Food cues and ghrelin recruit the same neuronal circuitry.

BACKGROUND: Cues that are associated with the availability of food are known to trigger food anticipatory activity (FAA). This activity is expressed as increased locomotor activity and enables an animal to prepare for maximal utilization of nutritional resources. Although the exact neural network that mediates FAA is still unknown, several studies have revealed that the medial hypothalamus is involved. Interestingly, this area is responsive to the anorexigenic hormone leptin and the orexigenic hormone ghrelin that have been shown to modulate FAA. However, how FAA is regulated by neuronal activity and how leptin and ghrelin modulate this activity is still poorly understood. OBJECTIVE: We aimed to examine how the total neuronal population and individual neurons in the medial hypothalamus respond to cue-signaled food availability in awake, behaving rats. In addition, ghrelin and leptin were injected to investigate whether these hormones could have a modulatory role in the regulation of FAA. DESIGN: Using in vivo electrophysiology, neuronal activity was recorded in the medial hypothalamus in freely moving rats kept on a random feeding schedule, in which a light cue signaled upcoming food delivery. Ghrelin and leptin were administered systemically following the behavioral paradigm. RESULTS: The food-predictive cue induced FAA as well as a significant increase in neural activity on a population level. More importantly, a sub-population of medial hypothalamic neurons displayed highly correlated identical responses to both ghrelin and FAA, suggesting that these neurons are part of the network that regulates FAA. CONCLUSION: This study reveals a role for ghrelin, but not leptin, signaling within medial hypothalamus in FAA on both a population level and in single cells, identifying a subset of neurons onto which cue information and ghrelin signaling converge, possibly to drive FAA.

Attachment representations in Dutch veterans with and without deployment-related PTSD.

In this study we tested for a protective effect of secure attachment representations in the development of posttraumatic stress disorder (PTSD). In a design with a control group, we replicated and extended a recent study that found no underrepresentation of secure attachment representations in veterans with PTSD (Nye, Katzman, Bell, Kilpatrick, Brainard, & Haaland, 2008). Furthermore, we examined the association of the Adult Attachment Interview (AAI) classification of unresolved loss or trauma and PTSD symptomatology. The Adult Attachment Interview and the Clinician Administered PTSD Scale (CAPS) were administered with 31 veterans with PTSD and 29 trauma-exposed veterans without PTSD of similar age and country of deployment. Patient and control groups did not differ in the prevalence of secure attachment representations, neither did unresolved and not unresolved subjects differ in prevalence of secure attachment representations. Unresolved state of mind with respect to deployment related trauma was found to correlate strongly with total CAPS score. This study shows no protective effect of secure attachment representations in the development of PTSD. AAI unresolved state of mind with respect to deployment related trauma and PTSD correlate strongly, due to the common core phenomenon of lack of integration.

Elevated plasma corticotrophin-releasing hormone levels in veterans with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is associated with alterations in corticotrophin-releasing hormone (CRH) secretion. Plasma CRH levels, which are easily acquired, might serve as a predictor of hypothalamic CRH levels. Assessment of plasma CRH, adrenocorticotrophin hormone (ACTH), and cortisol levels in 31 veterans with PTSD, 30 traumatized veterans without PTSD matched on age, year, and region of deployment (traumacontrols), and 28 age-matched healthy controls (HCs) was carried out. Plasma CRH levels were higher in PTSD patients compared to both HCs (p=0.005) and traumacontrols (p=0.007). This led to our conclusion, that elevated plasma CRH levels are specifically related to PTSD and not to exposure to traumatic stress during deployment.

Elevated plasma arginine vasopressin levels in veterans with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with altered hypothalamic-pituitary-adrenal (HPA) axis functioning. Arginine vasopressin (AVP), in conjunction with corticotrophin releasing hormone, has shown to be an important modulator of the HPA axis. In order to evaluate the effect of trauma and PTSD on central AVP secretion we assessed plasma AVP levels in equally trauma exposed veterans with and without PTSD and a non-traumatized healthy control group. METHODS: Assessment of plasma AVP in 29 male veterans with PTSD, 29 traumatized veterans without PTSD, matched for age, gender, year and region of deployment (trauma controls), and 26 age matched healthy controls. RESULTS: Plasma AVP levels were higher in PTSD patients compared to both healthy controls (p = 0.004) and trauma controls (p < 0.001). In PTSD patients without a comorbid MDD a significant correlation was observed between plasma AVP levels and symptoms of avoidance measured with the Clinician Administered PTSD Scale (CAPS). CONCLUSION: Elevated plasma AVP levels are specifically related to PTSD and not to exposure to traumatic stress during deployment. Our results indicate that AVP may play a role as an anxiogenic factor, but they do not support a role for AVP in the altered response to dexamethasone in PTSD.

Perception of facial expressions in obsessive-compulsive disorder: a dimensional approach.

The study examined the perception of facial expressions of different emotional intensities in obsessive-compulsive disorder (OCD) subtypes. Results showed that the High Risk Assessment and Checking subtype was more sensitive in perceiving the emotions fear and happiness. This suggests that altered affective processing may underlie the clinical manifestation of OCD.

Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder.

BACKGROUND: While enhanced cortisol suppression in response to dexamethasone is one of the most consistent biological findings in posttraumatic stress disorder (PTSD), the relative contribution of trauma exposure to this finding remains unclear. METHODS: Assessment of diurnal salivary cortisol levels and 1600 h salivary cortisol before and after oral administration of 0.5mg dexamethasone in veterans with PTSD, veterans without PTSD (trauma controls) and healthy controls. Assessment of 1600 h plasma cortisol, ACTH and corticotrophin binding globulin (CBG) in response to dexamethasone in PTSD patients and trauma controls. RESULTS: Both PTSD patients and trauma controls demonstrated significantly more salivary cortisol suppression compared to healthy controls. Salivary cortisol, plasma cortisol and ACTH suppression as well as CBG levels did not differ between PTSD patients and trauma controls. PTSD patients showed a reduced awakening cortisol response (ACR) compared to healthy controls that correlated significantly with PTSD symptoms. No significant differences were observed in ACR between PTSD patients and trauma controls. CONCLUSIONS: These data suggest that enhanced cortisol suppression to dexamethasone is related to trauma exposure and not specifically to PTSD. The correlation between the ACR and PTSD severity suggests that a flattened ACR may be a result of clinical symptoms.

Behavioural effects of rapid intravenous administration of meta-chlorophenylpiperazine (m-CPP) in patients with generalized social anxiety disorder, panic disorder and healthy controls.

Findings from epidemiological, pharmacotherapeutical, genetic and neurobiological studies suggest a possible overlap in the neurobiology of generalized social anxiety disorder (gSAD) and panic disorder (PD). Previously we have found a rapid intravenous m-CPP challenge of 0.1 mg/kg to be highly sensitive and selective in the provocation of panic attacks in patients with PD. We therefore directly compared the behavioural, neuroendocrine and physiological effects of this rapid m-CPP challenge in a small sample of patients with gSAD, patients with PD and matched healthy controls. Panic attacks were significantly more provoked in patients with PD (85%), but not in patients with gSAD (14%) as compared to healthy controls (0%). Effects on the other behavioural parameters, but not on the neuroendocrine and physiological parameters, were significantly greater in patients with PD compared to patients with gSAD and controls. Our preliminary data do not support a shared neurobiology of gSAD and PD.

[Sleep disturbances in post-traumatic stress disorder. An overview of the literature]. / Slaapafwijkingen bij posttraumatische stressstoornis. Overzicht van onderzoeksbevindingen.

BACKGROUND: Nightmares and insomnia are experienced by 70% of patients suffering from post-traumatic stress disorder (PTSD). These sleep problems are often resistant to treatment and exert a strong negative influence on the quality of life. In the last few decades several studies have reported on the characteristics of sleep disturbances in PTSD. AIM: To provide an overview of objective features of sleep disturbances - as opposed to self-report methods - in patients with PTSD. METHOD: Articles on this topic, published in peer-reviewed journals between 1980 and the present, were retrieved from Medline and Embase, using the search terms 'PTSD', 'sleep', 'nightmares', 'insomnia', 'polysomnography'. RESULTS: Studies reported on changes in sleep efficiency, arousal regulation, motor activity during sleep, rem characteristics and delta sleep activity during sleep. Also, correlations were found between nightmares and sleep apnoea in ptsd. In some studies on sleep disturbance no objective sleep disturbances were found in PTSD patients. However, most studies on PTSD related sleep disturbances were conducted in small, heterogeneous groups, and results were therefore inconsistent. Even the results of larger and more homogeneous studies were sometimes contradictory. CONCLUSION: There is a discrepancy between the clinical importance of sleep problems in PTSD and unambiguous objective sleep disorders. Future research should try to establish objective criteria for identifying the altered sleep patterns in PTSD. These criteria should help us to understand the neurobiological mechanisms of sleep disturbances in PTSD and develop new treatment strategies.

d-cycloserine addition to exposure sessions in the treatment of patients with obsessive-compulsive disorder.

BACKGROUND: Preliminary studies have shown that the addition of the partial NMDA-agonist d-cycloserine (DCS) might be promising in enhancing the results of exposure therapy in obsessive-compulsive disorder (OCD). We examined the effect of DCS addition to exposure therapy in a somewhat larger sample of OCD patients with special attention to subgroups, because of the heterogeneity of OCD. METHODS: A randomized, double-blind, placebo controlled trial was conducted in 39 patients with OCD. Patients received 6 guided exposure sessions, once a week. One hour before each session 125mg DCS or placebo was administered. RESULTS: Scores on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) declined more in the DCS group than in the placebo group, but the difference did not reach statistical significance (P=0.076, partial η2=0.13). Response percentages also did not differ between the DCS and the placebo group (37% and 15% respectively). In the 'cleaning/contamination' subgroup a significant effect was found in favour of DCS (P=0.033, partial η2=0.297). CONCLUSIONS: The results of this study did not support the application of DCS to exposure therapy in OCD. Some specific aspects need further investigation: efficacy of DCS in a larger 'cleaning/contamination' (sub-)group, DCS addition only after successful sessions, interaction with antidepressants.

Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review.

Posttraumatic stress disorder (PTSD) is typically accompanied by acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but several studies have also used a challenge model to further assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. This paper reviews common methodology and research findings on HPA function in PTSD, and discusses the pathophysiological mechanisms underlying these findings. We reviewed the literature and selected all English-language, human subject, data driven, pharmacological and non-pharmacological challenge studies pertaining to the HPA axis, and in vitro leukocyte glucocorticoid receptor studies in adult PTSD subjects. Studies using a non-pharmacological stress paradigm (cognitive stress, trauma reminders) to stimulate the HPA axis showed an exaggerated cortisol response in PTSD. The most widely used pharmacological challenge with consistent results was the low dose dexamethasone-suppression test (DST). These DST studies showed enhanced cortisol suppression in subjects with PTSD. Different hypotheses have been purported to explain the alterations in HPA axis functioning in PTSD. The results of the reviewed challenge tests, however, did not exclusively support one of the hypothesized mechanisms. Further research assessing hormones at all levels of the HPA axis at both baseline and at challenge conditions with a proper stratification of study population, will be necessary for a better understanding of stress-responsivity on the level of the HPA axis in PTSD.

No effects of l-dopa and bromocriptine on psychophysiological parameters of human selective attention.

Patients with schizophrenia exhibit diverse cognitive deficits, one of which is a loss of the ability to focus attention. According to the revised dopamine hypothesis of schizophrenia both an increased mesolimbic and a decreased prefrontal dopaminergic activity is suggested to be involved in schizophrenia. The current study was designed to explore the relationship between dopamine and two psychophysiological parameters of selective attention, i.e. P300 amplitude and processing negativity (PN) in healthy volunteers. In two separate experiments, with a double-blind, balanced and placebo-controlled crossover design, 18 healthy male volunteers were orally administered either 300 mg l-dopa (precursor of dopamine) or placebo (experiment I), or 1.25mg bromocriptine (D2 agonist) or placebo (experiment II). Following this treatment they were tested in an auditory, dichotic selective attention paradigm. An increase in P300 amplitude was found following deviant stimuli when compared to standard stimuli and following attended stimuli when compared to unattended stimuli, regardless of treatment. Similarly, PN was found regardless of treatment. Neither l-dopa nor bromocriptine affected task performance or the amplitudes of PN or P300. In the present study neither l-dopa nor bromocriptine affected PN, P300 amplitude or task performance in healthy controls, phenomena which are usually found to be disrupted in schizophrenia. This indicates that P300 amplitude and PN are neither affected by a global (l-dopa) increased dopaminergic activity, nor by a more selectively towards striatal areas targeted (bromocriptine) increase in dopaminergic activity.

[Body dysmorphic disorder in 3-8% of patients in outpatient dermatology and plastic surgery clinics]. / Stoornis in de lichaamsbeleving bij 3-8% van de patiënten op de poliklinieken Dermatologie en Plastische Chirurgie.

OBJECTIVE: To determine the 6-month prevalence of body dysmorphic disorder (BDD) in outpatient clinics of dermatology and plastic surgery in a university medical centre. DESIGN: Questionnaire study. METHOD: In the period January 2004-June 2004, the self-reported Body dysmorphic disorder questionnaire was completed by 530 and 475 new patients in the outpatient clinics of dermatology and plastic surgery, respectively. The dermatologist or plastic surgeon assessed the severity of the defect. To meet the DSM-IV criteria for BDD, the patient must have been preoccupied with treatment of all or part of their appearance, experienced obvious suffering or restriction of function with minimal or no defect present (defect score 1 or 2). RESULTS: In the outpatient clinics ofdermatology and plastic surgery 8.5% (95% CI: 6.1-10.9) and 3.2% (95% CI: 1.7-4.7) of patients screened positive for BDD, respectively. CONCLUSION: A high prevalence of BDD was found in the outpatient clinics ofdermatology and plastic surgery. Because dermatologists and plastic surgeons do not often recognise BDD, a simple screening tool is needed.

Behavioral biochemical and neuroendocrine concomitants of lactate-induced panic anxiety.

In a single-blind study using sodium lactate infusions to provoke panic attacks, 11 of 15 patients with panic disorder panicked with lactate. None of the 15 control subjects panicked during lactate administration. Before receiving lactate, higher preinfusion anxiety levels were present in the patient group as compared to controls. Preinfusion Acute Panic Inventory (API) scores were significantly higher in patients who panicked compared to nonpanicking patients. In addition, patients who panicked during lactate infusion showed a higher mean plasma MHPG level at baseline. During lactate infusion, however, no increase in plasma MHPG was seen in patients who panicked, nor in nonpanickers and controls. Several other biochemical and hormonal variables were measured. No single biochemical or neuroendocrine variable was found to correlate with lactate-induced panic attacks. It is argued that the baseline arousal level of patients with panic disorder may be increased, which renders these patients more vulnerable to panic attacks.

Immunoglobulin production in vitro in major depression: a pilot study on the modulating action of endogenous cortisol.

To investigate the possible differential sensitivity of hydrocortisone (HCO) on immunoglobulin (Ig) production in depression in relation to endogenous cortisol levels, blood was obtained at 8 AM and 4 PM from 10 inpatients with major depression according to DSM-III-R criteria and 10 age- and sex-matched healthy subjects. Peripheral blood lymphocytes were cultured in the presence of graded concentrations (10(-9)-10(-5) M) of HCO to study the effect on immunoglobulin (IgG and IgM) synthesis. In addition, peripheral blood lymphocytes were cultured in the presence of pokeweed mitogen (PWM) to study any additional effect of graded concentrations of HCO (10(-9)-10(-5) M) on IgG and IgM synthesis. Mean plasma cortisol levels at both time points were higher in patients compared to controls. HCO--preferentially at concentrations of 10(-8)-10(-6) molar--stimulated IgG and IgM production in controls, except for IgM production in the 8 AM samples, when the cells were cultured in the absence of PWM. Under these culture conditions, HCO stimulated IgG but not IgM synthesis in depressed patients. PWM-driven IgG and IgM synthesis in controls was stimulated by HCO in both the 8 AM and the 4 PM samples. In patients PWM driven IgG synthesis was stimulated by HCO in the 8 AM but not in the 4 PM samples. PWM-stimulated IgM synthesis was not augmented by HCO in depressed patients. We conclude that a differential sensitivity to the effects of HCO exists in in vitro IgG and IgM synthesis between depressed patients and controls. Furthermore, we suggest that immunocompetent cells of depressed patients possess corticosteroid-resistant properties.

Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients.

BACKGROUND: Disturbances of affect, impulse regulation, and autoaggressive behavior, which are all said to be related to an altered function of the central serotonergic (5-HT) system, are prominent features of borderline personality disorder (BPD). A high coincidence of childhood physical and sexual abuse is reported in these patients. Animal studies indicate that early, sustained stress correlates with a dysfunctional central 5-HT system. Therefore, we hypothesize that sustained traumatic stress in childhood affects the responsivity of the postsynaptic serotonergic system of traumatized BPD patients. METHODS: Following Axis I, Axis II, and trauma assessment, a neuroendocrine challenge test was performed with the postsynaptic serotonergic agonist meta-chlorophenylpiperazine (m-CPP) in 12 impulsive and autoaggressive female patients with BPD and 9 matched healthy volunteers. RESULTS: The cortisol and prolactin responses to the m-CPP challenge in BPD patients were significantly lower compared to those in controls. Within the group of patients with BPD, the net prolactin response showed a high inverse correlation with the frequency of the physical (r = -.77) and sexual abuse (r = -.60). CONCLUSIONS: Our data suggest that severe and sustained traumatic stress in childhood affects the 5-HT system and especially 5-HT(1A) receptors. This finding confirms the data from animal research. The blunted prolactin response to m-CPP appears to be the result of severe traumatization and independent of the BPD diagnosis.

Effects of meta-chlorophenylpiperazine on cerebral blood flow in obsessive-compulsive disorder and controls.

BACKGROUND: A number of studies have shown that the serotonin receptor agonist meta-chlorophenylpiperazine (mCPP) can exacerbate symptoms in patients with obsessive-compulsive disorder (OCD). The aim of the present study was to study the effect of this compound on regional cerebral blood flow (rCBF) in patients and controls. METHODS: Seven OCD patients and 8 healthy controls were randomly allocated to a double-blind challenge study with mCPP (0.5 mg/kg orally). rCBF was measured by 99m-Tc-hexamethyl-propyleneamineoxime single photon emission computed tomography. RESULTS: mCPP did not induce OCD symptoms in patients, but caused a significant decrease in rCBF in OCD patients, but not in controls. The decrease was seen in the reference regions cerebellum and whole brain, and in the frontal cortex, caudate nucleus, putamen, and thalamus. CONCLUSIONS: The effect of mCPP on the reference regions in patients posed methodological problems in the normalization methods. A possible role of the cerebellum in OCD is discussed.

Kinetics of carbamazepine and carbamazepine-epoxide, determined by use of plasma and saliva.

The concentration-time curves of carbamazepine (CBZ) and its metabolite (carbamazepine-10,11-epoxide; CBZ-epoxide) were determined in patients undergoing long-term antiepileptic drug treatment with the use of plasma and saliva data. Plasma and saliva samples were assayed concurrently for each patient by liquid chromatography. There was excellent linear correlation between CBZ levels in saliva and plasma (r = 0.991, p less than 0.001) over a large concentration range. The saliva/plasma ratio for CBZ concentration was 0.26 +/- 0.01 (SD). Since CBZ binding to plasma proteins is in the order of 76%, saliva CBZ concentration seems to reflect the unbound fraction of the drug in plasma. CBZ-epoxide has not been detected in saliva. The pharmacokinetic parameters of CBZ-epoxide were determined in 6 patients. The pharmacokinetic parameters of CBZ obtained from saliva concentrations were in excellent agreement with those obtained from plasma concentrations. Thus, CBZ determination in saliva is convenient for controlling blood levels in patients as well as for studying pharmacokinetics. The half-life, the relative body clearance of CBZ, and the metabolite concentration during steady-state, expressed as percent the parent compound, appear to be significantly different in patients on single and combined drug therapy.

The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress.

BACKGROUND: Increased brain serotonin may improve the ability to cope with stress, whereas a decline in serotonin activity is involved in depressive mood. The uptake of the serotonin precursor, tryptophan, into the brain is dependent on nutrients that influence the cerebral availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). Therefore, a diet-induced increase in tryptophan availability may increase brain serotonin synthesis and improve coping and mood, particularly in stress-vulnerable subjects. OBJECTIVE: We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, may increase the plasma Trp-LNAA ratio and reduce depressive mood and cortisol concentrations in stress-vulnerable subjects under acute stress. DESIGN: Twenty-nine highly stress-vulnerable subjects and 29 relatively stress-invulnerable subjects participated in a double-blind, placebo-controlled study. Subjects were exposed to experimental stress after the intake of a diet enriched with either alpha-lactalbumin or sodium-caseinate. Diet-induced changes in the plasma Trp-LNAA ratio and prolactin were measured. Changes in mood, pulse rate, skin conductance, and cortisol concentrations were assessed before and after the stressor. RESULTS: The plasma Trp-LNAA ratio was 48% higher after the alpha-lactalbumin diet than after the casein diet (P = 0.0001). In stress-vulnerable subjects this was accompanied by higher prolactin concentrations (P = 0.001), a decrease in cortisol (P = 0.036), and reduced depressive feelings (P = 0.007) under stress. CONCLUSIONS: Consumption of a dietary protein enriched in tryptophan increased the plasma Trp-LNAA ratio and, in stress-vulnerable subjects, improved coping ability, probably through alterations in brain serotonin.

The effect of olanzapine treatment on monoamine metabolite concentrations in the cerebrospinal fluid of schizophrenic patients.

The mechanism of action of both typical antipsychotics and the atypical antipsychotic, clozapine, may be related to the (changing) interaction of dopamine and serotonin in schizophrenia. This study examined the effect of olanzapine in schizophrenic patients on cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA). Twenty-three male schizophrenic patients, who were drug-free for at least 2 weeks (mean drug-free period of 35 days +/- 43; median 16 days), underwent a lumbar puncture (LP). Patients were subsequently treated with olanzapine 10 mg/day for 6 weeks, after which the LP was repeated. CSF was assayed for HVA and 5-HIAA concentrations. Psychiatric symptoms were rated once a week. Olanzapine significantly increased HVA concentrations and the HVA/5-HIAA ratio while 5-HIAA concentrations were not altered. These changes did not significantly correlate with treatment response. A negative correlation was found between HVA concentrations and negative symptoms after olanzapine treatment. In conclusion, olanzapine treatment increases HVA concentrations and the HVA/5-HIAA ratio in CSF of schizophrenic patients, but these changes are unrelated to its clinical efficacy.

Effects of single and repeated oral administration of fluvoxamine on extracellular serotonin in the median raphe nucleus and dorsal hippocampus of the rat.

The delay in clinical effects of selective serotonin reuptake inhibitors (SSRIs) suggest the existence of adaptive phenomena, such as receptor sensitivity changes. To examine the effects of repeated administration of SSRIs on serotonin neurotransmission, we investigated the effects of acute and chronic administration of the SSRI fluvoxamine on the extracellular levels of 5-HT in the median raphe nucleus and dorsal hippocampus of conscious rats by means of brain microdialysis. A single oral dose of fluvoxamine (30 mg/kg) augmented extracellular 5-HT in the median raphe and dorsal hippocampus to 270 and 191% of baseline level, respectively. Administration of fluvoxamine (30 mg/kg) or vehicle for 14 days did not affect 5-HT baseline levels. Moreover, the increase in extracellular 5-HT in the median raphe nucleus and dorsal hippocampus after an oral dose of fluvoxamine (30 mg/kg) in rats chronically treated with fluvoxamine was not different from rats treated with vehicle. Using RU 24969 as a probe for the sensitivity of the 5-HT1B autoreceptors in the dorsal hippocampus, no change in receptor sensitivity could be observed. These results demonstrate that repeated oral treatment with fluvoxamine does not affect extracellular 5-HT in the median raphe and dorsal hippocampus, suggesting that presynaptic functional changes of 5-HT in the brain areas tested are not implicated in the observed delayed onset of action of this SSRI in humans.