Repeated treatment with reserpine as a progressive animal model of depression

Treatment-resistant depression is a major health problem worldwide. Restricted validity of the existing animal models of depression along with the need for the study of progressive development of resistance to antidepressants, demands the modeling of a progressive animal model of depression. Present study was designed to test the hypothesis that the repeated administration of reserpine could serve as a progressive animal model of depression. Animals were injected with reserpine [1.0mg/kg; once a day] for three weeks. Results from the present study showed impaired locomotive effects of reserpine in Skinner's box following second as well as third week. These hypolocomotive effects were more pronounced after third week than the second week. Reserpine-induced behavioral depression was evident in the animals after 2 weeks, as assessed by using forced swim test. Depletion of 5-HT, dopamine and metabolites was also observed in the brain samples. Results from the present study suggest that repeated administration of reserpine could be serve as a progressive model of depression and could be used as a convenient and economic animal model for the face validity of anxiolytic compounds. Findings have potential implications with reference to the understanding and the management of treatment-resistant depression

Gender and stress perception based differences in BMI, hormonal response and appetite in adult Pakistani population

To evaluate and compare the gender based variations in stress perception induced changes in leptin, cortisol and serotonin [5-HT] trends, appetite and Body Mass Index [BMI]. An analytical comparative study. Neurochemistry Laboratory, University of Karachi, from January to August 2013. Appetite, BMI and serum leptin, cortisol, and 5-HT were measured in 100 men and women of aged 30 - 60 years, working in teaching institutes of Karachi, to evaluate gender based, stress perception induced variations. The samples were identified by stratified random technique. The chemical variables were estimated through ELISA. Results were analysed using one-way ANOVA and multivariate general linear model using SPSS version 17. Mean stress perception, BMI and serum leptin levels were significantly more in women [p < 0.05]. Serum cortisol and 5-HT were found significantly reduced in women [p < 0.05]. BMI, serum cortisol and leptin were found to be increased with increasing level of stress perception [p < 0.05]. VAS for hunger and desire to eat as the measure of appetite was significantly higher in men [p < 0.05]. Stress perception attenuates the positive effect of cortisol and negative effects of leptin and 5-HT on appetite through changes in their circulatory levels. Women perceive more stress and exhibit significantly attenuated changes in hormonal levels and appetite which may be the contributing factor towards obesity. Increased BMI in women despite decreased appetite merits more studies

Influence of serotonergic 5-HT2C receptor antagonist mesulergine in the reversal of memory deficits induced by mCPP

To determine the effect of non-selective 5-HT2C antagonist mesulergine and 5-HT2C agonist mCPP [metachlorophenylpiperazine] on learning acquisition [LA], short-term memory [STM] and long-term memory [LTM]. Experimental study. Department of Biochemistry, University of Karachi, from December 2009 to June 2010. Twenty-four male albino Wistar rats were used in this study. The agonist and antagonist [mCPP and mesulergine] were injected intraperitoneally at a dose 3.0 mg/kg in volumes of 1 ml/kg. Control animals were injected with saline [1 ml/kg]. Animals were randomly divided into four groups [n=6]. 1st being control group, 2nd being mCPP injected group, 3rd being mesulergine injected group and 4th group being injected with both mesulergine and mCPP. Behavioural activities of rats were monitored after 30 minutes of injection. For assessment of memory functions, water maze apparatus was used. Administration of mCPP impaired STM, LTM and LA of rats. Mesulergine injected rats exhibited no alteration in memory functions. However, when it was injected with mCPP then there were no memory deficits induced by mCPP. Ability of 5-HT2C receptor antagonist mesulergine to block the memory impairment effect of mCPP indicated an important regulatory role of 5-HT2C receptors in cognitive processes

Reversal of haloperidol-induced motor deficits by mianserin and mesulergine in rats

Although haloperidol is widely prescribed for the treatment of schizophrenia, its beneficial effects are accompanied by extrapyramidal side effects [EPS]. Role of 5-HT-2A/2C receptors in the attenuation of acute Parkinsonian-like effects of typical antipsychotics is investigated by prior administration of mianserin and mesulergine to rats injected with haloperidol. In the first part of study effects of various doses of haloperidol [0.5, 1.0, 2.5 and 5.0 mg/kg] were determined on motor activity and a selected dose [1 mg/kg] was used to monitor attenuation of parkinsonian effects by two different doses of 5-HT-2A/2C receptor antagonists mianserin [2.5 and 5.0 mg/kg] and mesulergine [1.0 and 3.0 mg/kg]. Rats treated with haloperidol at doses of 0.5-5.0 mg/kg exhibited impaired motor coordination and a decrease in exploratory activity in an open field. The dose response curve showed that at a dose of 1 mg/kg significant and submaximal effects are produced on motor coordination and exploratory activity. Coadministration of mianserin and mesulergine attenuated and reversed haloperidol-induced motor deficits in a dose dependent manner. The mechanism involved in the attenuation / reversal of haloperidol-induced parkinsonian like symptoms by mianserin and mesulergine is discussed. Prior administration of mianserin or mesulergine may be of use in the alleviation of EPS induced by conventional antipsychotic drugs. The findings have potential implication in the treatment of schizophrenia and motor disorders

Long term administration of HMG-COA-reductase inhibitor [simvastatin] affects brain serotonin neurotransmission in male rats

Simvastatin, an important member of statin family is widely prescribed as cholesterol-lowering agent. Like other statins it acts by inhibiting the rate limiting enzyme 3-hydroxy-3-methylglutaryl-CoA [HMG-CoA] reductase, responsible for the endogenous production of cholesterol which forms an essential part of neuronal cell membranes. Lowering of cholesterol has been reported to alter the brain chemistry and hence neurotransmission. To understand the association between low cholesterol and brain serotonin [5-HT] we monitored the effect of oral administration of simvastatin for 4 weeks on brain serotonin levels. Drug treated rats exhibited significantly low plasma cholesterol levels. Brain serotonin and 5- HIAA[5-hydroxyindole acetic acid] levels were also decreased in drug treated rats. Plasma tryptophan [TRP] was significantly increased but brain tryptophan levels were significantly decreased in drug treated rats. Weekly food intake during the entire experimental period was comparable in control and drug treated rats. Results of the present study suggest that simvastatin induced lowering of cholesterol may be responsible for the decrease in brain 5-HT neurotransmission and hence may be a cause of depression observed in subjects taking simvastatin to lower cholesterol levels

Enhancement of memory by lithium in animal model of stress

Numerous studies have consistently shown that repeated restraint stress produces functional neuromorphological and physiological alteration that are linked to the pathophysiology of brain disorder, like depression and bipolar disorder, causes alteration in cognition and learning memory. Lithium is the drug of choice in the treatment of depression and mania in bipolar disorder as a mood-stabilizing agent. Present study was designed to investigate the effects of long term lithium administration on memory function and its relation with 5-HT metabolism following repeated restraint stress. In this experiment memory was assessed by novel object recognition task in water treated and lithium treated unrestraint and restraint rats. Recognition memory decreased in water treated repeated restraint rats while in lithium treated repeated restraint rats recognition memory increase. 5-HIAA level increased in water treated restraint rats while decreased in lithium treated restraint rats. The findings indicate a role of brain serotonin in improved memory function in repeated restraint rats following long term lithium administration

m-Cpp induced hypolocomotion does not interfere in the assessment of memory functions in rats

Central serotonergic system plays a critical role in the regulation of memory processes in rats. Evidence suggests that a dysfunction of serotonergic system contributes to various pathological conditions. Among the multiple classes of serotonin [5-Hydroxytryptamine, 5-HT] receptors described in CNS, much attention has been devoted to the role of 5-HT2C receptor family on memory functions. A number of studies have shown that 5-HT2C receptor agonists impair memory function and also decreased locomotor activity of rats. The present study was designed to investigate the effect of different doses of 5-HT2C receptor agonist metachlorophenylpiperazine [mCPP] on locomotion and cognitive behavior in rats. Groups of adult male rats were injected mCPP intraperitoneally at doses of 1, 3 and 5 mg/kg. The learning and memory of rats were assessed by water maze [WM] and passive avoidance [PA] tests. Locomotor activity of rats was monitored by open field test. mCPP decreased locomotor activity of rats as reported earlier. A negative correlation between memory function and 5-HT2C receptor stimulation was observed in WM. Furthermore the administration of mCPP dose dependently impaired memory functions and the impairment of memory induced by mCPP was greatest at the highest dose. PA test was also performed in the present study to confirm that the decreased locomotor activity exhibited by mCPP injected rats did not affect the memory assessment in WM. Irrespective of hypolocomotion induced by mCPP, drug injected rats took less time to enter the punishable compartment which confirmed that the impairment in memory functions following mCPP was not due its effect on locomotion. It is suggested that 5-HT2C receptors might be involved in memory function probably mediating a suppressive or constraining action by decreasing dopamine levels. It can be therefore concluded that 5-HT2C receptors have a negative influence on memory function, which raises the possibility of using 5-HT2C receptor antagonists in the improvement of memory functions

Behavioral effects of l-[m-chlorophenyl] piperazine [m-CPP] in a rat model of tardive dyskinesia

The present study was designed to monitor the responsiveness of 5-hydroxy tryptamine [5-HT]-2C receptor in rats treated with haloperidol exhibiting tardive dyskinesia [TD]. Results show that haloperidol injected at a dose of 1 mg/kg twice a day for two weeks elicited vacuous chewing movements [VCMs]. Which increased in a time dependent manner following the drug administration for 3-5 weeks. The behavioral effects of 1-[m-chlorophenyl]piperazine [m-CPP] a 5-HT-2C and 5-HT-1B agonist were monitored 2 days after 5 weeks of saline or haloperidol administration. The results show that hypophagic as well as anxiogenic-like effects of m-CPP are greater in repeated haloperidol than repeated saline injected animals, while hypolocomotive effects of m-CPP are not different in repeated saline and haloperidol injected animals. Results are discussed in the context of role of 5-HT-2C receptors in the regulation of the activity of dopaminergic neuron and its possible impact on elicitation of TD

Desensitization of pre and post synaptic 5-HT-1a receptor responses following long term consumption of sugar rich diet: implications for sugar-induced obesity

The present study concerns the effectiveness of a selective 5-hydroxytryptamine [5-HT] -1A receptor agonist 8- hydroxy-2-[di-n-propylamino] tetralin [8-OH-DPAT] in long term sugar diet treated rats. Male albino wistar rats were divided into control and test groups. Test animals were given sugar [5 g/10ml water] orally for three weeks. Food intakes and body weight of all rats were measured weekly. After three weeks control and test animals were further divided into two groups i.e. saline injected and drug injected. 8-OH-DPAT at a dose of 0.25mg/kg was injected to a group of normal diet treated and another group of sugar diet treated rats. Other two groups were injected with saline. 5-HT syndrome and food intakes at 2h and 4h were monitored. Then animals were decapitated to collect brain samples for the estimation of 5-HT and 5-hydroxyindole acetic acid [5-HIAA] levels by HPLC-EC method. We observed that weekly cumulative food intakes increased and body weights decreased in sugar diet treated rats. 8-OH-DPAT produced hyperactivity syndrome in both control and sugar treated rats. But these values were smaller in sugar diet than normal diet treated rats. Hyperphagic effects of 8- OH-DPAT were greater in normal diet than sugar diet treated rats. 5-HT and 5-HIAA levels were not altered. The results suggesting a desensitization of pre as well as postsynaptic 5-HT-1A receptors in rats treated with sugar diet are discussed in the context of a role of sugar diet in the precipitation of obesity and other neuropsychiatric illnesses

Serotonin [1A] receptor agonism in the expression of behavioral dopaminergic supersensitivity in subchronic haloperidol treated rats

The idea that serotonin [5-hydroxytryptamine; 5-HT] is contributed in schizophrenia has long been advocated and alterations in 5-HT neurotransmission has been hypothesized to modulate both the therapeutic and extrapyramidal symptoms [EPS] liability of conventional neuroleptics. The 8-hydroxy-2-[di-n-propylamino] tetralin [8-OH-DPAT], a preferential 5-HT1A ligand, has been reported to attenuate EPS functions of haloperidol in animals. In view of a possible role of 5-HT1A receptors in the management of EPS functions of a neuroleptic drug, the present study was designed to investigate behavioral responses of 8-OH-DPAT at a challenge dose of 0.5mg/kg in rats with subchronic haloperidol administration at a dose of 5mg/kg twice daily for 5 days. The intensity of 5-HT syndrome provoked by 8-OH-DPAT was taken as a measure of postsynaptic responses. In the present study administration of haloperidol at a dose of 5mg/kg twice daily for 5 days decreased locomotion significantly [p<0.01] in familiar [home cage] environment. Subchronic administration of haloperidol at the same dose elicited significant [p<0.01] cataleptic responses in rats when compared with saline treated rats. Results revealed that 8-OH-DPAT-induced hyperlocomotion [p<0.05] and forepaw treading [p<0.1] were significantly smaller in rats pre-treated with haloperidol for 5 days than repeatedly saline injected rats. Conversely, the other components of the syndrome i.e. flat body posture [p<0.001], hind limb abduction [p<0.001] and straub tail [p<0.01] were significantly greater in repeated haloperidol treated rats when compared with repeated saline injected rats. These findings help to demonstrate a causal link between the upregulation of DA-D2 receptors and the decrease in the effectiveness of presynaptic 5-HT1A receptors following subchronic haloperidol administration and this may further help to yield an antipsychotic agent with an improved profile of efficacy to EPS, thereby widening its therapeutic window

Dose related effects of Buspirone on serum electrolyte balance, plasma osmolality and systolic blood pressure [SBP] in rats

Buspirone is a potent anxiolytic that decreases serotonin transmission. Changes in electrolyte balance, plasma osmolality and systolic blood pressure are often associated with stress-induced anxiety in rats as well as in human but effects of buspirone on changes in serum electrolytes balance, plasma osmolality and SBP of rats has not been reported. Present study concerns the effects of different doses of buspirone [0.25, 0.5, and 1mg/kg] on serum electrolyte, plasma osmolality and systolic blood pressure [SBP] of rats. Anxiolysis related variable are also monitored. Results show that the administration of buspirone [0.25mg/kg and 0.5mg/kg] significantly increased the serum concentration of electrolytes and plasma osmolality but decreased the serum level of magnesium. These doses also reduced the systolic blood pressure [SBP]. A dose of 1mg/kg buspirone produced no effect on the concentration of serum electrolytes, and plasma osmolality. Anxiolytic effects of the drug were dose dependent but 1mg/kg dose decreased the effect. The results are discussed in the context of serotonin receptors [5-HT[1A] to be involved in buspirone-induced changes of electrolytes, SBP and plasma osmolality

Gender difference in memory functions following long term tryptophan supplementation in rats

Evidence shows that tryptophan [TRP] and serotonin [5HT] have a role in memory function. It has been shown in various studies that increase in serotonergic neurotransmissionis associated with increased memory consolidation whereas low brain 5HT impairs memory performance. In view of a possible role of TRP and 5HT in memory, the present study was designed to investigate the effect of TRP supplementation on male and female rats and to investigate sex related differences in memory processes. Tryptophan at a dose of 100mg/kg was used. Short term memory [STM] and long term memory [LTM] were evaluated using the Morris water maze. TRP treatment for 6 weeks significantly enhanced STM of female rats but it did not have any effect on the STM of male rats. Female rats when compared with male rats exhibited better performance in the Morris water maze and enhanced memory was observed both before and after TRP treatment, however after TRP treatment a greater improvement was observed. Both male and female rats exhibited improvement in LTM following TRP treatment. The present results emphasize on the involvement of sex difference and 5HT in learning and memory processes. A greater increase in 5HT metabolism and turnover seen in female rats correlates with the enhanced memory function observed in females than male rats

Relationship of brain tryptophan and serotonin in improving cognitive performance in rats

Brain function can be affected by the availability of dietary precursors of neurotransmitters. The diet induced increase in tryptophan [TRP] availability has been shown to increase brain serotonin synthesis and various related behaviors. Evidence shows that TRP and serotonin [5HT; 5 Hydroxytryptamine] play a significant role in memory function. Enhanced brain serotonin activity has been shown to improve cognitive performance in animals and human whereas decreasing brain 5HT levels by acute TRP depletion has been shown to impair cognition. A number of methods have been used for the assessment of memory in animals. In the present study, the radial arm maze and the passive avoidance was used for the assessment of memory in rats following long-term TRP administration. TRP at doses of 50 and 100 mg/kg body weight was orally administered for 6 weeks. The present study shows a significant improvement in memory of rats following both doses of tryptophan. Plasma TRP, brain TRP, 5HT and 5 hydroxy indol acetic acid [5HIAA] levels were increased significantly following administration of TRP. The results of the present study suggest that increase in brain 5HT metabolism following long term TRP administration may be involved in enhancement of memory

Effects of tryptophan and valine administration on behavioral pharmacology of haloperidol

Development of antipsychotics with slight/no extra-pyramidal symptoms [EPS] and/or other side effects is one of the exploring fields of drug research. Haloperidol is a high potency typical neuroleptic used in the treatment of schizophrenia but produces muscles related side effects commonly known as EPS. These effects are not produced following the administration of atypical neuroleptics such as clozapine. A severe side effect of clozapine treatment is however, agranulocytosis. This involves investigation on the mechanism by which a typical neuroleptic acting via serotonergic mechanism tends to produce less or no EPS. The present study was, therefore, designed to determine the effect of serotonin precursor tryptophan and a large neutral amino acid other than tryptophan [valine] on the modulation of haloperidol induced catalepsy and akinesia. Cataleptic effects of the drug and activity reducing effects were monitored on inclined surface and in an activity box or open field respectively. The results are discussed in the context of a role of tryptophan and valine induced changes of brain serotonin in modifying the extrapyramidal and monoaminergic effects of the typical neuroleptic haloperidol. In the present study administration of TRP and valine decreased activity in rats, haloperidol-induced catalepsy' was not modulated by prior administration of tryptophan or valine. Brain serotonin levels were elevated by haloperidol treatment and correlated very well with the behavioral response. These findings suggest a possible serotonergic involvement in neuroleptic induced tardive dyskinesia and an amelioration of the disorder through TRP supplementation

Decrease of ethanol intake following repeated injection of serotonin-1A agonist in rats: relationship with receptor responsiveness

To monitor pre and postsynaptic receptor responsiveness and consumption of ethanol following the repeated administration of a selective serotonin-1A receptor agonist, 8-hydroxy-2-di-n-propylaminotetralin [8-OH-DPAT], to ethanol treated rats. Design: The experimental protocol was designed to administer ethanol orally to rats for three weeks and 8-OH-DPAT during the 3rd week. Place and Duration of Study: The experiments were performed in the department of Biochemistry, Karachi University. Samples collected after three weeks of treatment were analyzed within a week. Subjects and The study was conducted on 24 males albino Wistar rats treated with ethanol for three weeks. 8-OH-DPAT at a dose of 1mg/kg or saline was injected to ethanol treated rats from day 1 to day 5 during the 3rd week to monitor the effects on ethanol consumption. Pre and postsynaptic responses to 8-OH-DPAT were monitored by injecting the drug on the 6th day to a group of 5-day saline and a group of 5-day 8-OH-DPAT injected animals. Control animals of the two groups were injected with saline. Before the injection of 8-OH-DPAT, weekly intakes of ethanol were highly comparable in the two groups. Administration of 8-OH-DPAT, from day 1 to day 5, decreased ethanol intake. Pre and postsynaptic serotonin-1A receptor dependent responses monitored on the 6th day were higher in 5-day saline than 5-day 8-OH-DPAT injected animals. A decrease in the effectiveness of negative feedback control over the synaptic availability of serotonin following 5-day administration of 8-OH-DPAT is involved in the decreases of ethanol consumption

Serotonergic mechanism of antidepressant action and adaptation to stress

Investigations on the mechanism of action of antidepressants suggested that they enhance neurotransmission across monoamine synapse by inhibiting neuronal reuptake or degradation of monoamines. Development and introduction of specific serotonin reuptake inhibitors [SSRIs] was prompted by the desire to eliminate some side effects of traditional antidepressants. These drugs act by selectively inhibiting the neuronal reuptake of 5-hydroxytryptamine [5-HT; serotonin]. Theories on the causative agents of depressive symptoms, therefore, focused on the hypoactivity of the monoaminergic and particularly serotonergic systems of the brain. However, a number of points remain unclear. The effects of SSRIs and other antidepressants on serotonin and/or monoamine synapse are immediate whereas clinical improvement may take place some weeks. Several compounds could increase serotonergic/monoaminergic activity but are not antidepressant. Animal studies show that an episode of stress although increases brain 5-HT metabolism but behavioral deficits comparable to a model of depression are produced. On the other hand, increases of brain 5-HT metabolism do not occur in animals adapted to a repeated stress schedule. Recent studies show that long term antidepressant administration as well as adaptation to stress both desensitize 5-HT-1A receptors located on cell soma and/or dendrites of serotonergic neurons. In view of serotonin hypothesis of depression, a fall in the efficacy of negative feedback action at 5-HT synapse would be a possible mechanism of antidepressant action and adaptation to stress

Serotonin and anxiety: a review of current research and clinical implications

Benzodiazepines [BNs] are known to pose risks associated with drug dependence, abuse and withdrawal symptoms. Arylpiperazines such as buspirone, gepirone and ipsapirone have been introduced as useful alternatives to/the BZs in the treatment of anxiety and depression, which are distinct illnesses and often coexist. This new class of drugs is distinguished from its predecessors by a wider margin of safety and a lower potential for fatal overdose. This article addresses salient issues and provides evidence in the burgeoning field of serotonin-related management of anxiety in clinical psychiatry

Central serotonin functions and availability of Tryptophan to the brain

Tryptophan [TRP] was the first amino acid to be recognized initially as being essential for normal growth of young animals and later as an essential amino acid for human nutrition. It plays an important role in maintaining a large number of normal physiological functions. It is the precursor of several neuroactive compounds including serotonin [5- hydroxytryptamine 5 - HT] which functions as a neurotransmitter in the brain and is involved in the regulation of a variety of physiological and behavioral functions. It is well established that TRP changes clearly influence brain 5 - HT synthesis but how much this might affect the availability of serotonin to its receptors in order to produce a function is what has been analysed in the present article

Injected monosodium glutamate increases holotryptophan pyrrolase activity and plasma corticosterone levels more in male than female rats

Monosodium glutamate [MSG] injected intra - peritoneally at doses 4 g/kg increased holotryptophan pyrrolase activity significantly by 61.6% in male rats. The increases were smaller [24%] and non- significant in females. Apotryptophan was decreased by 61% and comparably in the two sexes. Cumulative effect on total enzyme activity was a reduction of 37.5% in female rats. A decrease of 20.6% in male rats was not significant. Plasma levels of corticosterone were increased significantly in male but not in female rats. The sex differences are explained in terms of female hormones being effected by MSG administration and higher circulating MSG - induced corticosterone levels being involved in the enhancement of holotryptophan pyrrolase activity in male rats. Plasma total tryptophan levels were increased due to an inhibition of total tryptophan pyrrolase activity in female but not in male. Plasma free tryptophan concentrations were decreased in both sexes