Irwin Lucki

Assessing antidepressant activity in rodents: recent developments and future needs

Animal models are indispensable tools in the search to identify new antidepressant drugs and to provide insights into the neuropathology that underlies the idiopathic disease state of depression. As new targets are developed, both serendipitously and through hypothesis-driven research, existing animal paradigms are being modified and new tests are being developed to detect antidepressant actions of compounds acting on a broad range of neural and genetic targets. This review focuses on recent findings regarding some of the most widely employed animal models used currently to predict antidepressant potential. Emphasis is placed on recent modifications to such paradigms that have increased their utility and reliability. Furthermore, some key issues that need to be addressed for future discovery of novel antidepressant agents are examined, and the available data on genetically altered mice that might lead to the discovery of novel targets for antidepressant action are collated.

Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants

This study demonstrated that distinct patterns of active behaviors are produced by antidepressants that selectively inhibit norepinephrine (NE) or serotonin (5-HT) uptake in the rat forced swimming test (FST). A behavior sampling technique was developed to score the active behaviors swimming, climbing and diving, as well as immobility. The rats behavior was recorded at the end of each 5-s period during the test session. The sampling technique was both reliable, as demonstrated by test-retest reliability and inter-rater reliability, and valid, as shown by comparison to the timing of behavior durations. Five different antidepressant drugs which block monoamine uptake and two 5-HT1A receptor agonists were shown to decrease immobility in the FST; however, they produced distinct patterns of active behaviors. The selective NE uptake inhibitors desipramine and maprotiline selectively increased climbing, whereas the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline and paroxetine selectively increased swimming. The 5-HT1A receptor agonists 8-OH-DPAT and gepirone also selectively increased swimming. These results show that:1) SSRIs are not false negatives in the FST; 2) at least two behaviorally distinct processes occur in the FST; and 3) enhancement of NE neurotransmission may mediate climbing in the FST, whereas enhancement of 5-HT neurotransmission may mediate swimming.

The spectrum of behaviors influenced by serotonin

The diverse array of behavioral effects of serotonin form the basis for understanding its potential role as an etiological marker in psychiatric disorders and for the successful pharmacologic intervention of drugs regulating serotonin neurotransmission in behavior. General theories of the behavioral functions of serotonin have implicated serotonin as a general inhibitor of behavioral responding and in modulating motor behavior. The ability of serotonin to regulate behavioral satiety and macronutrient selection provides the basis for pharmacologic treatment of obesity and eating disorders. The role of serotonin in behavioral suppression may be important in social behavior involving aggression and anxiety. The role of serotonin in neuroendocrine regulation provides a basis for understanding serotonin dysregulation in depression. Animal behavior tests are being used to better understand the neural substrates underlying the behavioral effects of antidepressant drugs and to address important issues in clinical treatment. The integration of information between basic and clinical studies provides the basis for future development of more sophisticated pharmacologic treatments of psychiatric disorders.

Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their antidepressant-like effects by increasing synaptic concentrations of serotonin (5-HT). The rat forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Procedural modifications recently introduced by our laboratory have enabled SSRI-induced behavioral responses to be measured in the modified FST. The use of this model to understand the pharmacological and physiological mechanisms underlying the role of 5-HT in the behavioral effects of antidepressant drugs is reviewed. Although all antidepressants reduced behavioral immobility, those antidepressants that increase serotonergic neurotransmission predominantly increase swimming behavior whereas those that increase catacholaminergic neurotransmission increase climbing behavior. The 5-HT(1A), 5-HT(1B/1D) and 5-HT(2C) receptors are the 5-HT receptors most important to the therapeutic effects of SSRIs, based on extensive evaluation of agonists and antagonists of individual 5-HT receptor subtypes. Studies involving chronic administration have shown that the effects of antidepressants are augmented following chronic treatment. Other studies have demonstrated strain differences in the response to serotonergic compounds. Finally, a physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF).

5-HT1A receptor function in major depressive disorder

Dysfunction of the serotonin 1A receptor (5-HT(1A)) may play a role in the genesis of major depressive disorder (MDD). Here we review the pharmacological, post-mortem, positron emission tomography (PET), and genetic evidence in support of this statement. We also touch briefly on two MDD-associated phenotypes, cognitive impairment and somatic pain. The results of pharmacological challenge studies with 5-HT(1A) receptor agonists are indicative of blunted endocrine responses in depressed patients. Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other treatment, such as electroconvulsive shock therapy (ECT), all increase post-synaptic 5-HT(1A) receptor signaling through either direct or indirect effects. Reduced somatodendritic and postsynaptic 5-HT(1A) receptor numbers or affinity have been reported in some post-mortem studies of suicide victims, a result consistent with well-replicated PET analyses demonstrating reduced 5-HT(1A) receptor binding potential in diverse regions such as the dorsal raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus. 5-HT(1A) receptor knockout (KO) mice display increased anxiety-related behavior, which, unlike in their wild-type counterparts, cannot be rescued with antidepressant drug (AD) treatment. In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5-HT(1A) receptor gene (HTR1A; rs6295), which abrogates a transcription factor binding site for deformed epidermal autoregulatory factor-1 (Deaf-1) and Hes5, has been reported to be over-represented in MDD cases. Conversely, the C allele has been associated with better response to AD drugs. We raise the possibility that 5-HT(1A) receptor dysfunction represents one potential mechanism underpinning MDD and other stress-related disorders.

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test

Abstract Rationale: The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. Objectives: The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Methods: Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Results: Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Conclusions: Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems.

cAMP Response Element-Binding Protein Is Essential for the Upregulation of Brain-Derived Neurotrophic Factor Transcription, But Not the Behavioral or Endocrine Responses to Antidepressant Drugs

Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two antidepressants, desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly to DMI and FLX administration in the forced swim test and tail suspension test. Furthermore, the ability of DMI to suppress an acute corticosterone response after swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular target of CREB, BDNF, is abolished in the CREB-deficient mice after chronic administration of DMI. These data are the first to demonstrate that CREB activation is upstream of BDNF mechanistically in response to antidepressant drug treatment. Therefore, although behavioral and endocrine responses to antidepressants may occur by CREB-independent mechanisms, CREB is critical to target gene regulation after chronic drug administration, which may contribute to long-term adaptations of the system to antidepressant drug treatment.

Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects

Drug development research has identified neurotrophic factors as a downstream target of chronic antidepressant treatments. In order to study their antidepressant-like effects, two neurotrophic factors, brain-derived neurotrophic factor and insulin-like growth factor I, were examined in the rat modified forced swimming test after a single icv administration. Both neurotrophins produced antidepressant-like behavioral effects in the modified rat forced swimming test, reducing immobility and increasing swimming. In contrast to currently used antidepressants, which produce acute effects in the forced swimming test, the effects of the neurotrophins were unusually long lasting and persisted at least 6 days after the treatment. Neither neurotrophic factor had an effect on locomotor activity. The results support a role for neurotrophic factors mediating the behavioral effects of antidepressant drugs.

Adult Hippocampal Neurogenesis: Regulation, Functional Implications, And Contribution to Disease Pathology

It is now well established that the mammalian brain has the capacity to produce new neurons into adulthood. One such region that provides the proper milieu to sustain progenitor cells and is permissive to neuronal fate determination is located in the dentate gyrus of the hippocampus. This review will discuss in detail the complex process of adult hippocampal neurogenesis, including proliferation, differentiation, survival, and incorporation into neuronal networks. The regulation of this phenomenon by a number of factors is described, including neurotransmitter systems, growth factors, paracrine signaling molecules, neuropeptides, transcription factors, endogenous psychotropic systems, sex hormones, stress, and others. This review also addresses the functional significance of adult born hippocampal granule cells with regard to hippocampal circuitry dynamics and behavior. Furthermore, the relevance of perturbations in adult hippocampal neurogenesis to the pathophysiology of various disease states, including depression, schizophrenia, epilepsy, and diabetes are examined. Finally, this review discusses the potential of using hippocampal neurogenesis as a therapeutic target for these disorders.

Strain Differences in the Behavioral Effects of Antidepressant Drugs in the Rat Forced Swimming Test

Wistar–Kyoto (WKY) rats provide a model of stress-induced depressive behavior, because they show enhanced vulnerability to the effects of stressors. The present study examined differences in the behavioral response to different types of antidepressant drugs between WKY and Sprague–Dawley (SD) rats in the forced swimming test (FST). WKY rats displayed significantly greater immobility than SD rats during their exposure to the FST. The noradrenergic antidepressant, desipramine, produced a dose-dependent reduction of immobility and increase of climbing behavior in the SD rats. In WKY rats, desipramine reduced immobility at a lower dose and produced increases of both swimming and climbing behavior. The serotonergic compounds, fluoxetine and 8-OH-DPAT, produced dose-dependent reductions of immobility and increases of swimming behavior in the FST in SD rats, but the response to the serotonergic drugs were blunted in WKY rats. These results indicate that genetic or constitutive differences may determine the distinct behavioral profiles for antidepressant compounds with selective pharmacological effects in different rat strains, and these effects may be related to genetic heterogeneity of antidepressant responses in depressed patients.