Corina O. Bondi

Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment

Chronic stress is a risk factor for the development of many psychopathological conditions in humans, including major depression and anxiety disorders. There is a high degree of comorbidity of depression and anxiety. Moreover, cognitive impairments associated with frontal lobe dysfunction, including deficits in cognitive set-shifting and behavioral flexibility, are increasingly recognized as major components of depression, anxiety disorders, and other stress-related psychiatric illnesses. To begin to understand the neurobiological mechanisms underlying the cognitive and emotional consequences of chronic stress, it is necessary to employ an animal model that exhibits similar effects. In the present study, a rat model of chronic unpredictable stress (CUS) consistently induced a cognitive impairment in extradimensional set shifting capability in an attentional set shifting test, suggesting an alteration in function of the medial prefrontal cortex. CUS also increased anxiety-like behavior on the elevated plus-maze. Further, chronic treatment both with the selective norepinephrine reuptake blocker, desipramine (7.5 mg/kg/day), and the selective serotonin reuptake blocker, escitalopram (10 mg/kg/day), beginning 1 week before CUS treatment and continuing through the behavioral testing period, prevented the CUS-induced deficit in extradimensional set-shifting. Chronic desipramine treatment also prevented the CUS-induced increase in anxiety-like behavioral reactivity on the plus-maze, but escitalopram was less effective on this measure. Thus, CUS induced both cognitive and emotional disturbances that are similar to components of major depression and anxiety disorders. These effects were prevented by chronic treatment with antidepressant drugs, consistent also with clinical evidence that relapse of depressive episodes can be prevented by antidepressant drug treatment.

Behavioural assays to model cognitive and affective dimensions of depression and anxiety in rats.

Animal models have been used extensively to investigate neuropsychiatric disorders, such as depression, and their treatment. However, the aetiology and pathophysiology of many such disorders are largely unknown, which makes validation of animal models particularly challenging. Furthermore, many diagnostic symptoms are difficult to define, operationalise and quantify, especially in experimental animals such as rats. Thus, rather than attempting to model complex human syndromes such as depression in their entirety, it can be more productive to define and model components of the illness that may account for clusters of co‐varying symptoms, and that may share common underlying neurobiological mechanisms. In preclinical investigations of the neural regulatory mechanisms linking stress to depression and anxiety disorders, as well as the mechanisms by which chronic treatment with antidepressant drugs may exert their beneficial effects in these conditions, we have employed a number of behavioural tests in rats to model specific cognitive and anxiety‐like components of depression and anxiety disorders. In the present study, we review the procedures for conducting four such behavioural assays: the attentional set‐shifting test, the elevated‐plus maze, the social interaction test and the shock‐probe defensive burying test. The purpose is to serve as a guide to the utility and limitations of these tools, and as an aid in optimising their use and productivity.

Chronic treatment with desipramine improves cognitive performance of rats in an attentional set-shifting test

Alterations in central monoaminergic neurotransmission are important in the actions of many antidepressants. This study tested the hypothesis that tonic elevation of noradrenergic (NA) neurotransmission in medial prefrontal cortex (mPFC) by chronic treatment with the selective norepinephrine (NE) reuptake blocker desipramine (DMI) may contribute to the beneficial cognitive effects of this antidepressant drug (AD). Male Sprague–Dawley rats were treated with DMI acutely (15 mg/kg, i.p.) or chronically for 21 days (7.5 mg/kg/day via osmotic minipump) before assessing performance on an attentional set-shifting test. The extradimensional set-shifting component of this test reflects a process of cognitive flexibility that is dependent upon mPFC, and that we have shown previously to be facilitated by NA activity in mPFC. Microdialysis was performed to measure NE release in mPFC concurrently with behavioral testing. Acute DMI treatment produced an increase in extracellular NE levels in mPFC, and a modest improvement in overall performance across all task stages of the attentional set-shifting test, but failed to produce a significant improvement in any of the individual specific tasks comprising the test sequence. Chronic DMI treatment tonically elevated basal extracellular NE levels in mPFC, associated with a significant improvement in performance specifically on the extradimensional set-shifting component of the test. There was also a significant reduction in set loss errors in rats treated chronically with DMI. Hence, tonic elevation of NA transmission in mPFC by chronic DMI treatment was associated with a time-dependent facilitation of cognitive flexibility that may contribute to the mechanism whereby chronic treatment with ADs, specifically NE reuptake blockers, may exert a beneficial therapeutic effect on cognition in depressed patients.

Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by α1-adrenergic receptors in medial prefrontal cortex

Chronic stress is a risk factor for many psychopathological conditions, including depression and anxiety disorders. Cognitive impairments associated with prefrontal cortical dysfunction are a major component of such illnesses. Using an attentional set-shifting test (AST), we have previously shown that elevating noradrenergic activity in rat medial prefrontal cortex (mPFC) can facilitate cognitive set-shifting, and that chronic unpredictable stress (CUS) caused set-shifting deficits. It is not known, however, if noradrenergic modulatory function is compromised by chronic stress, perhaps contributing to the stress-induced cognitive deficit. Thus, the first study investigated whether acutely elevating noradrenergic activity in mPFC still enhances cognitive function after chronic stress. As previously demonstrated, CUS impaired cognitive set-shifting on the AST. This deficit was abolished by acute systemic administration of the alpha(2)-adrenergic autoreceptor antagonist, atipamezole. Microdialysis revealed no differences in extracellular norepinephrine (NE) levels in mPFC of CUS-exposed and unstressed control rats at baseline or during behavioral testing, and comparable increases after atipamezole. In the second experiment, rats were treated chronically with the selective NE reuptake blocker, desipramine, during the CUS treatment through behavioral testing. Again, CUS impaired cognitive set-shifting in vehicle-treated rats, and chronic desipramine treatment prevented such deficits. Acute blockade of post-synaptic alpha(1)-adrenergic receptors in mPFC prior to testing blocked the beneficial effect of desipramine on cognitive set-shifting. These results suggest that desipramine restores cognitive set-shifting capability that has been compromised by chronic stress by activating alpha(1)-adrenergic receptors in the mPFC. Thus, noradrenergic modulatory capability in mPFC remains intact after CUS, and this represents one possible substrate by which antidepressants may exert their beneficial effects in the treatment of depression.

Adolescent Behavior and Dopamine Availability Are Uniquely Sensitive to Dietary Omega-3 Fatty Acid Deficiency

BACKGROUND Understanding the nature of environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. These factors are typically experiential in nature, such as stress and urbanicity, but nutrition--in particular dietary deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs)-has increasingly been implicated in the symptomatic onset of schizophrenia and mood disorders, which typically occurs during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult. METHODS A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the basis of the assumption that dietary trends toward decreased consumption of these fats began 4-5 decades ago when the parents of current adolescents were born. Behavioral performance in a wide range of tasks as well as markers of dopamine-related neurotransmission was compared in adolescents and adults fed n-3 PUFA adequate and deficient diets. RESULTS In adolescents, dietary n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum. CONCLUSIONS These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. Furthermore, they suggest that n-3 PUFA deficiency disrupts adolescent behaviors through enhanced dorsal striatal dopamine availability.

Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine

We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus maze and in social behavior on the social interaction test. Since these responses represent inhibition of ongoing behavior, it is important to also address whether NE facilitates a response that represents an activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1, shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH, taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were allowed to bury the probe compared to rats prevented from burying by providing them with minimal bedding, indicating that the active defensive burying behavior is an effective coping strategy that reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)- or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment. Moreover, rats treated chronically with DMI showed no significant rise of plasma ACTH in response to shock-probe exposure. Thus, acute stress-induced release of NE in LS facilitated defensive burying, an active, adaptive behavioral coping response. Chronic treatment with the NE reuptake blocker and antidepressant drug DMI attenuated acute noradrenergic facilitation of the active burying response, and also attenuated the level of perceived stress driving that response. These results suggest that long-term regulation of the acute modulatory function of NE by chronic treatment with reuptake blockers may contribute to the mechanisms by which such drugs exert their anxiolytic effects in the treatment of stress-related psychiatric conditions, including depression and anxiety.

Reduced Presynaptic Dopamine Activity in Adolescent Dorsal Striatum

Adolescence coincides with symptomatic onset of several psychiatric illnesses including schizophrenia and addiction. Excess limbic dopamine activity has been implicated in these vulnerabilities. We combined molecular and dynamic indices of dopamine neurotransmission to assess dopamine function in adolescent rats in two functionally distinct striatal subregions: nucleus accumbens (NAc) and dorsal striatum (DS). In adolescents, we find an overall reduction in dopamine availability selective to the DS. Dopamine release in the DS, but not in the NAc, was less responsive to amphetamine in adolescents compared to adults. The dopamine transporter (DAT) inhibitor, nomifensine, similarly inhibited basal and amphetamine-induced dopamine release in either regions of both the age groups, suggesting that the reduced effectiveness of amphetamine is not due to differences in DAT function. Furthermore, DAT and vesicular monoamine transporter-2 expressions were similar in the DS and NAc of adolescent rats. In contrast, expression of tyrosine hydroxylase (TH) was reduced in the DS, but not in the NAc, of adolescents compared to adults. Behaviorally, adolescents were less sensitive to amphetamine but more sensitive to a TH inhibitor. These data indicate that, in contrast to the general notion that dopamine is hyperactive in adolescents, there is diminished presynaptic dopamine activity in adolescents that is selective to the DS and may result from attenuated TH activity. Given recent reports of altered dopamine activity in associative/dorsal striatum of individuals at a clinically high risk of psychosis, our data further support the idea that dorsal, as opposed to ventral, regions of the striatum are a locus of vulnerability for psychosis.

Norepinephrine Transporter Regulation Mediates the Long-Term Behavioral Effects of the Antidepressant Desipramine

The relationship between the ability of repeated desipramine treatment to cause downregulation of the norepinephrine transporter (NET) and produce antidepressant-like effects on behavior was determined. Treatment of rats with 15 mg/kg per day desipramine reduced NET expression, measured by 3H-nisoxetine binding and SDS–PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET expression resulted in reduced norepinephrine uptake, measured in vitro, and increased noradrenergic neurotransmission, measured in vivo using microdialysis. Overall, the dose–response and time-of-recovery relationships for altered NET expression matched those for production of antidepressant-like effects on behavior. The importance of increased noradrenergic neurotransmission in the persistent antidepressant-like effect on behavior was confirmed by demonstrating that it was blocked by inhibition of catecholamine synthesis with α-methyl-p-tyrosine. The present results suggest an important role for NET regulation in the long-term behavioral effects of desipramine and are consistent with clinical data suggesting that enhanced noradrenergic neurotransmission is necessary, but not sufficient, for its antidepressant actions. Understanding the mechanisms underlying NET regulation in vivo may suggest novel targets for therapeutic intervention in the treatment of depression.

Glutamatergic animal models of schizophrenia

Dysregulation of glutamate neurotransmission has been implicated in schizophrenia primarily because antagonists of the n-methyl-d-aspartate (NMDA) subtype of glutamate receptors exacerbate preexisting symptoms of schizophrenia in patients and produce behavioral disruptions that resemble some symptoms of schizophrenia in healthy individuals. Given this, NMDA receptor antagonists have been used extensively to model aspects of the disease in laboratory animals and have provided a useful preclinical tool for testing novel treatment strategies. More recent genetic and postmortem findings have implicated proteins other than the NMDA receptor in the pathophysiology of schizophrenia which play a role in regulation of the glutamate synapse. Animal models developed based on these findings have the potential of increasing our mechanistic understanding of the disease. Here we review some of the pertinent literature related to pharmacological and genetic animal models of glutamate dysfunction in schizophrenia.

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.