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Pharmacological validation of the chronic mild stress model of depression
S166
S.24. Animal models of depression
behavioral paradigms to measure sensitivity to reward is intracranial self-stimulation (ICSS) behavior. This technique offers direct activation of brain substrates involved in these hedonic processes (such as the ventral tegmental area). Self-stimulation threshold can thus be used as valid index of the hedonic state of an animal (Markou & Koob, 1991). An additional advantage of the ICSS technique is that brain stimulation reward can be readily varied in intensity (as opposed to food reward), allowing determination of individual sensitivity to reward in a much more precise manner. ICSS thresholds are determined prior to, during and after an extended period of exposure to a variety of stressors. In stressed animals, ICSS threshold progressively increases over a lo-day to 2-week period, indicating a gradual decrease in sensitivity to reward. This anhedonic state lasts throughout the stress regimen. This animal model of depression has been extensively investigated (see table 1) over the past few years (for review, see Moreau, 1998). It offers a fair predictive validity (Papp et al., 1996) as active treatments include representatives of clinically effective antidepressants such as tricyclics, atypical antidepressants, SSRIs, MAO inhibitors, and electroconvulsive therapy. In addition, expected ineffective treatments include well-established anxiolytics, antipsychotics, and analgesics. As shown in table 1, this model also offers a number of other interesting features, as it addresses a core symptom of depression (anhedonia), is vulnerable to the same kind of risk factors, and exhibits similar sleep abnormalities (Moreau et al., 1995). It thus qualifies as a validated model of some aspects of human depression. It can be confidently used for both characterizing novel drugs and investigating novel mechanisms potentially involved in the generation of depressive episodes. Table I : Similaritiesbetween aspects of human depression and stress-induced anhedonia in rats DEPRESSIONIN MAN SYMPTOMS
RISK FACTORS
depressed mood lossof interest or pleasure decreased sexual drive lowself-esteem stressful life events social isolation in childhood
ANHEDONIA IN RATS cannot be simulated reduced sensitivity to reward (anhedonia) decreased sexual activity decreased aggressive behavior chronic mild stress isolation-reared animals are lIlOR
BIOLOGICAL sleep abnormalities MARKERS - decreased REM sleep latency - increased total REM sleep ACTIVE tricyclics TREATMENTS atypicals SSRIs MAO inhibitors electroconvulsivetherapy INEFFECTIVE anxiolytics TREATMENTS antipsychotics psychostimulants analgesics
vulnerable to chronic mild stress sleep abnormalities - decreased REM sleep latency - increased total REM sleep amitriptyline, imipramine, desipramine maprotiline, mianserin fluoxetine moclobemide, brofaromine electroshock treatment chlordiazepoxide halopetidol, risperidone, chlorprothixene amphetamine morphine
References [l] Markou, A. and Koob, G. (1991) Postcocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology 4: 17-25.
PI Moreau, J.-L., Scherschlicht, R., Jenck, F. & Martin, J.R. (1995)
Chronic mild stress-induced anhedonia model of depression: sleep abnormalities and curative effects of electroshock treatment. Behavioural Pharmacology 6: 682-687. 131 Moreau, J.-L. (1998) Simulation of a core symptom of human depression in rats. Current Topics in Pharmacology 4: 37-50 [41 Papp, M., Moryl, E. & Willner, I? (1996) Pharmacological validation of the chronic mild stress model of depression. Psychopharmacology 296: 129-136. PI Willner, P (1997) Validity, reliability and utility of the chronic mild stress model of depression. Psychopharmacology 134: 3 19-329.
(s.24.021
Pharmacological validation of the chronic mild stress model of depression
M. Papp. institute of Pharmacology. Polish Academy 12 Smetna St., 31-343 Krakow, Poland
of Sciences,
Chronic mild stress (CMS) is a procedure, in which animals subjected to a variety of mild stressors (e.g. short periods of food or water deprivation, change of cage mate, soiled cage, intermittent illumination) for a period of several weeks develop a variety of behavioural, physiological and biochemical abnormalities, which strongly speak to the face and construct validity of this procedure as an animal simulation of depression (see: Willner, 1997). This review will present results of studies design to evaluate the effect of a large number of psychoactive substances on the CMS-induced.decrease in responsiveness to rewarding stimuli, which is one of the best described consequences the CMS procedure and appears to reflect anhedonia, a core symptom of major depressive disorders. Drugs shown to be active in the CMS model include the tricyclics (imipramine, desipramine and amitriptyline), the SSRIs (fluoxetine, fluvoxamine, citalopram and its active enantiomer-escitalopram), the selective NA reuptake inhibitor (maprotiline), the monoamine oxidase inhibitors (moclobemide and brofaromine), the atypical antidepressant (mianserin), the anti-manic drugs (lithium and carbamazepine), and the atypical antipsychotics (amisulpride and clozapine; Papp & Wieronska, 2000). Other agents, which have been occasionally reported to have clinical antidepressant activity and were also found effective against the CMS-induced anhedonia include the 5-HT1A receptor partial agonists buspirone and amespirone (Munoz & Papp, 1999), the selective (72 ligand Lu 28-179 (Sanchez & Papp 2000), the NKl-receptor antagonist NKP608 (Papp et al., 2000), the corticosterone synthesis inhibitor ketoconazole and repeated electroconvulsive shocks. Ineffective agents in the CMS model include chlordiazepoxide, amphetamine, morphine and the neuroleptics chlorprothixene, haloperidol and risperidone (for detailed review see: Wilhrer, 1997). The action of drugs active in the CMS model is characterized by a few important properties, which appear to closely resemble the clinical picture of antidepressant action. First, the effect of drugs is specific to stressed animals; the sucrose consumption of non-stressed controls is usually unchanged by antidepressant treatment. This feature may correspond to the failure of these drugs to elevate mood in non-depressed human subjects. Second, in the CMS model, a treatment is usually commenced after the stress-induced anhedonic deficit in stressed animals is established. This allows studying the therapeutic mode of action of a tested drug. Third, drugs active in the CMS model require at least three to five weeks of treatment before they can gradually normalize the behaviour of stressed animals, and this effect is sustained for at least one week after cessation of a treatment. Since this time-course is characteristic for
S.24. Animal models of depression the clinical action of antidepressant treatment, these data provide further support for the predictive validity of the CMS model. References
[I] Munoz C, Papp M. Pharmacol Biochem Behav, 1999, 63, 647653. 121 [3j [4] [5]
Paup M, Vassout A, Gentsch C. Behav Brain Res, 2000, 115, 19-23 P&p M, Wieronska J. J Psychopharmacol, 2000, 14, 46-52 Snchez C, Papp M. Behav Pharmacol, 2000, 11, 117-124. Willner P Psychopharmacology 1997, 134, 319-329.
[%%%I
Genetically modified animals to analyse the abnormalities in the hypothalamic-pituitary adrenal axis in depression
T. Steckler’, M.M. Van Gaalen2, M. Sauvage3, J.M.H.M. Reu13, MI? Stenzel-Poore4, F. Holsboer3. ‘CNS Discovery, Janssen Pharmaceutics NY Turnhoutseweg 30, B-2340 Beerse, Belgium; ‘Department of Pharmacology, Free Uniuersity Amsterdam, van der Boechorststraat 7, N-1081 BT Amsterdam, The Netherlands, 3Max Planck institute of Psychiatry, Kraepelinstr 2-10, D-80804 Munich, Germany; 4Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, USA Functional abnormality of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most prominent features of depression, including impaired mineralocorticoid receptor function, restrained glucocorticoid receptor feedback, raised plasma cortisol level, and increased corticotropin-releasing hormone (CRH) activity. Normalisation of the neuroendocrine abnormalities seems to be a prerequisite for stable remission in depressed patients (Steckler et al., 1999). One possibility to model these changes is the use of mouse mutants with altered HPA axis activity, which show a range of neuroendocrine and behavioural alterations comparable to those seen in depression. Transgenic mice overexpressing CRH mice, for example, show an overactive HPA axis, increased anxiety-related behaviour, and decreased sexual function (Heimichs et al., 1997; Stenzel-Poore et al., 1994). A great body of evidence suggests important interactions between the HPA axis and the serotonergic system, in particular the S-HT~A receptor. When challenged with the 5HT~A agonist &OH-DPAT, plasma corticosterone levels increased in wild type, but not in CRH overexpressing transgenic animals, while 8-OH-DPAT had no differential effect on the hypothermic response in transgenic and wildtype mice. This suggests desensitisation of postsynaptic, but not presynaptic, ~-HT~A receptors in mice overproducing CRH and/or a blunted corticotrophic response at the level of the pituitary to CRH release after postsynaptic 5HT~A receptor stimulation. Interestingly, this finding resembles the changes seen in depressed patients following ~-HT~A challenge, which have been reported to exhibit significantly decreased cortisol responses to the partial ~-HT~A agonist ipsapirone, while basal cortisol secretion is increased when compared to controls. Next, it was investigated whether long-term treatment with the selective serotonin reuptake inhibitor citalopram would normalise HPA axis stimulation after ~-HT~A receptor stimulation. Chronic treatment with citalopram resulted in desensitisation of ~-HT~A autoreceptars, as indicated by the attenuated hypothermic response to 8OH DPAT administration, but this was independent of genotype. Citalopram failed to affect plasma corticosterone levels after 8OH-DPAT challenge. Interestingly, however, chronic citalopram was able to attenuate the increased anxiety-related behaviour in CRH overexpressors, suggesting that long-term antidepressive
S167
treatment partially restored the abnormalities seen in CRH overexpressing mice. CRH overexpressors also show a range of cognitive impairments, such as impaired attentional and learning performance. Since lack of a functional Crhrl has anxiolytic-like effects in mice (Timpl et al., 1998), it could be suggested that CRH overstimulation of this receptor may be involved in the altered anxiogenic-like and cognitive effects seen in mice overexpressing CRH. Indeed administration of the non-peptidergic Crhrl antagonist R 121919 has recently been reported to normalise the increased anxietyrelated behaviour and to restore sexual receptivity in transgenic mice. Acute administration of R121919, however, failed to improve cognitive performance in transgenic animals, suggesting that the latter deficits might not be primarily mediated through Crhrl stimulation. Given the importance of the glucocorticoid receptor (GR) in the regulation of negative feedback at HPA axis level, mice with alterations in GR activity would also be expected to exhibit severe disturbances of HPA axis function. This was investigated in greater detail in transgenic mice expressing a neurofilament promoterdriven antisense RNA directed against the GR, which show about 50% reduction in brain GR mRNA expression (Pepin et al., 1992). Glucocorticoid negative feedback efficiency is reduced and dexamethasone suppression is impaired in these transgenic mice. Furthermore, enhanced CRH- and stress-induced increases in plasma ACTH and adrenocortical hyper-responsiveness to ACTH can be observed in these animals. Dopaminergic system activity is increased in these animals and, more recently, increased numbers of striatal dopaminergic Dl and D2 receptors, and decreased dopamine transporter levels have been reported in these transgenics. Hippocampus-related learning is impaired in these mutants, which also exhibit increased impulsive behaviour, and hippocampal long-term potentiation (LTP) is disrupted. The enhanced behavioural disinhibtion, but not the accuracy deficit, seen in these mice could be attenuated by dopaminergic Dl and D2 antagonists SCH23390 and sulpiride, opening the possibility that alterations in dopaminergic activity might also be a major contributor to the performance deficits seen in other tasks used to study behavioural alterations in these animals. Moreover, food intake is reduced in GR antisense transgenic mice, while sensitivity to amphetamine and conditioned approach responses to food and amphetamine are enhanced, and it is possible that the latter behavioural alterations are also due to changes in the dopaminergic system, rather than a primary effect of altered CR function. This points towards an important role of secondary mechanisms in these animals. On the other hand, it is tempting to speculate that these mutants may represent a valuable model for psychotic depression. Interestingly, long-term antidepressant treatment has been shown to induce GR mRNA expression in GR antisense transgenic mice. Furthermore, the monoamine oxidase A inhibitor moclobemide improved not only the neuroendocrine dysfunction seen in these mice, but also altered the threshold for the induction of hippocampal LTP at low stimulation frequencies and improved a range of behavioural impairments. More recently, it has also been shown that antidepressant treatment with amitryptyline or fluoxetine also corrected the increase in striatal Dl and D2 receptors and decreased dopamine transporter levels in these transgenic mice. Thus, it is striking that many antidepressant drugs are successful in attenuating the neurochemical, neuroendocrinological and behavioural deficits seen in these mice. Importantly, the time period required to precipitate these actions is similar to that observed for HPA axis amelioration in depressed patients.
S.24. Animal models of depression
behavioral paradigms to measure sensitivity to reward is intracranial self-stimulation (ICSS) behavior. This technique offers direct activation of brain substrates involved in these hedonic processes (such as the ventral tegmental area). Self-stimulation threshold can thus be used as valid index of the hedonic state of an animal (Markou & Koob, 1991). An additional advantage of the ICSS technique is that brain stimulation reward can be readily varied in intensity (as opposed to food reward), allowing determination of individual sensitivity to reward in a much more precise manner. ICSS thresholds are determined prior to, during and after an extended period of exposure to a variety of stressors. In stressed animals, ICSS threshold progressively increases over a lo-day to 2-week period, indicating a gradual decrease in sensitivity to reward. This anhedonic state lasts throughout the stress regimen. This animal model of depression has been extensively investigated (see table 1) over the past few years (for review, see Moreau, 1998). It offers a fair predictive validity (Papp et al., 1996) as active treatments include representatives of clinically effective antidepressants such as tricyclics, atypical antidepressants, SSRIs, MAO inhibitors, and electroconvulsive therapy. In addition, expected ineffective treatments include well-established anxiolytics, antipsychotics, and analgesics. As shown in table 1, this model also offers a number of other interesting features, as it addresses a core symptom of depression (anhedonia), is vulnerable to the same kind of risk factors, and exhibits similar sleep abnormalities (Moreau et al., 1995). It thus qualifies as a validated model of some aspects of human depression. It can be confidently used for both characterizing novel drugs and investigating novel mechanisms potentially involved in the generation of depressive episodes. Table I : Similaritiesbetween aspects of human depression and stress-induced anhedonia in rats DEPRESSIONIN MAN SYMPTOMS
RISK FACTORS
depressed mood lossof interest or pleasure decreased sexual drive lowself-esteem stressful life events social isolation in childhood
ANHEDONIA IN RATS cannot be simulated reduced sensitivity to reward (anhedonia) decreased sexual activity decreased aggressive behavior chronic mild stress isolation-reared animals are lIlOR
BIOLOGICAL sleep abnormalities MARKERS - decreased REM sleep latency - increased total REM sleep ACTIVE tricyclics TREATMENTS atypicals SSRIs MAO inhibitors electroconvulsivetherapy INEFFECTIVE anxiolytics TREATMENTS antipsychotics psychostimulants analgesics
vulnerable to chronic mild stress sleep abnormalities - decreased REM sleep latency - increased total REM sleep amitriptyline, imipramine, desipramine maprotiline, mianserin fluoxetine moclobemide, brofaromine electroshock treatment chlordiazepoxide halopetidol, risperidone, chlorprothixene amphetamine morphine
References [l] Markou, A. and Koob, G. (1991) Postcocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology 4: 17-25.
PI Moreau, J.-L., Scherschlicht, R., Jenck, F. & Martin, J.R. (1995)
Chronic mild stress-induced anhedonia model of depression: sleep abnormalities and curative effects of electroshock treatment. Behavioural Pharmacology 6: 682-687. 131 Moreau, J.-L. (1998) Simulation of a core symptom of human depression in rats. Current Topics in Pharmacology 4: 37-50 [41 Papp, M., Moryl, E. & Willner, I? (1996) Pharmacological validation of the chronic mild stress model of depression. Psychopharmacology 296: 129-136. PI Willner, P (1997) Validity, reliability and utility of the chronic mild stress model of depression. Psychopharmacology 134: 3 19-329.
(s.24.021
Pharmacological validation of the chronic mild stress model of depression
M. Papp. institute of Pharmacology. Polish Academy 12 Smetna St., 31-343 Krakow, Poland
of Sciences,
Chronic mild stress (CMS) is a procedure, in which animals subjected to a variety of mild stressors (e.g. short periods of food or water deprivation, change of cage mate, soiled cage, intermittent illumination) for a period of several weeks develop a variety of behavioural, physiological and biochemical abnormalities, which strongly speak to the face and construct validity of this procedure as an animal simulation of depression (see: Willner, 1997). This review will present results of studies design to evaluate the effect of a large number of psychoactive substances on the CMS-induced.decrease in responsiveness to rewarding stimuli, which is one of the best described consequences the CMS procedure and appears to reflect anhedonia, a core symptom of major depressive disorders. Drugs shown to be active in the CMS model include the tricyclics (imipramine, desipramine and amitriptyline), the SSRIs (fluoxetine, fluvoxamine, citalopram and its active enantiomer-escitalopram), the selective NA reuptake inhibitor (maprotiline), the monoamine oxidase inhibitors (moclobemide and brofaromine), the atypical antidepressant (mianserin), the anti-manic drugs (lithium and carbamazepine), and the atypical antipsychotics (amisulpride and clozapine; Papp & Wieronska, 2000). Other agents, which have been occasionally reported to have clinical antidepressant activity and were also found effective against the CMS-induced anhedonia include the 5-HT1A receptor partial agonists buspirone and amespirone (Munoz & Papp, 1999), the selective (72 ligand Lu 28-179 (Sanchez & Papp 2000), the NKl-receptor antagonist NKP608 (Papp et al., 2000), the corticosterone synthesis inhibitor ketoconazole and repeated electroconvulsive shocks. Ineffective agents in the CMS model include chlordiazepoxide, amphetamine, morphine and the neuroleptics chlorprothixene, haloperidol and risperidone (for detailed review see: Wilhrer, 1997). The action of drugs active in the CMS model is characterized by a few important properties, which appear to closely resemble the clinical picture of antidepressant action. First, the effect of drugs is specific to stressed animals; the sucrose consumption of non-stressed controls is usually unchanged by antidepressant treatment. This feature may correspond to the failure of these drugs to elevate mood in non-depressed human subjects. Second, in the CMS model, a treatment is usually commenced after the stress-induced anhedonic deficit in stressed animals is established. This allows studying the therapeutic mode of action of a tested drug. Third, drugs active in the CMS model require at least three to five weeks of treatment before they can gradually normalize the behaviour of stressed animals, and this effect is sustained for at least one week after cessation of a treatment. Since this time-course is characteristic for
S.24. Animal models of depression the clinical action of antidepressant treatment, these data provide further support for the predictive validity of the CMS model. References
[I] Munoz C, Papp M. Pharmacol Biochem Behav, 1999, 63, 647653. 121 [3j [4] [5]
Paup M, Vassout A, Gentsch C. Behav Brain Res, 2000, 115, 19-23 P&p M, Wieronska J. J Psychopharmacol, 2000, 14, 46-52 Snchez C, Papp M. Behav Pharmacol, 2000, 11, 117-124. Willner P Psychopharmacology 1997, 134, 319-329.
[%%%I
Genetically modified animals to analyse the abnormalities in the hypothalamic-pituitary adrenal axis in depression
T. Steckler’, M.M. Van Gaalen2, M. Sauvage3, J.M.H.M. Reu13, MI? Stenzel-Poore4, F. Holsboer3. ‘CNS Discovery, Janssen Pharmaceutics NY Turnhoutseweg 30, B-2340 Beerse, Belgium; ‘Department of Pharmacology, Free Uniuersity Amsterdam, van der Boechorststraat 7, N-1081 BT Amsterdam, The Netherlands, 3Max Planck institute of Psychiatry, Kraepelinstr 2-10, D-80804 Munich, Germany; 4Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, USA Functional abnormality of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most prominent features of depression, including impaired mineralocorticoid receptor function, restrained glucocorticoid receptor feedback, raised plasma cortisol level, and increased corticotropin-releasing hormone (CRH) activity. Normalisation of the neuroendocrine abnormalities seems to be a prerequisite for stable remission in depressed patients (Steckler et al., 1999). One possibility to model these changes is the use of mouse mutants with altered HPA axis activity, which show a range of neuroendocrine and behavioural alterations comparable to those seen in depression. Transgenic mice overexpressing CRH mice, for example, show an overactive HPA axis, increased anxiety-related behaviour, and decreased sexual function (Heimichs et al., 1997; Stenzel-Poore et al., 1994). A great body of evidence suggests important interactions between the HPA axis and the serotonergic system, in particular the S-HT~A receptor. When challenged with the 5HT~A agonist &OH-DPAT, plasma corticosterone levels increased in wild type, but not in CRH overexpressing transgenic animals, while 8-OH-DPAT had no differential effect on the hypothermic response in transgenic and wildtype mice. This suggests desensitisation of postsynaptic, but not presynaptic, ~-HT~A receptors in mice overproducing CRH and/or a blunted corticotrophic response at the level of the pituitary to CRH release after postsynaptic 5HT~A receptor stimulation. Interestingly, this finding resembles the changes seen in depressed patients following ~-HT~A challenge, which have been reported to exhibit significantly decreased cortisol responses to the partial ~-HT~A agonist ipsapirone, while basal cortisol secretion is increased when compared to controls. Next, it was investigated whether long-term treatment with the selective serotonin reuptake inhibitor citalopram would normalise HPA axis stimulation after ~-HT~A receptor stimulation. Chronic treatment with citalopram resulted in desensitisation of ~-HT~A autoreceptars, as indicated by the attenuated hypothermic response to 8OH DPAT administration, but this was independent of genotype. Citalopram failed to affect plasma corticosterone levels after 8OH-DPAT challenge. Interestingly, however, chronic citalopram was able to attenuate the increased anxiety-related behaviour in CRH overexpressors, suggesting that long-term antidepressive
S167
treatment partially restored the abnormalities seen in CRH overexpressing mice. CRH overexpressors also show a range of cognitive impairments, such as impaired attentional and learning performance. Since lack of a functional Crhrl has anxiolytic-like effects in mice (Timpl et al., 1998), it could be suggested that CRH overstimulation of this receptor may be involved in the altered anxiogenic-like and cognitive effects seen in mice overexpressing CRH. Indeed administration of the non-peptidergic Crhrl antagonist R 121919 has recently been reported to normalise the increased anxietyrelated behaviour and to restore sexual receptivity in transgenic mice. Acute administration of R121919, however, failed to improve cognitive performance in transgenic animals, suggesting that the latter deficits might not be primarily mediated through Crhrl stimulation. Given the importance of the glucocorticoid receptor (GR) in the regulation of negative feedback at HPA axis level, mice with alterations in GR activity would also be expected to exhibit severe disturbances of HPA axis function. This was investigated in greater detail in transgenic mice expressing a neurofilament promoterdriven antisense RNA directed against the GR, which show about 50% reduction in brain GR mRNA expression (Pepin et al., 1992). Glucocorticoid negative feedback efficiency is reduced and dexamethasone suppression is impaired in these transgenic mice. Furthermore, enhanced CRH- and stress-induced increases in plasma ACTH and adrenocortical hyper-responsiveness to ACTH can be observed in these animals. Dopaminergic system activity is increased in these animals and, more recently, increased numbers of striatal dopaminergic Dl and D2 receptors, and decreased dopamine transporter levels have been reported in these transgenics. Hippocampus-related learning is impaired in these mutants, which also exhibit increased impulsive behaviour, and hippocampal long-term potentiation (LTP) is disrupted. The enhanced behavioural disinhibtion, but not the accuracy deficit, seen in these mice could be attenuated by dopaminergic Dl and D2 antagonists SCH23390 and sulpiride, opening the possibility that alterations in dopaminergic activity might also be a major contributor to the performance deficits seen in other tasks used to study behavioural alterations in these animals. Moreover, food intake is reduced in GR antisense transgenic mice, while sensitivity to amphetamine and conditioned approach responses to food and amphetamine are enhanced, and it is possible that the latter behavioural alterations are also due to changes in the dopaminergic system, rather than a primary effect of altered CR function. This points towards an important role of secondary mechanisms in these animals. On the other hand, it is tempting to speculate that these mutants may represent a valuable model for psychotic depression. Interestingly, long-term antidepressant treatment has been shown to induce GR mRNA expression in GR antisense transgenic mice. Furthermore, the monoamine oxidase A inhibitor moclobemide improved not only the neuroendocrine dysfunction seen in these mice, but also altered the threshold for the induction of hippocampal LTP at low stimulation frequencies and improved a range of behavioural impairments. More recently, it has also been shown that antidepressant treatment with amitryptyline or fluoxetine also corrected the increase in striatal Dl and D2 receptors and decreased dopamine transporter levels in these transgenic mice. Thus, it is striking that many antidepressant drugs are successful in attenuating the neurochemical, neuroendocrinological and behavioural deficits seen in these mice. Importantly, the time period required to precipitate these actions is similar to that observed for HPA axis amelioration in depressed patients.