ameliorates attentional set-shifting performance after brain trauma
2021, European Journal of PharmacologyCitation Excerpt :This effect occurred without any differences in total trials to criterion or total errors being distinguishable among the Sham groups. Given the effort put forth to minimize the number of rats subjected to animal research, we limited the number of rats in the sham groups to the minimum number reported in the literature and appropriately powered as sufficient to highlight group effects in the AST task (i.e., n = 6–7) (Bondi et al., 2010, 2014a). These uncommon results in the sham groups may be an artifact of the small group numbers.
Discovery and proteomics analysis of effective compounds in Valeriana jatamansi jones for the treatment of anxiety
2021, Journal of EthnopharmacologyDeficiencies of microglia and TNFα in the mPFC-mediated cognitive inflexibility induced by social stress during adolescence
2019, Brain, Behavior, and ImmunityMolecular aspects of depression: A review from neurobiology to treatment
2019, European Journal of PharmacologyCitation Excerpt :Regarding the location of the synapses of these neurotransmitter systems, there is evidence that antidepressants may be antagonized by interventions in the hippocampus or prefrontal cortex. These effects were observed in both animal and human models (Bondi et al., 2011; Furr et al., 2012) The clinical selectivity of antidepressants SSRIs and SNRIs to 5-HT (Delgado et al., 1999) and norepinephrine depletion (Delgado et al., 1993; Miller et al., 1996) also demonstrate another important situation: Antidepressants that are selective for the 5-HT and norepinephrine systems have distinct mechanisms of action and specifically involve serotonergic and noradrenergic synapses, respectively.