Elucidation of the neurobiology of depression: insights from a novel genetic animal model

Progress in Neurobiology 62 (2000) 353±378

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Elucidation of the neurobiology of depression: insights from a novel genetic animal model Gal Yadid*, Rachel Nakash, Ilana Deri, Grin Tamar, Noa Kinor, Iris Gispan, Abraham Zangen Neuropharmacology Section, Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel Received 3 February 2000

Abstract Development of drugs for the e€ective treatment of depressive disorders requires elucidation of factors that are critical for clinically antidepressant e€ects. During the past 4 years, we have studied in situ neurochemical alterations in the brain that may underlie depressive behavior. This was achieved using the genetically-selected Flinders Sensitive Line (FSL) of rats (a unique animal model of depression), before and after chronic antidepressant treatment. This line of rats exhibits behavioral features characteristic of depression, and responds to chronic, but not acute, antidepressant treatments. This review summarizes our ®ndings concerning the local neuro-dynamics in the brain during manifestation of depressive behavior and e€ective antidepressant treatment in this animal model of depression. Understanding the abnormalities manifested in neurochemical pathways during depressive disorders and the dynamic e€ects of these abnormalities on the onset of action and ecacy of pharmacological treatments are crucial for the development of e€ective antidepresssant drugs and therapeutic strategies. 7 2000 Elsevier Science Ltd. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354

2.

Depressive behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 2.1. Characteristics of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 2.2. Mechanism of action of antidepressant drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

3.

Animal models of depression . . . . . . . . . . . . 3.1. Various models and validation criteria 3.2. The learned helplessness model. . . . . . 3.3. The chronic mild stress (CMS) model . 3.4. The swim low-active (SwLo) model. . .

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Abbreviations: CMS, chronic mild stress; CSF, cerebral spinal ¯uid; DOPAC, dihydroxyphenylacetic acid; ECF, extracellular ¯uid; FSL, Flinders sensitive line; 5-HIAA, 5-hydroxyindolacetic acid; HPLC, high pressure liquid chromatography; 5-HT, 5-hydroxytriptamine (Serotonin); 5HTP, 5-hydroxytryptophan; HVA, homovanillic acid; L-DOPA, 3,4-dihydroxy-phenylalanine; MAO, monoamine oxidase; MAOI, monoamine oxidase inhibitors; NA, noradrenaline; NAc, nucleus accumbens; NASI, NA selective reuptake inhibitors; NaSSA, noradrenergic and speci®c serotonergic antidepressant; NDRI, NA/DA reuptake inhibitors; PKA, protein kinase A; REM, rapid eye movement; SN, substantia nigra; SNRI, 5-HT/NA reuptake inhibitor; SARI, serotonin reuptake inhibitor and 5-HT2 blocker; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; TH, tyrosine hydroxylase; TRH, tryptophan hydroxylase; VTA, ventral tegmental area. * Corresponding author. Tel.: +972-3-531-8123; fax: +972-3-535-1824. E-mail address: [email protected] (G. Yadid). 0301-0082/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 3 0 1 - 0 0 8 2 ( 0 0 ) 0 0 0 1 8 - 6

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3.5.

4.

The Flinders sensitive line (FSL) of rats model . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 3.5.1. Establishment of the FSL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 3.5.2. Validity of the FSL as a model of depression . . . . . . . . . . . . . . . . . . . . . . . 359 3.5.2.1. Face validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 3.5.2.2. Construct validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 3.5.2.3. Predictive validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 3.5.3. Serotonergic functionality in FSL rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 3.5.3.1. Serotonergic pharmacology in the FSL rat . . . . . . . . . . . . . . . . . . 361 3.5.3.2. Alterations in 5-HT levels in limbic regions of the FSL rat . . . . . . 361 3.5.3.3. Impaired uptake of 5-HT in the FSL rat . . . . . . . . . . . . . . . . . . . 362 3.5.3.4. Monoamine oxidase (MAO) activity in limbic areas of the FSL rat 362 3.5.4. Dopaminergic functionality in the FSL rat . . . . . . . . . . . . . . . . . . . . . . . . . 364 3.5.4.1. The link between DA release in the nucleus accumbens to motivation and hedonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 3.5.4.2. Abnormal levels of DA and its metabolites in FSL rats . . . . . . . . . 365 3.5.5. Impaired communication between serotonergic and dopaminergic systems in the FSL rat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 3.5.6. Pharmacodynamics of 5-HT receptors in the FSL rat. . . . . . . . . . . . . . . . . . 368 3.5.7. Monoaminergic±endorphinic interaction in FSL rats . . . . . . . . . . . . . . . . . . 369 3.5.7.1. The neuropharmacology of b-endorphin . . . . . . . . . . . . . . . . . . . . 369 3.5.7.2. b-endorphin in relation to depression . . . . . . . . . . . . . . . . . . . . . . 369 3.5.7.3. E€ect of 5-HT on b-endorphin in the nucleus accumbens of rats (control and FSL)) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

1. Introduction Depressive disorders are serious illnesses, and a major public health problem. These ubiquitous disorders are characterized by similar manifestations and symptoms irrespective of country, cultural group or socio-economic status (Sartorius et al., 1983, 1993). Lifetime prevalence rates of 4.4±19.6% for major depression and 3.1±3.9% for dysthymia have been reported (Angst, 1992). Major depression usually develops early in life and can last for a lifetime, during which it will impair the overall function (with regard to occupation and social roles), and a€ect the quality of life (Weissman et al., 1988; Ormel et al., 1992) of the a€ected individual. A variety of methods, such as psychotherapy, pharmacological, electroconvulsive, and magnetic therapies, can be used to e€ectively treat depression but still with limited success (Nestler, 1998; Stahl, 1998c; Ressler and Nemero€, 1999). The available antidepressant treatments attempt to alleviate the symptoms of the disorder, to decrease the functional disability of the a€ected individual, and to increase their subjective well-being, quality of life and overall function. The direct costs of depression, such as expenditures associated with inpatient and outpatient care and drug therapy, as well as lost work time, are a great burden on the economy (Kind and Soren-

sen, 1993). Successful treatment with antidepressants can shorten and lessen inpatient and outpatient care, which together compose up to 18% of the direct costs of depression (Greenberg et al., 1993). Alleviation of personal su€ering is an important reason for developing more e€ective therapies, since the long period (2±6 weeks) required before signi®cant improvement is seen probably contributes to the high percentage (15%) of depressed patients that commit suicide (Akiskal, 1995). With regard to the evolution of antidepressant drugs, the ®rst ones are pharmacologically-a€ected multiple neurotransmitter systems, next came selective drugs with single pharmacological mechanisms, and later drugs that selectively a€ected multiple systems. The ecacy of antidepressants for treating major depression is well established (Dubovsky, 1994; Stahl, 1998c). Neurobiological and neuroanatomical studies indicate the importance of changes in both noradrenergic and serotonergic systems for successful antidepressant treatment (van Praag et al., 1990; Delgado et al., 1993; Cummings, 1993). Consequently, newlydeveloped antidepressant drugs are designed to a€ect both noradenergic and serotonergic neurotransmitter systems. Dual action and receptor-speci®c actions are being stressed in order to improve tolerability (Baldessarini, 1989; Potter et al., 1991; Stahl, 1998a, 1998b). The goals in developing e€ective antidepressants are

G. Yadid et al. / Progress in Neurobiology 62 (2000) 353±378

to achieve a fast onset of action and to enhance clinical ecacy, while reducing undesirable e€ects (Montgomery et al., 1991; Briner and Dodel, 1998). Adverse e€ects of antidepressants are probably related to the e€ects of monoamines on multiple receptors. A major goal of ongoing research is to design an antidepressant that will preserve receptor e€ects required for clinical ecacy, while eliminating receptor e€ects responsible for adverse e€ects (Sambunaris et al., 1997). The present review discusses recent ®ndings concerning alterations in the neurobiology of the brain that accompany depressive behavior and e€ective antidepressant treatment in a unique animal model of depression [Flinders Sensitive Line (FSL) of rats]. The relevance of these ®ndings to clinical situations is also discussed. 2. Depressive behavior 2.1. Characteristics of depression Major depression is de®ned as a chronic state (r2 weeks) of a patient su€ering from at least one core symptom and at least four of the following secondary symptoms. The core symptoms are: (i) lack of motivation and loss of interest in practically everything, and (ii) inability to experience pleasure in anything (anhedonia). The secondary symptoms are: (i) loss of appetite, (ii) insomnia [increased amount and decreased latency of rapid eye movement (REM) sleep, as determined by EEG measurements], (iii) motor retardation or agitation, (iv) feelings of worthlessness or guilt, (v) continues fatigue, (vi) cognitive diculties, and (vii) suicidal thoughts (Whybrow et al., 1984). The following physiological and biochemical characteristics are often observed in depressed patients: (i) chronic pain [50% of the depressed patients su€er from chronic pain (von Knorring et al., 1983, 1984)], (ii) high levels of plasma cortisol (Meltzer and Lowy, 1987; Maes and Meltzer, 1995), (iii) resistance in the dexamethasone suppression test (Stokes et al., 1975), (iv) supersensitivity to cholinergic agonists (Janowsky et al., 1980; Risch, 1982; Janowsky and Risch, 1984; Janowsky and Overstreet, 1995), and (v) ®rst degree relatives that also su€er from depressive disorders, i.e., a genetic component (Gershon et al., 1987). Whether certain biochemical markers characterize individuals su€ering from depressive disorders is not yet clear. In some studies, the levels of 5-hydroxyindolacetic acid [5-HIAA; a metabolite of serotonin (5hydroxytriptamine, 5-HT)] in the cerebral spinal ¯uid (CSF) of depressed patients were lower than in healthy volunteers (Asberg et al., 1984). However, in other studies, normal (Roy et al., 1985) or even higher (Reddy et al., 1992) levels of 5-HIAA were observed in the

355

CSF of depressed patients. Data from various postmortem samples of brain regions of suicide victims were inconclusive, except those from the brainstem where all studies showed decreased levels of 5-HT in suicide victims as compared to normal subjects (Cheetham et al., 1989; Mann et al., 1989). Although decreases in the quantity of presynaptic 5-HT uptake sites and increases in the quantity of 5-HT postsynaptic receptors have been reported in depressed patients, normal levels and even opposite results have been observed in some studies (Nestler, 1998). Lower than normal levels of 5-HT in platelets of depressed patients were reported in some studies (Coppen et al., 1976; Banki, 1978; Le Quan-Bui et al., 1984; Quintana, 1992), but not observed in others (Todrick et al., 1960; Stahl et al., 1983; Meltzer and Arora, 1986; Muck-Seler et al., 1991). A decreased uptake of 5-HT and its uptake sites in platelets of depressed patients were reported in several studies (Tuomisto and Tukianen, 1976; Briley et al., 1980; SuranyiCadotte et al., 1985). The density of 5-HT uptake sites in the prefrontal cortex of suicide victims was lower than in control (postmortem) brains (Stanley et al., 1982). A lower density of these sites was also seen in the occipital cortex and hippocampus of depressed patients in one study (Perry et al., 1983), but not in other studies (Owen et al., 1986; Gross-Issero€ et al., 1989). With regard to the density of 5-HT2 receptors in platelets of depressed patients and suicide victims, the density was higher than normal in three studies, but normal in another (Arora and Meltzer, 1989). In the prefrontal cortex of depressed patients and suicide victims, the density of 5-HT2 receptors was higher than normal in several studies (Arango et al., 1992; Arora and Meltzer, 1989), but not in others (Cheetham et al., 1988). A decrease in the uptake of 5-HT and an alteration in postsynaptic 5-HT receptors in depressed individuals would be indicative of a compensating mechanism for too low serotonergic activity (Meltzer and Lowy, 1987). Reports on the density of 5-HT1A receptors are contradictory as well. Higher levels of 5-HT1A receptors have been reported in the prefrontal cortex of nonviolent depressed suicides than in the brains of violent suicides and normal postmortem brains (Matsubara et al., 1991). In other studies, the density and anity of 5-HT1A receptors in the frontal and temporal cortex were similar for suicide victims who took no drugs and for normal postmortem samples (Cheetham et al., 1990; Arranz et al., 1994). Also, a low number and a low anity of these receptors were found in the hippocampus and amygdala, respectively, of suicide victims (Cheetham et al., 1990). The observed variations in the serotonergic system, even with the contradictions, led to the ``serotonergic

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theory'', which claims that in depressed patients there is a general decrease in serotonergic activity (Meltzer and Lowy, 1987; Maes and Meltzer, 1995; Feldman et al., 1997). An increase in serotonin availability in the synapse caused by antidepressant drugs supports this theory (Blier et al., 1990; see also Section 2.2). However, this phenomenon is observed immediately, while the clinical e€ect of the drugs is only observed after chronic (r2 weeks) treatment. In a few studies, a diet low in tryptophan (the precursor of 5-HT) caused a small and temporary lowering in the mood of depressed individuals, while a surplus of tryptophan caused a slight rise in mood (Young et al., 1985; Delgado et al., 1990). However, this was not seen in other studies (Cowen et al., 1985; Meltzer and Lowy, 1987; Maes and Meltzer, 1995). An increase in serotonergic activity causes a decrease in appetite (Meltzer and Lowy, 1987), which is one of the characteristic symptoms of depressed patients. Sleep disturbances (manifested by high frequency of REM-sleep and which are also characteristic symptoms of depressed patients) are in agreement with the serotonergic theory, since an increase in the availability of 5-HT in the synapse, caused by serotonin reuptake blockers, can cause a decrease in the frequency of REM-sleep (Fornal and Radulovacki, 1983). The lowering of pain threshold, which would facilitate manifestation of chronic pain, is also in accordance with the serotonergic theory, since there are many instances of analgesia following an increase in serotonergic activity (von Knorring et al., 1984). Analgesia may be mediated by an interaction between serotonin and endogenic opioids (von Knorring et al., 1984), and in depressed patients, the serotonergic activity is low, which may be conducive to a low pain threshold (see also Section 3.5.7). A direct link between the above biological parameters and the symptoms of the disease is not yet clear. 2.2. Mechanism of action of antidepressant drugs Although tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) were introduced as antidepressant drugs 40 years ago, they are still the standard of clinical ecacy, despite multiple adverse e€ects. The so-far unsurpassed clinical ecacy of TCAs probably results from their nonselective interaction with the NA (noradrenaline) and 5-HT neurotransmitter systems (Alpers and Himwich, 1972; Richelson and Nelson, 1984; Potter et al., 1991; Richelson, 1991). However, the actions of TCAs on other neurotransmitter systems (cholinergic, histaminergic) also produce a wide range of clinically relevant side e€ects. Over the last 40 years, six other classes of antidepressants have become available (Baldessarini, 1989; Potter et al., 1991; Stahl, 1998a, 1998b): selective

serotonin reuptake inhibitors (SSRIs; such as ¯uvoxamine, ¯uoxetine, citalopram, paroxetine and sertaline), 5-HT/NA reuptake inhibitor (SNRI; such as venlafaxine and minacipram), serotonin reuptake inhibitor and 5-HT2 blocker (SARI; such as nefazodone), NA and speci®c 5-HT antidepressant (NaSSA; such as mitrazapine), NA selective reuptake inhibitors (NASI; such as reboxetine), and NA/DA reuptake inhibitors (NDRI; such as bupropion). Selective, though receptor subtype-nonspeci®c, action of SSRIs increase the bioavailability of 5-HT in the synaptic cleft, including both the terminals and the bodies of neurons, in all brain regions. The ecacy of this class of antidepressants, especially in the severely depressed patients, is no greater than that of TCAs (Anderson and Tomenson, 1994; Burke and Preskorn, 1995); however, overdosing is less of a problem, since SSRIs produce multiple, but minor, clinically-relevant central and peripheral side e€ects (Baldessarini, 1989). The SNRIs enhance 5-HT as well as NA activity. Both the SSRIs and the SNRIs cause some adverse e€ects due to the drug-induced spillover of both NA and 5-HT, which nonselectively e€ect multiple 5-HT or NA receptors. Activation of 5-HT2 receptors may induce agitation, akinesia, anxiety, insomnia, panic attacks, and sexual dysfunction (Nelson, 1997; de Boer, 1996). Stimulation of 5-HT3 receptors may lead to diarrhea, gastrointestinal distress, headache, and nausea (Nelson, 1997; Stahl, 1997). In fact, depressed patients that undergo treatment with SSRIs or NSRIs experience such adverse e€ects. The antidepressant nefazodone is both a serotonin reuptake inhibitor and a potent 5-HT2 blocker. Its side e€ects do not include sexual dysfunction (Stahl, 1996; Frazer, 1997; Stahl, 1997). It is claimed that it may have fast onset of action in regard to some Hamilton parameters (Mendels et al., 1995; Davis et al., 1997). Mitrezapine (NaSSA) increases NA and 5-HT neurotransmission via a blockade of the central a2auto and hetro-adrenoceptors. This drug also blocks binding to 5-HT2 and 5-HT3 receptors. An increase in the release of 5-HT is believed to occur via increased ®ring of 5-HT neurons and stimulation of 5-HT1 receptors (Wheatley et al., 1998; Stahl, 1997). Reboxetine, the most selective NA reuptake antidepressant is not associated with sexual dysfunction and is more e€ective in certain subtypes of depression (Montgomery, 1997; Schatzberg et al., 1989). Bupropion (NDRI) is particularly e€ective in bipolar depression (Pitts et al., 1983) with a postmetabolic e€ect (Ascher et al., 1995). All the above-mentioned antidepressants are believed to facilitate monoaminergic neurotransmission. However, the clinical therapeutic action of these drugs cannot be explained by this facilitation alone, since the onset of the bene®cial e€ects of the

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drugs is only evident after several weeks of continued administration (Dubovsky, 1994; Nestler, 1998; Ressler and Nemero€, 1999). For the bene®cial e€ect of SSRIs, it was reported recently that they may also e€ect neurosteroids in the brain, separate of their e€ect on monoamines (Matheson et al., 1997; Uzunova et al., 1998). Recently, antidepressants have been administered together with pindolol (which among other actions antagonizes 5-HT1B receptors and is believed to increase 5-HT ®ring) or lithium, with mixed results (Artigas et al., 1994; Blier and de Montigny, 1994; Blier and Bergeron, 1995; Briner and Dodel, 1998). 3. Animal models of depression Animal models of depression can be used to dynamically study biological parameters that have been implicated in the expression of depression in humans. A model is de®ned as an experimental preparation (in this case animal) developed for the purpose of studying a condition in the same or di€erent species. Numerous animal models have been developed to mimic major depression in humans (see below); however, the extrapolation of the results to humans obtained with such models must be done cautiously and the validity of the models must be examined closely (Yadid, 1998). 3.1. Various models and validation criteria So far the following 18 animal models for depression in humans have been developed: (i) predatory behavior (Horowitz, 1965; Ueki, 1982), (ii) yohimbine I potentiation (Quinton, 1963; Malick, 1981), (iii) kindling (Goddard et al., 1969; Babington and Wedeking, 1973; Babington, 1975), (iv) dopa potentiation (Everett, 1967; Sigg and Hill, 1967), (v) 5-HTP-induced behavioral depression (Nagayama et al., 1980, 1981; Aprison et al., 1982), (vi) olfactory bulbectomy (Cairncross et al., 1977, Cairncross and Cox, 1978; Cairncross et al., 1979), (vii) isolation-induced hyperactivity (Einon et al., 1975; Sahakian et al., 1975, 1977), (viii) exhaustion stress (Hatotani and Nomura, 1982), (ix) circadian rhythms (Baltzer and Weiskrantz, 1973), (x) behavioral despair (Porsolt et al., 1977a, 1977b, 1978a, 1978b), (xi) chronic unpredictable stress (Katz, 1981; Katz and Sibel, 1982a, 1982b; Katz et al., 1981), (xii) separation models (Kaufman and Rosenblum, 1967; McKinney and Bunney, 1969; Hinde et al., 1978; Katz, 1981; Reite et al., 1981), (xiii) incentive disengagement (Klinger et al., 1974), (xiv) intra-cranial self-stimulation (Leith and Barrett, 1976, 1980; Barrett and White, 1980; Kokkinidis and Zacharko, 1980; Simpson and Annau, 1977), (xv) learned helplessness (Maier and Seligman, 1976; Maier, 1984), (xvi) chronic mild stress

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(CMS) (Willner, 1997), (xvii) Swim Low-Active (SwLo) line rat (Weiss et al., 1998), and (xviii) FSL of rats (Overstreet, 1993). Animal models of psychiatric conditions can be assessed on the basis of how well they ful®ll three major criteria: face validity (how well the model resembles the psychiatric condition), construct validity (how well the model is consistent with theoretical rationale) and predictive validity (how well the model responds favorably to the same drugs as humans with the condition). Some of the models listed above (i±iv) can only be assessed for predictive validity, others (v± ix) can be assessed for both predictive and face validities, and some (x±xviii) can be assessed for predictive, face, and construct validities (Willner, 1984). Depressive disorders are common in humans and are believed to be in¯uenced and/or induced by a wide variety of factors including biological, environmental, and genetic ones. Among the most potent environmental factors that may trigger or induce depressive episodes are stressful stimuli and events. Furthermore, individuals may be variedly sensitive to such stressful stimuli, i.e., only a subset of the population, when exposed to a particular stimuli, will develop a depressive disorder (Overstreet, 1998; Adell et al., 1988). Herein, four rat models of depression Ð learned helplessness, CMS, SwLo, and FSL for which predictive, face, and construct validities have been demonstrated Ð will be discussed. Two of these animal models of depression are environmental and two are genetic. The learned helplessness model (Seligman and Beagley, 1975) is one of the oldest and most widely used animal models of depression. The newer CMS model (Willner, 1997) uses environmental methods to induce abnormal behavioral states and exhibits chronicity. The genetically-selected rat models for depression provide a new type of model for studying depression. Originally, the FSL of rats (Overstreet, 1993) was selectively bred for di€erences in cholinergic sensitivity and the SwLo line of rats (Weiss et al., 1998) for low motor activity in a forced swim test. The FSL model is well established and expresses alterations in neurotransmitter functions that have been implicated in depressive disorders (Janowsky et al., 1994; Maes and Meltzer, 1995; Overstreet, 1998; see also Section 3.5). The innovative SwLo model integrates genetic and behavioral components. 3.2. The learned helplessness model Learned helplessness is a behavioral phenomenon in which animals are exposed to aversive stimuli under circumstances in which they cannot control or predict these stimuli (Seligman, 1975; Seligman and Beagley, 1975; Seligman et al., 1975). Exposure to such stimuli results in a long-lasting de®cit in escape performance,

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which has been termed learned helplessness. It has been argued that the model has good face validity because there is similarity between the behavioral characteristics of learned helplessness of animals and signs of depression in humans (Willner, 1984, 1986). For example, animals with learned helplessness exhibit loss of appetite and weight (Weiss, 1968), exhibit decreased locomotor activity (Wagner et al., 1977), and perform poorly in both appetitively- and aversively-motivated tasks (Anderson et al., 1968; Rosellini, 1978; Rosellini and de Cola, 1981; Zacharko et al., 1982). These behavioral characteristics are considered to correspond to the loss of appetite and weight, psychomotor retardation, and anhedonia, demonstrated by depressed humans (DSM-IIIR). Pharmacological treatments that are clinically e€ective in treating depression, such as tricyclics, MAOIs, atypical antidepressants, and electroconvulsive shock therapy, are e€ective in reducing the behavioral and physical abnormalities of rats exposed to uncontrollable stress (Willner, 1984; Willner, 1986; Petty et al., 1992). Thus, the learned helplessness model appears to have good predictive validity for identifying potentially useful pharmacotherapies for depression in humans. The construct validity of the learned helplessness model of depression rests on the following assumptions: that animals exposed to uncontrollable aversive events do become helpless, that a similar state is induced in people by uncontrollable aversive events, and that helplessness in people is the central symptom of depression. However, the ``helplessness'' in the animal experiments has not been conclusively established, the ``helplessness'' in human experiments is even less certain, and the relationship between helplessness and depression remain elusive (Willner, 1984). Furthermore, normal humans do not unambiguously develop learned helplessness under conditions of uncontrollable stress and only 10±50% of rats develop this syndrome (Garber et al., 1979), which casts doubt on the reliability of the phenomenon and its generality across species. Thus, construct validity has not been conclusively demonstrated for the learned helplessness model of depression. Over the years, several theoretical neurochemical models have been developed to explain depressive disorders. One of these models is the indolamine hypothesis, which postulates that depressive disorders are related to de®ciencies of indolamines, particularly 5HT (see also Section 3.5.3). Indeed, alterations in the 5-HT system have been described in rats subjected to the learned helplessness procedures (Miyauchi et al., 1981; Naitoh et al., 1992). Local injection into the hippocampus of an antisense oligonucleotide to the 5HT2A receptor signi®cantly reduced both the amounts of 5-HT2A receptors and learned helplessness (Papolos et al., 1996). Furthermore, local injection of a 5-HT1A

receptor agonist into the raphe nuclei also reduced learned helplessness (Maier et al., 1995). Thus, both presynaptic 5-HT1A autoreceptors and postsynaptic 5HT2A receptors modulate the expression of learned helplessness. Therefore, the learned helplessness model of depression appears to have only partial construct validity. 3.3. The chronic mild stress (CMS) model The CMS model was developed (Willner, 1997) to mimic anhedonia, a fundamental symptom of depressive disorders. In rats, anhedonia is assessed by measuring the intake of a sweet solution. After exposure of rats to a series of chronic mild stresses, such as overnight illumination, deprivation of food and/or water, cage tilt, and change of cage-mate, there is a decline in the intake of sucrose. Although the model was speci®cally developed to assess anhedonia in rats, rats exposed to such mild stresses for an extended period of time exhibit a variety of other changes that are consistent with depression. These changes include decreased investigational behaviors, disrupted sleep patterns (Cheeta et al., 1997), and decreased locomotor activity (D'Aquila et al., 1994; Gorka et al., 1996; Willner, 1997). Once behavioral changes are induced in the rats by CMS, they persist for up to 3 months. Therefore, the CMS model has considerable face validity as an animal model of depression. Virtually, all clinically e€ective antidepressants tested in the CMS model reverse the induced reduction in sweet intake. Thus, the predictive validity of the CMS model appears to be high. Recently, neurochemical changes caused by CMS have been studied. In rats exposed to CMS, the 5-HT2A and beta adrenergic receptors in the cortex increase, and these increases are normalized by chronic treatment with imipramine (Papp et al., 1994a). Such increases have been reported in presumably depressed suicides (Arango et al., 1990). Similarly, in rats exposed to CMS, DA2/3 receptors were decreased and the decrease was reversed after chronic imipramine treatment (Papp et al., 1994b). CMS also causes a decrease in the in vivo release of DA (dopamine) in rats (Willner, 1997). The observed serotonergic and noradrenergic catecholaminergic changes in the CMS model are related to hedonic responses and reward, which further supports the CMS model as a valid model of depression. 3.4. The swim low-active (SwLo) model Sprague±Dawley rats were selectively bred for lower motor activity (low struggling and high ¯oating time) than randomly bred Sprague±Dawley rats, in a forced swim test (Weiss et al., 1998). The SwLo rat line is considered to express more ``depression-like'' behavior:

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reduced ambulation in the home cage, in open ®eld activity, in exploratory activity, in a novel home cage situation and immobility in the Porsolt test. Studies have indicated that dopaminergic functionality is reduced in SwLo rats. Infusion of amphetamine into the nucleus accumbens (NAc) of the SwLo rats produced only moderate increase in ambulation, compared to their counterparts (West et al., 1999a, 1999b). The behavior response to the administration of apomorphine, in doses that stimulate postsynaptic receptors, was attenuated, suggesting that this line di€ers in DA1, DA2 and DA3 postsynaptic receptors (West et al., 1999a, 1999b). Treatment with the antidepressant drugs imipramine, desipramine, venafaxine, fenelsine and bupropion, but not SSRIs, increased struggling behavior of SwLo rats in the swim test. This pro®le of the pharmacological response of SwLo rats represents an atypical depression, and the line was suggested for both face construct and predictive validities (West and Weiss, 1998). 3.5. The Flinders sensitive line (FSL) of rats model 3.5.1. Establishment of the FSL The FSL was established by genetically selecting (breeding) Sprague±Dawley rats for a behavioral trait, supersensitivity to cholinergic agents (Overstreet and Russell, 1982; Overstreet, 1986; Overstreet et al., 1986). (Flinders refers to University of Flinders, Australia, where the line was ®rst selected.) The usefulness of the FSL as an animal model of depression became evident because it has many behavioral similarities to depressed individuals and responds to antidepressants (Table 1; see also Overstreet, 1993; Overstreet et al., 1995). Furthermore, FSL rats have a variety of serotonergic abnormalities, including supersensitive hypothermic responses to the 5-HT1A agonist, 8-OHDPAT (Overstreet et al., 1994a, 1994b), elevated 5-HT and 5-HIAA content in limbic regions (Zangen et al., 1997; see also Section 3.5.3), and reduced 5-HT transporter binding of platelets (Owens, personal communication). The exaggerated levels of 5-HT and 5-HIAA in FSL rats are normalized by chronic treatment with Table 1 Simillarities between FSL rats and depressed humans Symptoms/characteristic

FSL rats

Depressives

General activity REM-sleep amount REM-sleep latency Appetite Cognitive impairment Anhedonia AD therapuetic response

Reduced Increased Reduced Reduced Yes/No? Yes Yes

Reduced Increased Reduced Reduced Yes Yes Yes

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antidepressants, a treatment that does not cause changes in the levels of 5-HT and 5-HIAA in normal rats (Zangen et al., 1997; see also Section 3.5.3.2). This improvement parallels that observed in the behavior of the treated FSL rats. 3.5.2. Validity of the FSL as a model of depression The behavior of the FSL rats resembles that observed in many depressed patients (Table 1; see also Section 3.5.2), thus the model has face validity. Both FSL rats and depressed individuals are sensitive to cholinergic agonists (cholinergic supersensitivity; Janowsky et al., 1994; Janowsky and Overstreet, 1995) and have serotonergic (see Section 3.5.3) and dopaminergic (see Section 3.5.4) abnormalities, thus the model has construct validity (see Section 3.5.2.2). Both FSL rats and depressed individuals respond positively to chronic treatment with antidepressants, thus the model has predictive validity (see Section 3.5.2.3). Since the FSL rat has ful®lled all three major criteria for determining the validity of an animal model of depression (face, construct, and predictive validities), it appears to be a suitable animal model for studying the neurochemical basis of depression and the neurochemical consequences of antidepressant agents. 3.5.2.1. Face validity. The behavior of FSL rats mimics that of depressed patients in several respects (Table 1). The FSL rat has a lower body weight and a lesser appetite than the Sprague±Dawley strain from which it was derived (Overstreet, 1993; Bushnell et al., 1995), which correlates with the loss of weight and reduced appetite frequently observed in depressed patients. The FSL rat is less active in a novel open ®eld and responds more slowly in operant responding paradigms than the Sprague±Dawley rat (Overstreet, 1993; Bushnell et al., 1995), which correlates with the reduced activity and psychomotor retardation often observed in depressed patients. FSL rats exhibit elevated REM sleep and a reduced latency between REM cycles, when compared to Sprague±Dawley rats (Shiromani et al., 1988; Benca et al., 1996), which correlates with the shortened REM latency and increased REM density typically observed in depressed patients (Benca et al., 1996; Maes and Meltzer, 1995). FSL rats exhibit a greater decrease in saccharin intake when exposed to the chronic mild stress paradigm than Sprague±Dawley rats (Pucilowski et al., 1993), which might correlate with the anhedonia observed in many severely depressed patients. Neither FSL rats when stressed nor depressed patients appear to be able to experience reward (see also Section 2.1). On measures of performance in the elevated plus maze, FSL rats do not di€er from Sprague±Dawley rats (Overstreet, 1993), which suggests that the FSL rat mimics the type of depression that does not have a signi®cant anxiety com-

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ponent. FSL rats exhibit impaired performance in active avoidance tasks, superior performance in passive avoidance tasks (Overstreet, 1993), and longer latencies in a food-maintained operant response (choice accuracy was una€ected), when compared with Sprague± Dawley rats (Bushnell et al., 1995). The latter suggests that FSL rats do not exhibit the cognitive impairment commonly reported in depressed patients. Since a substantial number of behaviors of the FSL rat resemble those of depressed patients, the FSL rat model of depression has a substantial degree of face validity. 3.5.2.2. Construct validity. Several theoretical models have been developed to explain depressive disorders (Overstreet et al., 1988; Overstreet, 1993). For example, the catecholamine hypothesis, which postulates that depressive disorders are related to de®ciencies of catecholamines, particularly NA (Schildkraut et al., 1970; Schildkraut, 1995), and the indolamine hypothesis (Maes and Meltzer, 1995), which postulates that depressive disorders are related to de®ciencies of indolamines, particularly 5-HT. As part of a cholinergic±adrenergic interaction model, Janowsky and his coworkers (Janowsky et al. 1980; Janowsky and Risch, 1984; Janowsky et al., 1994; Janowsky and Overstreet, 1995) proposed that depression might be associated with an overactive cholinergic system. While each of these theoretical models is supported, at least partially, by a substantial amount of experimental evidence, they cannot account for all the ®ndings obtained from human and animal studies (Nestler, 1998), and as a result, other models that suggest an interaction between multiple neuronal systems have been proposed (Stahl, 1998c). In fact, in the FSL rats, there are substantial changes (as compared to the strain from which it was derived) in both their cholinergic and serotonergic function, which led to the proposal of a model of depression that involves cholinergic/serotonergic interaction (Overstreet et al., 1986; Overstreet et al., 1992). We reported abnormal monoaminergic (DA, NA, and 5-HT) metabolism in the FSL rat (Zangen et al., 1997; Serova et al., 1998; Zangen et al., 1999a, 1999b; see also Sections 3.5.3 and 3.5.4), which is consistent with previous pharmacological evidence for neuronal alterations (Overstreet et al., 1992, 1994a) in this strain. Therefore, the FSL meets the criterion of construct validity for a model of depression. 3.5.2.3. Predictive validity. The predictive validity of the FSL model of depression was tested using the forced swim test, which is commonly used to predict the ecacy of antidepressants in rats (Borsini and Meli, 1988). In the standard forced swim test developed by Porsolt (Porsolt et al., 1978a, 1978b), and utilized by others, a rat is subjected to a 15 min pretest in the swim tank and a 5 min test 24 h later and the time

of immobility of the animal limbs is measured. In order to test the e€ects of putative antidepressants on this behavioral characteristic, the putative antidepressant is typically administered subacutely between the two tests, usually at 23, 5 and 1 h prior to the second test. Under subacute conditions, tricyclics increase the mobility of the rat, i.e., are active, SSRIs often do not (false negatives), and psychomotor stimulants, such as amphetamine and scopolamine, increase the mobility of the rat (false positives) (Borsini and Meli, 1988; Pucilowski and Overstreet, 1993; Overstreet et al., 1994a). Since the FSL rats are more immobile than controls (Overstreet, 1986; Overstreet et al., 1992), a modi®ed testing protocol was used in which the 15 min pretest to induce immobility was eliminated (Pucilowski and Overstreet, 1993). In humans, antidepressants must typically be administered for 2±6 weeks before clinical bene®ts are seen (see Section 2.1). Therefore, with the FSL rats, the antidepressant drugs were administered chronically for 14 days, not subacutely within 24 h (at 23, 5 and 1 h) prior to the test as is common with other studies (Borsini and Meli, 1988), and swim tests were carried out in 5 min sessions that occurred 24 h after the last drug administration. Desipramine and imipramine (tricyclics), sertraline and paroxetine (selective 5-HT uptake inhibitors), and nefazodone (a mixed 5-HT antagonist/reuptake blocker) were ine€ective when given subacutely, but reduced immobility in FSL rats, and not in controls, when given chronically (Fig. 1). Chronic treatment for 14 days with the calcium channel modulators, verapamil and nicardipine, signi®cantly reduced the exaggerated immobility of the FSL rats in the forced swim test, while lithium (a prophylactic medicine for bipolar

Fig. 1. Immobility of FSL and control rats during the swim test. Rats were treated for 14 days and then tested for immobility in the swim test. Mean2SEM depicted from 6±13 rats in each group. Signi®cantly di€erent values were detected with ANOVA followed by post-hoc Student±Newman±Keuls.  p < 0.05, FSL-treated vs. all other groups.

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a€ective disorder), exposure to bright light (an ecacious treatment for winter depression), and the psychostimulants amphetamine and scopolamine did not signi®cantly e€ect the immobility of either FSL or control rats (Pucilowski and Overstreet, 1993; Overstreet et al., 1995). Since chronic treatment with accepted antidepressants, but not with a variety of other agents, reduces the immobility of FSL rats, the FSL model of depression has a high degree of predictive validity (see also Section 3.5.2).

3.5.3. Serotonergic functionality in FSL rats 3.5.3.1. Serotonergic pharmacology in the FSL rat. When serotonergic abnormalities in the FSL rat were ®rst reported (Overstreet et al., 1992), only nonselective antidepressant drugs were available. After treatment with mChlorophenylpiperazine (a 5-HT1b/c agonist) and cyprohyptadine (a nonselective 5-HT2 antagonist), FSL rats exhibited a greater degree of hypothermia (Wallis et al., 1988). These ®ndings supported the hypothesis of a 5-HT1 supersensitivity in the FSL rat, since 5-HT1 agonists were reported to produce hypothermia and 5-HT2 agonists to produce hyperthermia (Gudelsky et al., 1986). Subsequently, the hypothermic e€ects of buspirone and 8-OH-DPAT (selective 5-HT1A agonists) con®rmed the 5-HT1 supersensitivity of the FSL rat (Overstreet et al., 1992). With an operant responding paradigm, FSL rats were more sensitive to the behavioral suppressant e€ects of quipazine (a 5-HT2 agonist) and mChlorophenylpiperazine (Schiller et al., 1991) than controls; there also appeared to be increased amounts of both 5-HT1 and 5-HT2 subtypes of receptors in the FSL rats (Overstreet et al., 1992, 1994b). This experimental evidence supports a serotonergic supersensitivity of the FSL rat. Since 5-HT1A agonists exert anti-immobility e€ects in the forced swim test (Detke et al., 1995), the exaggerated immobility exhibited by FSL rats might be related to their 5-HT1A supersensitivity (Overstreet et al., 1992). In fact, genetic crosses and backcrosses of the FSL and the Flinder Resistant Line (a line bidirectionally selected from the FSL and not expressing ``depressed'' behavior or biochemical abnormalities) indicated that immobility in the forced swim test was positively correlated with the degree of the hypothermic response to 8-OH-DPAT (Overstreet et al., 1994a). The association between hypothermia and immobility was further strengthened by the observation that ``normal'' rats selectively bred for increased hypothermic responses to 8-OH-DPAT were also more immobile in the forced swim test (Overstreet et al., 1994a, 1994b).

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3.5.3.2. Alterations in 5-HT levels in limbic regions of the FSL rat. As discussed before (Section 2.1), in some studies, the levels of 5-HT and of its metabolite, 5HIAA, in the blood and cerebrospinal ¯uid of depressed patients were reported to be lower than those observed in healthy volunteers (Coppen et al., 1976; Banki, 1978; Asberg et al., 1984; Le Quan-Bui et al., 1984; Quintana, 1992), but were reported to be unchanged or higher in other studies (Todrick et al., 1960; Stahl et al., 1983; Roy et al., 1985; Meltzer and Arora, 1986; Muck-Seler et al., 1991; Reddy et al., 1992). In postmortem samples taken from depressed suicides, the levels of 5-HT and 5-HIAA in the brainstem were consistently lower than in samples from nondepressed subjects; however, the results from other brain regions were not consistent (Cheetham et al., 1989; Mann et al., 1989). The latter might be due to varying time intervals between the onset of death and tissue sampling, the in¯uence of the anxiety/distress factor (van Praag, 1986), and in some cases, the e€ects of unknown drugs taken by the suicide victim. Furthermore, suicide victims su€ering from depression represent only a speci®c subtype of depressive disorder (15% of all the depressed patients), that usually has an aggressive component (van Praag, 1986; Beskow, 1990; Akiskal, 1995). Therefore, it was intriguing to re-evaluate the indolamine hypothesis for depression, using the FSL rats as a model. With FSL rats, the time between death and sampling of brain tissue for 5-HT and 5HIAA content, and the timing of the administration of drugs, could be and were controlled. The levels of 5HT (Fig. 2) and 5-HIAA (Fig. 3) in tissue punches from the limbic, but not the striatum, brain regions of untreated FSL rats were higher than in the corre-

Fig. 2. Levels of 5-HT in brain regions of FSL and control rats. Mean 2 SEM depicted from 10 rats in each group. Signi®cance between groups was tested by independent two-tailed t-test.  p < 0.05 vs. the corresponding control group. Reproduced from Zangen et al. (1997).

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depressants (Corona et al., 1982; Sarrias et al., 1987; Wagner et al., 1990).

Fig. 3. Levels of 5-HIAA in brain regions of FSL and control rats. Mean 2 SEM depicted from 10 rats in each group. Signi®cance between groups was tested by independent two-tailed t-test.  p < 0.05 vs. the corresponding control group. Reproduced from Zangen et al. (1997).

sponding Sprague±Dawley controls as measured by HPLC. This could be due to a decreased release or increased utilization of 5-HT by the FSL rats (see Section 3.5.3). The high levels of 5-HT and 5-HIAA observed in tissue punches from the limbic regions of untreated FSL rats were normalized by chronic treatment (5 mg/kg/day for 14 days) with the tricyclic antidepressant desipramine (Fig. 4), which could be caused by a decrease in the synthesis of 5-HT. Interestingly, the levels of 5-HT and 5-HIAA in various regions of the brains of the Sprague±Dawley rats were not a€ected by the same chronic desipramine treatment, which is consistent with other studies on the e€ects of antidepressants in normal rats (Alpers and Himwich, 1972; Lassen et al., 1980; Hrdina, 1987; Caccia et al., 1993; Dewar et al., 1993). Our ®ndings that an e€ective antidepressant treatment caused a decrease in the levels of 5-HT and 5-HIAA in several brain regions of a rat model of depression (Fig. 4) are consistent with the decreased levels of 5-HT observed in the platelets of depressed patients chronically treated with anti-

3.5.3.3. Impaired uptake of 5-HT in the FSL rat. Impaired ``serotonergic tone'', suggested to occur in depression (Meltzer and Lowy, 1987), could be due to an alteration in receptor expression (post or presynaptic) and/or to an increase in the reuptake and intracellular metabolism (deamination) of 5-HT. Previously, polymorphism in regulation of 5-HT reuptake sites was suggested to be associated with depression and anxiety in patients (Lesch et al., 1996). In a preliminary study, we found (using microdialysis) that the levels of 5-HT in the extracellular ¯uid (ECF) of the NAc were slightly higher in FSL rats than in their normal counterparts, although the magnitude (1.4 fold increase; Table 2) was less than that obtained from tissue extracts (7.5 fold increase; Fig. 2), the latter of which re¯ects tissue content. These results suggest an increase in 5-HT uptake in the FSL rats if increased 5HT release occurs. When paroxetine (a SSRI) was administered i.p., the levels of 5-HT in the ECF of the NAc of FSL and Sprague±Dawley rats increased, with the increase being more pronounced in the FSL rats (Table 2). If the synthesis and release of 5-HT by the cells in the NAc is enhanced in the ``depressed'' rats, increased uptake may ensue in order to clear excess 5HT from the ECF. In this case, lower ``serotonergic tone'' may depend on post-rather than presynaptic alterations (see Section 3.5.6) at least in the NAc. This may reveal compensation in 5-HT bioavailability in other brain regions, especially the raphe nucleus, where 5-HT cell bodies locate and the prefrontal cortex (see Section 2.1). 3.5.3.4. Monoamine oxidase (MAO) activity in limbic areas of the FSL rat. An association of MAO activity with depression has been suggested (Schildkraut et al., 1977; Meltzer et al., 1980). Therefore, we examined whether the activity of both MAO-A and MAO-B in the brain could account for the increased levels of 5HIAA in the brain tissue of ``depressed'' rats. In the

Table 2 Levels of 5-HT and 5-HIAA in microdialysates from the nucleus accumbens of FSL and Sprague±Dawley rats Treatment

Compound assayed

Sprague±Dawley rats (n = 6)

FSL rats (n = 6)

pg/30 ml Saline Paroxetine (10 mg/kg) Saline Paroxetine (10 mg/kg) a

5-HT 5-HT 5-HIAA 5-HIAA

Signi®cantly di€erent from respective control groups.

2.320.46 6.421.2 12002162 582.3265

3.020.5 15.425.3a 15602212 876257

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363

Fig. 4. (A±G) E€ect of chronic desipramine treatment on the 5-HT and 5-HIAA levels in brain regions of FSL and control rats. Rats were pretreated with desipramine or saline for 18 days. q Control saline; , control desipramine; Q FSL saline; K FSL desipramine. Mean 2 SEM depicted from six rats in each group. Signi®cantly di€erent values were detected with ANOVA followed by post-hoc Student±Newman±Keuls.  p < 0.05, FSL saline vs. FSL-desipramine or control groups. Reproduced from Zangen et al. (1997).

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prefrontal cortex, the level of MAO-A activity was essentially the same in control and FSL rats, but the level of MAO-B activity was twice as high as that in the FSL rats (210230%; n = 8; p < 0.01). In the hippocampus, the activity of MAO-B in the FSL and control rats was similar, whereas the level of MAO-A activity was signi®cantly higher in FSL rats (12528%; n = 8; p < 0.01). These ®ndings indicate a mechanism in depressed subjects, such as FSL rats, to deal with an increased turnover of 5-HT, and are in agreement with an increased synthesis and utilization of 5-HT being able to compensate for a low function of serotonergic neurons (see Section 3.5.3). 3.5.4. Dopaminergic functionality in the FSL rat 3.5.4.1. The link between DA release in the nucleus accumbens to motivation and hedonia. As suggested before (Sections 2.1 and 3.3) motivation and hedonia may be characteristics of depressive behaviour. Many studies point to the NAc, a region that belongs to the limbic system in the brain, as the central region involved in Ð and mediating Ð activities relating to motivation and hedonia (pleasure) (Phillips et al., 1991; Robinson and Berridge, 1993; Salamone, 1994; Wise, 1996; Breiter et al., 1997; Schultz et al., 1997). Samples taken in vivo, by microdialysis, from the rat brain show an increase in DA release during eating and sexual activity (Phillips et al., 1991). Determination of whether the observed release of DA is linked to motivation before eating or sexual activity, or to pleasure felt during the act is dicult (di Chiara et al., 1993). In rats, injection of various addictive substances, such as amphetamine, cocaine, heroin, morphine, ethanol and nicotine, causes an increase in DA release in the NAc (Koob and Bloom, 1988; Kuhar et al., 1991; di Chiara et al., 1993; Self and Nestler, 1995). The dopaminergic cells that project to the NAc are located in the VTA. When an electrode is inserted into the VTA of a rat, and it can be stimulated by the rat pressing a pedal, the rat quickly learns to excite itself and presses the pedal without interruption. Stimulation by the electrode also causes DA release in the NAc (Robinson and Berridge, 1993). In this system, administration of DA leads to the cessation of self-excitation, and also of pedal pressing as a means to obtain drugs, food, or drink (Bergman et al., 1989; Robinson and Berridge, 1993; Salamone, 1994). In another system, a rat is taught to avoid (passively or actively) receiving an electrical shock, and the injection of DA antagonists into the NAc of the rat decreases its performance of the reaction needed to avoid the shock. These studies lead to the conclusion that dopaminergic activity is important for motivation (Salamone, 1994). Furthermore, there is evidence that in humans DA antagonists

impede euphoria caused by drugs like amphetamine, but not heroin (Salamone, 1994); thus, hedonia is not necessarily mediated by DA. Mapping of brain activity in humans by functional magnetic resonance imaging (a mapping method based on imaging of hemodynamic changes and oxygen consumption during activity) upon administration of cocaine demonstrates a longterm activation of cells in the NAc, which parallels the development of craving (related to motivation), and is inversely related to the short-term increase in ``high'' (which is more representative of hedonia) (Breiter et al., 1997). In rats, destruction of dopaminergic neurons in the NAc does not restrain their preference for sucrose, which is used to determine hedonia and anhedonia (Salamone, 1994). These and other ®ndings support the release of DA in the NAc being essential to motivation, but not necessarily to hedonia (or at least not to every type of hedonia) (Robinson and Berridge, 1993; Salamone, 1994; Breiter et al., 1997). Natural release of DA in the NAc is mainly due to activation of dopaminergic neurons in the VTA, where the cell bodies of most dopaminergic neurons are located. In the NAc, release of DA may also occur due to a local release of 5-HT, mediated by a local activation of the 5-HT3 receptor in dopaminergic terminals (Chen et al., 1993; di Chiara et al., 1993; Parsons and Justice, 1993; de Deurwaerdere et al., 1998). In rats, injection of nicotine, ethanol, and morphine also induces an increase in release of DA in the NAc, while injection of an 5-HT3 receptor antagonist suppresses this increase. Thus, this release of DA appears to be mediated by 5-HT3 receptors (Carboni et al., 1989).

Fig. 5. Levels of NA in brain regions of FSL and control rats. Mean 2 SEM depicted from 10 rats in each group. Signi®cance between groups was tested by independent two-tailed t-test.  p < 0.05 vs. the corresponding control group. Reproduced from Zangen et al. (1999a).

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Fig. 6. Levels of DA in brain regions of FSL and control rats. Mean 2 SEM depicted from 10 rats in each group. Signi®cance between groups was tested by independent two-tailed t-test.  p < 0.05 vs. the corresponding control group. Reproduced from Zangen et al. (1999a).

3.5.4.2. Abnormal levels of catecholamines and their metabolites in FSL rats. Our studies indicate that increased levels of both NA (Fig. 5) and DA (Fig. 6) in limbic brain regions might re¯ect depressive disorders. Thus, it was not surprising that the levels of mRNA for tyrosine hydroxylase (TH) were higher in the ventral tegmental area (VTA; the origin of dopaminergic cells that project to the limbic regions) of FSL rats than those in the VTA of controls (Serova et

Fig. 7. Levels of mRNA for TH in the VTA of FSL and control rats. mRNA levels for TH were determined in naive rats Q; and rats underwent repeated immobilization stress q. The summary data relative to unstressed control taken as 1.0 are shown as mean 2 SEM, depicted from seven to eight rats in each group. Signi®cance between groups was tested by independent two-tailed t-test.  p < 0.05 vs. the corresponding control group. Reproduced from Serova et al. (1998).

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al., 1998). Furthermore, continued stress did not change the levels of TH mRNA in the VTA of FSL rats, which may partially explain their inability to cope with changing environments, a characteristic of depressive behavior (Fig. 7). The levels of DA in the NAc [an important limbic site, in which the release of DA is associated with motivation and reward (Self and Nestler, 1995; Wise, 1996; Schultz et al., 1997; Koob and Bloom, 1988)] di€er greatly for FSL and Sprague± Dawley (control) rats (Fig. 6). The increased tissue content of catecholamines observed in some brain regions of FSL rats might re¯ect either increased synthesis or decreased elimination of catecholamines and their metabolites (Fig. 8). In FSL rats, a reduction in the elimination of DA solely due to a decreased activity of MAO is unlikely, since the levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) are increased and the [DOPAC]/[DA] ratios are not lower (Zangen et al., 1999a). However, a decreased elimination caused by a decreased release of catecholamines and metabolites from nerve terminals is possible (Fig. 9), since elimination of catecholamines and their metabolites from brain tissue requires exposure of the compounds to the extracellular space (Commissiong, 1985). Also, a decreased release of DA or NA from nerve terminals may cause increased synthesis of themselves via a compensatory feedback mechanism (Galloway et al., 1986, Galloway, 1990). The manifested behavioral de®cits (reduced motivation and hedonia) of FSL may be due to a decreased release of DA in their NAc (Fig. 9). In fact, the higher levels of mRNA for TH in the VTA of FSL rats than those of the Sprague±Dawley rats (Serova et al., 1998) are in agreement with our observations of increased tissue levels of 3,4-dihydroxy-

Fig. 8. Levels of DOPAC and HVA in brain regions of FSL and control rats. Mean2SEM depicted from 10 rats in each group. Signi®cance between groups was tested by independent two-tailed t-test.  p < 0.05 vs. the corresponding control group. Reproduced from Zangen et al. (1999a).

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Fig. 9. Levels of DA, DOPAC, HVA, 5-HT and 5-HIAA in the ECF of the nucleus accumbens of FSL and control rats. Mean 2 SEM depicted from 10 rats in each group. Signi®cance between groups was tested by independent two- tailed t-test.  p < 0.05 vs. the corresponding control group.

phenylalanine (L-DOPA) in the NAc of FSL rats (Zangen et al., 1999a), and overall suggest a compensatory increased synthesis of catecholamines in brain regions innervated by the VTA, since TH is the rate limiting enzyme for catecholamine biosynthesis. However, in regions innervated mainly by dopaminergic cells located in the SN, i.e., the striatum, of FSL rats, an increased catecholamine synthesis would not be expected. Indeed, in the striatum, as well as the hypothalamus, of FSL rats, the L-DOPA levels are not elevated (Zangen et al., 1999a). In FSL rats, the levels of DA were twice as high as those of L-DOPA (Zangen et al., 1999a), which suggests that both an increased synthesis and a decreased release of DA may account for the net increase in the levels of DA in speci®c limbic regions. In the raphe nucleus of FSL rats, the levels of DA were equivalent to those of ``normal'' rats; however, the levels of NA in the median, but not the dorsal raphe of the FSL rats, were elevated (Figs. 5 and 6). This is in agreement with the inhibitory e€ect of NA on 5-HT neurons in the raphe nucleus (Bel and Artigas, 1996; Baraban and Aghajanian, 1980). Since the 5-HT cell bodies in the raphe innervate limbic areas (Jacobs and Azmitia, 1992), the increased tissue levels of NA observed in the median raphe of FSL rats could contribute to the abnormal levels of 5-HT observed in some of their limbic regions (Zangen et al., 1997). Chronic treatment with desipramine, which improved the behavioral de®cit of FSL rats in the

swim test paradigm (Fig. 1), also normalized the catecholamine levels in all tested brain regions of the FSL rats, except for the striatum, which is the only nonlimbic region of those tested (Fig. 10). Thus, the increased catecholamine levels in limbic regions of FSL rats appear to correspond to the observed behavioral de®cit in this animal model of depression. Chronic treatment with desipramine a€ected the levels of catecholamines only in those brain regions of FSL rats where abnormal catecholamine levels were observed, and did not alter the catecholamine levels in any region of the brains of the Sprague±Dawley (control) rats. These ®ndings indicate a site-speci®c action of desipramine, and the importance of using depressed, rather than normal subjects, for studying the action of antidepressants. Since desipramine mainly inhibits NA reuptake, its e€ect on the levels of NA may be due to a feedback mechanism, i.e. decreased synthesis, caused by increased extracellular levels of the neurotransmitter a€ecting NA autoreceptors. However, the e€ect of desipramine on the levels of DA in some brain regions, such as the NAc, hippocampus, prefrontal cortex and median raphe of FSL rats (Fig. 10), indicates a possible interaction between noradrenergic and dopaminergic terminals in these regions. In postmortem samples taken from depressed suicides (as determined by suicidal behavior, rather than diagnosis), normal levels of NA, DA and HVA were observed (Pare et al., 1969; Beskow et al., 1976; Brown et al., 1985). However, suicide victims su€ering from depression represent only a speci®c subtype of depressive disorder (15% of all the depressed patients) that usually has an aggressive component (van Praag, 1986; Beskow, 1990; Akiskal, 1995). In previous studies with rats, chronic treatment with desipramine (and other antidepressants) did not a€ect the levels of DA in various brain regions (Schildkraut et al., 1970; Sedlock and Edwards, 1985; Chung et al., 1993), which is consistent with our observations with control rats (Fig. 10). Clinically, antidepressant treatment does not a€ect the mood and behavior of nondepressed individuals; therefore, interpretation of results from normal rats has limited relevance for understanding the neurochemical abnormalities observed in depression and the bene®cial therapeutic e€ects of antidepressant drugs. However, the parallel normalization of both behavioral and neurochemical abnormalities in FSL rats after chronic treatment with desipramine indicates the validity of the FSL model for studying the mode of action of antidepressants, and suggests that a decrease in the levels of catecholamines in speci®c regions of the brain may be involved in the manifestation of the therapeutic e€ect(s) of antidepressants. Such a decrease in the levels of catecholamines could be due to a direct decrease in catecholamine synthesis,

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367

Fig. 10. (A±G) E€ect of chronic desipramine treatment on catecholamines and their metabolites levels in brain regions of FSL and control rats. Rats were pretreated with desipramine or saline for 18 days. q control saline; , control desipramine; Q FSL saline; K FSL desipramine. Mean2 SEM depicted from six rats in each group. Signi®cantly di€erent values were detected with ANOVA followed by post-hoc Student±Newman± Keuls.  p < 0.05, FSL saline vs. FSL-desipramine or control groups. Reproduced from Zangen et al. (1999a).

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an increase in catecholamine release, or an increase in the postsynaptic responses to DA and NA in speci®c regions of the brain, especially the NAc. Since we also described an a€ect of desipramine on abnormal 5-HT levels in FSL rats (Section 3.5.3.2), we now postulate that more than one monoaminergic system, and perhaps more than one brain region, is involved in the etiology of depressive disorders. High levels of DA in tissue content may be due to increased demand (lower functionality) and/or decreased release of DA into the ECF (Fig. 9). Theoretically, if a decreased level of DA in ECF of the brain is the primary cause for depressive behavior, then antidepressants that correct behavioral de®cits in FSL rats should also increase the levels of DA in their ECF. However, such increases in the levels of DA were not observed in antidepressant-treated FSL rats, plus treatments with di€erent antidepressants had di€erent e€ects on the levels of DA in the ECF of the NAc (unpublished data). Therefore, basal levels of DA cannot be the primary cause for manifestation of depressive behavior. 3.5.5. Impaired communication between serotonergic and dopaminergic systems in the FSL rat The neurotransmission of DA is modulated by that of 5-HT (Parsons and Justice, 1993; Chen et al., 1991; Benloucif et al., 1993; Yadid et al., 1994; de Deurwaerdere et al., 1998), and as discussed above, the neurotransmission of DA in the limbic system is associated with hedonia and reward (Schultz et al., 1997). In the limbic system, 5-HT facilitates the release and metabolism of DA (Guan and McBride, 1989; Jiang et al., 1990; Parsons and Justice, 1993). In a preliminary study that involved microdialysis, a facilitatory e€ect of 5-HT (0.4 mM) on the release of DA into the ECF of the NAc, which occurred in control rats (200 2 22%; n = 8), was not observed in FSL rats (105 2

10%; n = 6), thus indicating that the tissue content or ECF levels of 5-HT or DA may not necessarily be an indication of healthy neurons, but rather the communication between neuronal circuits is important. Functional cross-talk between 5-HT and DA neurons may be essential for normal behavior. 3.5.6. Pharmacodynamics of 5-HT receptors in the FSL rat We assessed the anity and density of putative 5HT receptors in the NAc, prefrontal cortex, and striatum of FSL and Sprague±Dawley (control) rats, using ‰3 H]ketanserin and ‰3 H]zacopride as ligands for 5-HT2 and 5-HT3 receptors, respectively. Compared to Sprague±Dawley rats, an increase in the density and a decrease in the anity of the 5-HT2 receptor were observed in the NAc, but not in the prefrontal cortex and the striatum, of FSL rats (Table 3; Zangen et al., 1999c). In the FSL rats, an increased density of ‰3 H]zacopride binding, i.e. of 5-HT3 receptors, was observed in the NAc, and a decreased anity in both the NAc and the prefrontal cortex, but not the striatum, was also observed. These results are in agreement with 5-HT not facilitating the release of DA. Therefore, in FSL rats, changes in the binding anity and density of 5-HT2 and 5-HT3 receptors may be functionally related to the absence of 5-HT-DA interactions, and manifestation of depressive behavior could be due to the absence of the interaction between these monoamines (Zangen et al., 1998). Since the predominant receptor that stimulates release of DA in the NAc is 5-HT3 (Chen et al., 1991; de Deurwaerdere et al., 1998; Parker et al., 1996), and activation of 5-HT2 receptors may decrease this stimulation (Devaud et al., 1992), we suggest that these two 5-HT receptors, or the balance between them, may be the main site(s) for the abnormal behavioral manifestations that characterize anhedonia in depressive behavior. Molecular edit-

Table 3 Bmax and Kd of 5-HT2 and 5-HT3 receptors in the brains of FSL and Sprague±Dawley (control) rats Probe

[3 H]Ketanserin

Rats

Control (n = 5)

FSL (n = 5)

Control (n = 5)

FSL (n = 5)

8752141 1.8220.46

168821078 3.6922.72

1.2520.30 3.1420.57

1.4720.34 2.8820.71

9142505 0.9720.52

12862202 1.2420.56

7.3520.42 2.2620.13

5.6720.42 5.9820.99a

926279 1.8221.47

25572921a 3.6422.87

2.2520.32 1.520.10

420.55 4.520.46a

Striatum Bmax (fmol/mg protein) Kd (nM) Prefrontal cortex Bmax (fmol/mg protein) Kd (nM) Nucleus accumbens Bmax (fmol/mg protein) Kd (nM) a

Signi®cantly di€erent from respective control groups.

[3 H]Zacopride

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ing of these receptors may decrease their anity and alter this behavior (for review see Niswender et al., 1998). 3.5.7. Monoaminergic±endorphinic interaction in FSL rats 3.5.7.1. The neuropharmacology of b-endorphin. bEndorphin, which is an endogenous peptide composed of 31 amino acids, binds to receptors for opioids, such as morphine and heroin. The opioid receptors to which b-endorphin has a high anity are d and m. bEndorphin is a potent analgesic and, like morphine, is also able to induce euphoria (Foley et al., 1979; Amalric et al., 1987; Bals-Kubik et al., 1990; Fields et al., 1991; Dalayeun et al., 1993). b-Endorphin, which functions essentially as a neuromodulator, is present in every part of the brain. Its concentration is especially high in the pituitary, from which it is released into the blood, mainly in response to stress and pain (Lantos et al., 1995). The concentration of b-endorphin is also high in the hypothalamus, especially in the arcuate nucleus, where the cell bodies are located and where many terminals are concentrated around the walls of the third ventricle (Zakarian and Smyth, 1982; Lantos et al., 1995). There is also a dense track of neurons containing bendorphin that leads from the arcuate nucleus to the NAc (Bloom et al., 1978). Lesioning of the arcuate nucleus lowers an individual's pain threshold, while its stimulation induces analgesia (Hamba, 1988; Wang et al., 1990). Stimulation of the arcuate nucleus causes a massive release of b-endorphin in the periaqueductal gray matter of the brainstem, where one pain center is located. In fact, injection of b-endorphin into the arcuate nucleus, periaqueductal gray matter, and the NAc induces analgesia (Monroe et al., 1996; Tseng and Wang, 1992). Injection of b-endorphin into the brain ventricles of rats causes a rise in their intake of food and also ``place preference'' (preference of a ®xed place in the cage where the rat gets the b-endorphin injection); blocking of the opioid receptor by the antagonist naltrexone reduces these phenomena (Morley, 1987; BalsKubik et al., 1990; di Chiara et al., 1993; Olson et al., 1993). Injection of b-endorphin or other opioids into the NAc, VTA, or brain ventricles increases the release of DA in the NAc (Iyengar et al., 1989; Bals-Kubik et al., 1990; Spanagel et al., 1991; Johnson and North, 1992; di Chiara et al., 1993). However, the e€ect of bendorphin and other opioids on motivation and hedonia is not necessarily dependent on DA, since opioids can act directly on receptors in the limbic system, including the NAc, to induce motivation and hedonia (Koob, 1992; Mansour et al., 1994).

369

3.5.7.2. b-Endorphin in relation to depression. Little is known about the relationship between b-endorphin and depressive disorders. Injection of b-endorphin has resulted in temporary improvement in depressed patients in some studies, but not in others (Gerner et al., 1980; Olson et al., 1993). The levels of b-endorphin in the plasma of depressed patients were higher than in healthy volunteers in some studies (Risch, 1982; Goodwin et al., 1993), but similar or slightly lower in other studies (Cohen et al., 1984; Darko et al., 1992a, 1992b; Young et al., 1990). Upon injection of cholinergic agonists, an exaggerated increase in the level of b-endorphin in plasma has been reported in depressed patients (Risch, 1982). In the CSF of depressed patients, the level of b-endorphin is not markedly di€erent from that in healthy volunteers (Naber et al., 1981; Black et al., 1986; France and Urban, 1991). So far, the levels of b-endorphin in brain tissue have only been examined in animals. Upon treatment with antidepressants, the levels of b-endorphin, which are altered in brain tissue of rats, increase only in the hypothalamus (Sacerdote et al., 1987). Besides their antidepressant actions, antidepressants are also analgesics for chronic pain, and as such are used also with nondepressed patients (Stimmel and Escobar, 1986; Sacerdote et al., 1987; Brown and Bottomley, 1990; Magni, 1991). Furthermore, 50% of the depressed patients su€er chronic pain (von Knorring et al., 1983, 1984). Thus, antidepressants are thought to in¯uence the release of endogenous opioids, such as b-endorphin, which is a very potent analgesic and thereby capable of alleviating pain. Analgesia may be mediated by 5-HT such as depression (Sacerdote et al., 1987; Brown and Bottomley, 1990). Moreover, the etiology of depression has been suggested to be related to insuf®cient activity of endogenous opioids in the brain (von Knorring et al., 1984; Sacerdote et al., 1987; Brown and Bottomley, 1990). These hypotheses have not been directly investigated, because of inadequate methods for measuring the in vivo release of endogenous opioids in the brain. 3.5.7.3. E€ect of 5-HT on b-endorphin in the nucleus accumbens of rats (control and FSL). 5-HT, either endogenously or exogenously applied, appears to facilitate the release of b-endorphin in the arcuate nucleus and NAc of normal rats (Figs. 11 and 12). Destruction of 5-HT neurons, induced by a dose of 5,7-DHT that does not a€ect dopaminergic neurons (Baumgarten et al., 1971; Yadid et al., 1994), results in a 60±80% decrease in the basal extracellular levels of b-endorphin (Zangen et al., 1999b). This suggests that endogenous 5-HT, besides facilitating endogenous release of bendorphin, is involved in the tonic release of b-endorphin in both the arcuate nucleus and the NAc. Speci®c lesioning of the serotonergic system of FSL rats

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abolishes the stimulatory e€ect of the antidepressant ¯uoxetine on the release of b-endorphin (Zangen et al., 1999b), thus indicating that the e€ect of ¯uoxetine on b-endorphin release is mediated predominantly via 5HT (i.e., by inhibition of 5-HT uptake). The 5-HT mediated release of b-endorphin may be caused by a direct action of 5-HT on endorphinic neurons in the arcuate nucleus or NAc, however, intermediate substances like DA or GABA (g amino-butyric acid) may also be involved (Jacocks and Cox, 1992; de Deurwaerdere et al., 1998). Release of b-endorphin mediated by 5-HT, may, at least partially, account for the bene®cial e€ect of several antidepressant drugs on chronic pain, since antidepressants increase the 5-HT tone in the brain (Blier and de Montigny, 1994), and 5-HT can facilitate the release of b-endorphin in brain regions, such as the arcuate nucleus and NAc, where b-endorphin can mediate analgesia (Bloom et al., 1978; Loh et al., 1976; Foley et al., 1979; Tseng and Wang, 1992). Although the levels of b-endorphin in the ECF of the NAc of FSL and Sprague±Dawley rats are similar (Zangen et al., 1999b), its levels in the arcuate nucleus were higher in FSL rats (Fig. 13) and responded to antidepressant treatment (unpublished data). If, as postulated (Yadid, 1998 and herein), the FSL of rats is a valid model of depression, then b-endorphin may play a role in the manifestation of depression and the action of antidepressants.

talk between these neuronal systems, rather than their separate function, combined with elucidation of cascades of neurotransmitter- and neuro-factor-mediated events, will further our understanding of the neurochemical basis of depression and the action of antidepressant drugs. If neuronal activity of the brain is normally non-

4. Conclusions This review summarizes recent ®ndings concerning the local neurodynamics in the brain during manifestation of depressive behavior and e€ective antidepressant treatment in a novel animal model of depression (the genetically-selected FSL of rats). Recent ®ndings indicate that the ``catecholaminergic hypothesis'' (suggested by Schildkraut in the 1960s; Schildkraut et al., 1970) and the ``serotonergic hypothesis'' (suggested later by Lowy and Meltzer; Maes and Meltzer, 1995) of major depression, have to be broadened. Neuromodulators, like b-endorphin as presented herein, or other putative neurotransmitters/neuromodulators, such as GABA, neuropeptides (such as neuropeptide Y, substance P, and corticotropin releasing factor), neurosteroids, and growth factors may also be involved, albeit not centrally, in manifestation of depressive behavior (for review, see Nestler, 1998; Ressler and Nemero€, 1999). Neurochemical changes in the brain should be monitored dynamically and at multiparametrical levels. Although 5-HT, NA, and DA are not necessarily the primary causes of depressive behavior, they are involved in its dynamics. Investigation of the cross-

Fig. 11. E€ect of 5-HT and ¯uoxetine on b-endorphin levels in the ECF of the nucleus accumbens of FSL and control rats. Levels were monitored by microdialysis coupled to a HPLC. 5-HT (1 mM) or ¯uoxetine (100 mM) were administered for an interval (30 min) via the microdialysis probe (bar). Mean2SEM depicted from six rats in each group. Signi®cantly di€erent values were detected with ANOVA followed by post-hoc Student±Newman±Keuls.  p < 0.05. Reproduced from Zangen et al. (1999b).

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371

Fig. 13. Levels of b-endorphin in the ECF of the nucleus accumbens and arcuate nucleus of FSL and control rats. Samples were collected by microdialysis from control q and FSL Q rats and assayed by EILISA. Mean2 SEM depicted from six rats in each group. Signi®cance between groups was tested by independent two-tailed t-test.  p < 0.05 vs. the corresponding control group.

order to truly follow brain functionality. Furthermore, valid animal models for depression will be invaluable for the development of new antidepressant drugs, as will clinical information obtained by new methods like brain neuroimaging.

Acknowledgements We wish to thank Dr. Overstreet, University of North Carolina for supplying FSL rats that were used to establish a colony in G.Y. laboratory. The studies presented in this review were supported in part by grants from the Susan and Leslie Gonda (Goldschmied) Foundation, LA, California, Bar-Ilan Research Foundation (No. 2520) and the National Institute for Psychobiology in Israel (No. 3299) to Gal Yadid. Fig. 12. E€ect of 5-HT and ¯uoxetine on b-endorphin levels in the ECF of the arcuate nucleus of FSL and control rats. Levels were monitored by microdialysis coupled to a HPLC. 5-HT (5 mM) or ¯uoxetine (100 mM) were administered for an interval (30 min) via the microdialysis probe (bar). Mean2SEM depicted from six rats in each group. Signi®cantly di€erent values were detected with ANOVA followed by post-hoc Student±Newman±Keuls.  p < 0.05. Reproduced from Zangen et al. (1999b).

linear, i.e. chaotic (di Mascio et al., 1999a, 1999b), and psychiatric disorders pathologically decrease this chaotic response (King et al., 1984; Nahshoni et al., 2000), then current analytical methods should be modi®ed in

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