Aram El Khoury

The effects of social isolation on neuropeptide Y levels, exploratory and anxiety-related behaviors in rats

NPY is one of the most abundantly expressed peptides within the CNS, and has been previously demonstrated to be altered in several animal models of depression, as well as to be differentially regulated by acute and repeated stress. The effect of social deprivation, through isolation housing, on brain NPY concentrations in adult rats has not been previously investigated. The effects of 12 weeks of social isolation, in adult rats, on anxiety-related behaviors and central concentrations of NPY in: hypothalamus, amygdala, caudate-putamen, hippocampus, and frontal cortex were evaluated. Single housed animals spent significantly more time on the open arms of the elevated plus maze and in the central area of the open field as compared to pair housed controls. These data are most likely indicative of enhanced exploration and novelty seeking. Concentrations of neuropeptide Y were increased in the caudate-putamen of the single housed subjects. NPY levels in caudate/putamen and hypothalamus were also significantly correlated with time spent in the open arms of the elevated plus maze. These data suggest that chronic social isolation, in these adult Wistar rats, did not increase anxiety but produced enhanced exploration in tests of anxiety, an effect that was associated with NPY concentrations in the striatum and hypothalamus.

Increased CRF-like and NPY-like immunoreactivity in adult rats exposed to nicotine during adolescence: Relation to anxiety-like and depressive-like behavior

OBJECTIVE Recently, animal models have been developed that demonstrate that adolescent nicotine exposure produces neurobehavioral changes which persist into adulthood. This study further examined the impact of adolescent nicotine exposure on anxiety-like and depressive-like behavior, as well as on levels of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) in this model. METHODS Male adolescent rats (35-40 days old) were administered nicotine using Nicoderm CQ patches (Smith-Kline Beecham). Behavior in the elevated plus maze (EPM) and forced swim test (FST) was assessed 2-3 weeks after exposure ended. Brain levels of CRF and NPY were then assessed 5-6 weeks after behavioral tests were completed. In addition, blood and brain levels of nicotine resulting from nicotine treatment were examined. RESULTS After 5 days of exposure to 5 mg/kg/day nicotine, blood levels of nicotine averaged 66+/-5 ng/ml and brain nicotine levels averaged 52+/-4 ng/g. Rats exposed to nicotine displayed an anxiety-like profile in the EPM (i.e., decreased time spent in the open arms) and an antidepressant-like profile in the FST (i.e., less time spent immobile). Rats exposed to nicotine also had increased hypothalamic and frontal cortical CRF, increased hypothalamic and hippocampal NPY, and a decreased ratio of NPY to CRF in the amygdala. CONCLUSIONS This study demonstrates that adolescent nicotine exposure produces lasting increases in anxiety-like behavior and may reduce depressive-like behavior. These behavioral changes also occurred in concert with alterations in CRF and NPY systems. Thus, lasting neurobehavioral changes associated with adolescent nicotine exposure may be related to allostatic changes in stress peptide systems.

Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression

Stress has been shown to interact with genetic vulnerability in pathogenesis of psychiatric disorders. Here we investigated the outcome of interaction between genetic vulnerability and early-life stress, by employing a rodent model that combines an inherited trait of vulnerability in Flinders Sensitive Line (FSL) rats, with early-life stress (maternal separation). Basal differences in synaptic signaling between FSL rats and their controls were studied, as well as the consequences of early-life stress in adulthood, and their response to chronic antidepressant treatment (escitalopram). FSL rats showed basal differences in the activation of synapsin I and Erk1/2, as well as in alpha CaM kinase II/syntaxin-1 and alpha CaM kinase II/NMDA-receptor interactions in purified hippocampal synaptosomes. In addition, FSL rats displayed a blunted response of Erk-MAP kinases and other differences in the outcome of early-life stress in adulthood. Escitalopram treatment restored some but not all alterations observed in FSL rats after early-life stress. The marked alterations found in key regulators of presynaptic release/neurotransmission in the basal FSL rats, and as a result of early-life stress, suggest synaptic dysfunction. These results show that early gene-environment interaction may cause life-long synaptic changes affecting the course of depressive-like behavior and response to drugs.

CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls

The purpose of this study was to examine the differential effects of acute tryptophan (TRP) depletion vs. sham condition on plasma, cerebrospinal fluid (CSF) biochemical parameters, and mood in the following three subject groups: (1) nine antidepressant-free individuals with remitted depression, (2) eight paroxetine-treated individuals with recently remitted depression, and (3) seven healthy controls. Plasma TRP decreased during TRP depletion and increased during sham condition (p<.01). CSF TRP and 5-hydroxyindoleacetic acid were lower during TRP depletion than sham condition (p<.01 each). During TRP depletion, CSF TRP correlated significantly with the plasma sum of large neutral amino acids (SigmaLNAA) (R=-.52, p=.01), but did not significantly correlate with plasma TRP (R=.15, p=.52). The correlation between CSF TRP and ratio of TRP to SigmaLNAA was R=.41 and p=.06 during TRP depletion, and R=-.44 and p=.04 during sham condition. A negative correlation trend was observed between CSF-TRP levels and peak Hamilton Depression Rating Scale scores during TRP depletion in patients recovered from depression (R=-.45, p=.07), but not in healthy controls (R=-.01, p=.98). CSF neuropeptide Y was higher during TRP depletion than sham condition (t=1.75, p<.10). These results illustrate the importance of assessing plasma SigmaLNAA when using the TRP depletion paradigm. The use of a single CSF sampling technique although practical may result in data acquisition limitations.

Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder.

The authors investigated the effect of long-term lithium administration on intracellular calcium mobilization. The subjects were 13 women with bipolar affective disorder stabilized on lithium and 12 matched healthy controls. Total and ionized serum calcium, intracellular calcium ion concentration, plasma parathyroid hormone (PTH) and tyrotropin (TSH), serum electrolytes and cyclic AMP (cAMP) activity in platelets were measured. The serum electrolytes sodium, potassium and creatinine and plasma PTH and TSH were all within normal ranges in patients and controls and no differences were found between the two groups. No difference was found in basal and prostaglandin E1 (PGE1)-stimulated cAMP generation in platelets between patients and controls. However, total serum calcium and ionized serum calcium levels were higher in patients than in controls and there was a significant correlation between these two measures. In the patient group, serum lithium concentration correlated positively with stimulated levels of intracellular calcium in platelets. In the present study, no distinct hyperparathyroidism was found in lithium-treated patients. However, our findings indicate that lithium administration affects calcium metabolism in patients with bipolar affective disorder inducing mild hypercalcemia and a dose-dependent normalized calcium mobilization. Furthermore, our results did not support the hypothesis that lithiums primary site of action in bipolar illness may be on signal transduction mechanisms.

Nortriptyline influences protein pathways involved in carbohydrate metabolism and actin-related processes in a rat gene–environment model of depression

Although most available antidepressants increase monoaminergic neurotransmission, their therapeutic efficacy is likely mediated by longer-term molecular adaptations. To investigate the molecular changes induced by chronic antidepressant treatment we analysed proteomic changes in rat pre-frontal/frontal cortex and hippocampus after nortriptyline (NT) administration. A wide-scale analysis of protein expression was performed on the Flinders Sensitive Line (FSL), a genetically-selected rat model of depression, and the control Flinders Resistant Line (FRL). The effect of NT treatment was examined in a gene-environment interaction model, applying maternal separation (MS) to both strains. In the forced swim test, FSL rats were significantly more immobile than FRL animals, whereas NT treatment reduced immobility time. MS alone did not modify immobility time, but it impaired the response to NT in the FSL strain. In the proteomic analysis, in FSL rats NT treatment chiefly modulated cytoskeleton proteins and carbohydrate metabolism. In the FRL strain, changes influenced protein polymerization and intracellular transport. After MS, NT treatment mainly affected proteins in nucleotide metabolism in FSL rats and synaptic transmission and neurite morphogenesis pathways in FRL rats. When the effects of NT treatment and MS were compared between strains, carbohydrate metabolic pathways were predominantly modulated.

Decreased Plasma Prolactin Release in Euthymic Lithium-Treated Women with Bipolar Disorder

In order to evaluate the effect of treatment with citalopram (CIT) and lithium (Li) on hormone levels in women with bipolar disorder, morning plasma prolactin (PRL) and cortisol (CORT) were measured in 14 nonmedicated depressed patients, 13 depressed patients responding to CIT treatment, 17 euthymic patients on long-term Li treatment, and 11 healthy controls. Plasma PRL values in the Li group were significantly lower than those of the three other groups, suggesting a net inhibitory impact of augmentative effects of Li on dopaminergic activity and serotonergic neurotransmission in the central nervous system. Plasma CORT values in nonmedicated depressed patients were significantly higher than those of healthy controls, indicating hyperactivity of the hypothalamic-pituitary-adrenal system in depression, which appears to be a state-dependent phenomenon, and is normalized upon successful treatment with Li and CIT.

Effects of long-term lithium treatment on monoaminergic functions in major depression.

Platelet [14C]serotonin uptake, the density of serotonin transporters and 5HT(2) receptors, and 5HT(2) and alpha(2) receptor function in platelets were investigated in 29 outpatients (15 women and 14 men) diagnosed as having a major affective disorder (21 bipolar and 8 unipolar). The data were compared with data for 26 healthy volunteers matched for age, sex and season. No differences were found in the mean values for the uptake velocity (V(max)) and the affinity (K(m)) of the transport carrier for serotonin between patients and controls. However, female patients had lower V(max) compared to male patients and female control subjects. A positive correlation between plasma lithium and V(max) and a tendency toward a negative correlation between plasma lithium and K(m) was observed. Furthermore, there were no differences in platelet B(max) and K(d) for [3H]paroxetine binding and K(d) for [3H]LSD binding between patients and controls. However, there was an increased number of platelet 5-HT(2) receptors and a difference in serotonin-mediated potentiation of platelet ATP secretion between patients compared to controls, especially in women. The findings in the present study suggest that lithium has a net ameliorating impact on serotonin uptake which may render it resistant to change. They also postulate that the effect of lithium may be attained by a dual influence on postsynaptic serotonergic structures, as it increases both the density and the sensitivity of 5-HT(2) receptors.

Synaptoproteomics of Existing and new Animal Models of Depression

Depression is a severe and life-threatening psychiatric illness whose pathogenesis is still essentially unknown. Proteomic analysis of synaptic terminals (synaptoproteomics) in animal models of depression is a powerful approach to gain insight into the molecular mechanisms underlying vulnerability to mood disorders and the long-term action of drug treatments. Here, we employed two different animal models of depression, the Learned Helplessness rats (a classical behavioral model of depression) and a new model of depression with gene—environment interaction (Flinders Sensitive Line rats subjected to early life stress). Both animal models were treated with the antidepressant escitalopram. Analysis of their synaptoproteomic profile revealed a number of protein spots differently regulated by basic vulnerability and/or early life stress. Using this approach, we obtained information regarding biomarkers that may represent predictors of pathology or response/resistance to drug treatment, as well as potential targets for novel pharmacological and therapeutic strategies.

Neuropeptide Y in Euthymic Lithium-Treated Women with Bipolar Disorder

Plasma neuropeptide Y-like immunoreactivity (NPY-LI) and platelet cyclic AMP (cAMP) activity were determined in 13 women with bipolar disorder stabilized on lithium (Li) and 12 matched healthy controls. No differences in plasma NPY-LI were found between the two groups. In euthymic Li-treated bipolar patients, there was an inverse correlation between plasma NPY-LI levels and intracellular cAMP in prostaglandin E1-stimulated platelets. A positive correlation was found between plasma NPY-LI levels and age in both the patient and the control group. Our findings support earlier findings that NPY is capable of inhibiting adenylyl cyclase and that aging is a physiological factor in regulating NPY-LI levels.