Behavioral, Hormonal, and Serotonergic Responses to Different Restricted Feeding Schedules in Rats.

To determine the effect of long-term restricted feeding schedules on behavior, serotonergic responses, and neuro-endocrine functions, metabolism of serotonin (5-HT) in the striatum, expression of serotonin-1A (5-HT1A) auto-receptor in the raphe nuclei and circulating levels of leptin and corticosterone were determined in female Wistar rats kept on excessive food restriction schedule. Due to a role of dietary deficiency of tryptophan (Trp) in influencing serotonergic neurotransmission, circulating levels of Trp were also determined. Estimations were done in 2 different restricted feeding models: time-restricted feeding (TRF) and diet restricted (DR). TRF animals were given access to food ad libitum only for 2 hours/day. The DR animals were given a small calculated amount of food each day. We found that chronic food restriction for 5 weeks cause a significant decrease in the body weight and produced hyperactivity in both, TRF and DR animals. Levels of Trp were declined in circulation and in the striatum. Similarly, the levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were decreased in the striatum. Also, the expression of 5-HT1A auto-receptor was declined in the raphe nuclei. These changes in 5-HT metabolism and 5-HT1A auto-receptor expression were more profound in DR animals as compare to TRF animals. Similarly, hypoleptinemia and increased corticosterone found in both models was higher in DR animals. Effect of dietary deficiency of Trp in the modulation of striatal 5-HT metabolism and its consequences on circulating leptin and corticosterone are discussed.

Anxiolytic, anti-nociceptive and body weight reducing effects of L-lysine in rats: Relationship with brain serotonin an In-Vivo and In-Silico study.

L-lysine (L-lys) had long been comprehended as an essential amino acid for humans. There were reports that the absence or inadequate availability of L-lys in the diet may lead to mental and physical impairments. The present study was designed to explore the effects of L-lys on body weight changes, cumulative food intake, anxiety-like behavior and pain perception in rats. 5-Hydroxytryptamine (5-HT, serotonin) metabolism, and tryptophan (Trp) levels in the midbrain (MB), hippocampus (HP), and prefrontal cortex (PFC) were also determined. Animals were treated with L-lys in doses of 0.5 g/kg and 1 g/kg for 20 days and behavioral studies were performed on day 1st and day 20th. After monitoring behaviors on day 20th, animals were killed to collect the serum and brain regions MB, HP and PFC. 5-HT metabolism and Trp levels were determined by HPLC-EC. The treatment produce no effect on food intakes but body weights were reduced. 20 days administration of L-lys produced an anxiolytic effect and increased exploratory activity on day 1st. Repeated administration of L-lys increased 5-HT levels in the PFC and HP. 5-Hydroxyindoleacetic acid (5-HIAA), the metabolite of 5-HT, decreased in the HP. Trp, the precourser of 5-HT, decreased in the PFC. Results suggested a decrease in 5-HT degredation in enhancing 5-HT levels. Results of in-silico analysis showed that lysine had a potential binding affinity for MAO (monoamine oxidase) A and B with an energy of (-4.8 kcal/mol and -5.3 kcal/mol) respectively. The molecular dynamic simulation study revealed the stability of L-lys after 10 ns for each protein. Conclusively, the present study showed that L-lys produced an anxiolytic effect and reduced body weight. These beneficial effects were associated with an increase in 5-HT levels in the PFC and HP. In-silico analysis suggested that 5-HT increase were due to the binding of L-lys with MAOs resulting in an inhibition of the degradation of monoamine.

Glucocorticoids in the Physiological and Transcriptional Regulation of 5-HT1A Receptor and the Pathogenesis of Depression.

There is growing increase in the global prevalence of depression, but treatment outcome of this highly disabling disease is not satisfactory. Many patients are not benefitted by the currently prescribed antidepressants-together with this partial remission is very common. Improving treatment strategies and developing better therapeutic agents for treating depression is therefore highly needed. Stress-related epigenetic changes play a critical role in the pathogenesis as well as treatment of depression. Stressful events activate hypothalamic-pituitary-adrenal axis to increase circulating levels of glucocorticoids (GCs), and a greater sensitivity to this fright and flight response increases risk of depression. A role of serotonin (5-hydroxytryptamine; 5-HT) in responses to stress and in the pathogenesis and treatment of depression is well established. Substantial evidence supports a critical role of 5-HT1A receptors in these effects of 5-HT. The present article targets stress-induced higher and sustained increases of GCs and mediated influences on the physiological as well transcriptional regulation of 5-HT1A receptors to evaluate their causal role in the pathogenesis of depression. It is suggested that synthetic compounds with antagonist activity for GC receptors and agonist activity for 5-HT1A receptors may prove better therapeutic agents for treating depression.

Prevention of diet restriction induced hyperactivity but not body-weight reduction in rats co-treated with tryptophan: relationship with striatal serotonin and dopamine metabolism and serotonin-1A auto-receptor expression.

Anorexia Nervosa (AN) is an eating and behavioral disorder characterized with anxiety/depression, hyperactivity, behavioral impulsivity and psychosis. Most of the associated symptoms are related to the deficiency of serotonin (5-hydroxytryptamine: 5-HT) stores. A deficiency of 5-HT can modulate dopamine neurotransmission in the striatum to elicit hyperactivity and psychosis in AN patients. Also, the release and availability of 5-HT are modulated by serotonin-1A (5-HT1A) auto-receptor. The present study investigates the role of striatal metabolism of 5-HT and dopamine in precipitating hyperactivity in the rat model of diet restriction (DR) induced AN. The role of tryptophan (Trp) in influencing the 5-HT metabolism and the mRNA expression of 5-HT1A auto-receptor is also investigated. We find that long-term DR for 38 days reduces body-weight in rats and produces hyperactivity, similar to AN. This hyperactivity is characterized by declined striatal metabolism of both, dopamine and 5-HT. The mRNA expression of 5-HT1A auto-receptor in the raphe nuclei is also decreased. Trp co-treatment improves these deficiencies in monoamine metabolism and alleviates hyperactivity. Interestingly, DR-induced changes in body-weights are not effected by Trp co-treatment. The study suggests that the striatal metabolism of 5-HT and dopamine and mRNA expression of 5-HT1A auto-receptor has an important role in the pathogenesis of AN. The finding suggests that co-use of Trp can prevent precipitation of AN by normalizing 5-HT metabolism.

Co-treatment with low doses of buspirone prevents rewarding effects of methylphenidate and upregulates expression of 5-HT1A receptor mRNA in the nucleus accumbens.

Accumulating studies consistently show that methylphenidate (MPD), the first line drug for treating Attention-Deficit Hyperactivity Disorder (ADHD), is abused by patients to whom the drug is prescribed. Like other psychostimulants, only low doses of MPD improve cognitive performance while higher doses impair it. Preventing the use of high doses of MPD is important for retaining its therapeutic efficacy. Previously, it has been shown that performance in Morris water maze test is improved in rats treated, orally, with MPD in doses of 2.5 mg/kg; but higher doses (5 mg/kg) impair it. The present study is designed to monitor rewarding effects of 2.5 mg/kg MPD in conditioned place preference (CPP) paradigm and its potential inhibition in buspirone co-treated animals. Our results show that rewarding effects of MPD in CPP paradigm are prevented in rats co-treated with buspirone in doses of 0.1 and 0.3 mg/kg. Animals treated with MPD exhibit a downregulation of 5-HT1A receptor mRNA in the nucleus accumbens which is also prevented in rats co-treated with 0.1 and 0.3 mg/kg but not 1.0 and 2.0 mg/kg buspirone. Administration of buspirone in these doses is not rewarding in CPP test and upregulates 5-HT1A receptor mRNA in the nucleus accumbens. The findings suggest that co-use of low doses of buspirone can prevent rewarding effects of MPD to help retain its therapeutic efficacy.

Dose related acute behavioral and neurochemical profile of pioglitazone.

Diabetics are twice as likely to have depression. It's normal to have long periods of sadness and anxiety. Pioglitazone has important role in the inflammatory response, which suggests that it might have the associated anti-depressant effects being manifested by its anti-depressant profile which needs further exploration. Monitoring changes in behavioral and neurochemical profile of pioglitazone in a dose-dependent manner was the purpose of this study. Pioglitazone was injected to rats at the doses of 0mg/kg, 2.5mg/kg, 5mg/kg and 10mg/kg. Behavioral activities in open field, Skinner's box and elevated plus maze were monitored 20, 35 and 45 minutes respectively after pioglitazone injection. whole brain samples were collected following decapitation of rats one-hour after injection. Samples were kept at -70ºC till HPLC-EC analysis for neurochemical profile. Results show anxiogenic and sedative effects of pioglitazone at all three doses as indicated by Skinner's box, elevated plus maze activity and open field. Also there was an overall decreased dopamine metabolism and increased serotonin turnover. This suggests that diabetic patients using pioglitazone as a therapeutic option, may experience more potent effects of CNS depressants. Findings may help in extending therapeutics in diabetic patients suffering from anxiety and/or depression.

Elevated anxiety, hypoactivity, memory deficits, decreases of brain serotonin and 5-HT-1A receptors expression in rats treated with omeprazole.

Omeprazole (OM) is one of the most prescribed drugs worldwide for the treatment of hyperacidity and gastric reflux. However, concerns regarding its safety have emerged recently, and the drug is reported to enhance the risk for anxiety and cognitive deficits, particularly in elderly patients. The present study investigated these adverse effects, if any, in adult male rats. Associated changes in brain serotonin (5-hydroxytryptamine; 5-HT) and dopamine metabolism and the expression of 5-HT-1A receptors in the raphe and hippocampus were also determined. The drug was injected i.p. in doses of 10 and 20 mg/kg for 15 days. Both doses of OM decreased motor activity in an open field and impaired learning and memory in the Morris water maze test. Anxiety monitored in an elevated plus maze test was enhanced in rats treated with 20 mg/kg OM only. The levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid and of homovanillic acid, a metabolite of dopamine, determined by HPLC-EC, were decreased in the brain of OM treated rats. The expression of 5-HT-1A receptor, determined by qRT-PCR, was reduced markedly in the hippocampus and moderately in the raphe. Our results provide evidence that OM use can reduce raphe hippocampal serotonin neurotransmission to lead to anxiety/depression and cognitive impairment. There is a need for increased awareness and prescription guidelines for therapeutic use of OM and possibly also other proton pump inhibitors.

Brain serotonin in high-fat diet-induced weight gain, anxiety and spatial memory in rats.

Objectives: Effects of high-fat diet (HFD) consumption on body weight gain and its consequences on anxiety, learning and memory, and serotonin metabolism (5-hydroxytryptamine; 5-HT) in the hypothalamus and hippocampus are determined in rats. Methods: Male Wister rats treated with HFD or normal diet (ND) for 12 weeks to monitor food intakes, body weight changes, activity in an open field, anxiety in an elevated plus maze and learning/memory in Morris water maze. Animals decapitated to collect serum for determining leptin by an ELISA kit. The hippocampus and hypothalamus dissected out for determining 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and its precursor tryptophan by HPLC-EC. Results: Despite a significant decrease in the cumulative weekly food intake, gain in body weight was greater in HFD than ND treated rats. Total caloric intakes were not different in the two groups. The consumption of HFD resulted in an enhancement of exploratory activity and reduction in anxiety. It improved learning acquisition and memory retention but impaired reference memory. There was an attenuation of 5-HT in the hypothalamus, and an enhancement of 5-HT and 5-HIAA in the hippocampus, but no effect occurred on tryptophan levels in the hypothalamus or the hippocampus. Serum leptin levels increased in HFD treated animals. Conclusion: Serotonin acting via the hypothalamus and hippocampus is involved in HFD-induced weight gain, anxiety reduction and modulation of cognitive performance.

Restraint-induced behavioral deficits are attenuated or impaired by pre- or post-injection of apomorphine: A context-based study.

Apomorphine, a psycho stimulant, has neuroprotective effects due to its ability to decrease oxidative stress. Stress-induced dopaminergic dysfunction might lead to posttraumatic stress disorder, depression and related disorders. This dopaminergic dysfunction is more pre-dominant in basal ganglia and prefrontal cortex. Targeting of this dysfunction by psychostimulants, involves elevating dopamine in these brain regions and reduction of stress. On the other hand, stress itself can aggravate addictive effects to psycho stimulants. Present study was therefore designed to monitor the role of apomorphine in the attenuation of stress-induced behavioral deficits. Rats were exposed to 2hr restraint stress either before or after the apomorphine administration, to monitor effects of apomorphine administration on stress-induced behavioral deficits. Stress-induced decreases in food intake, growth rate and elevated plus maze activity were exacerbated if apomorphine was experienced during restraint stress. Conversely, these behavioral deficits were attenuated if apomorphine was experienced after restraint stress. It shows that apomorphine, if experienced during restraint stress, produces greater behavioral deficits, while the same were attenuated in rats receiving apomorphine after the termination of restraint stress. Results suggest that apomorphine and possibly the other CNS stimulants may help to cope stress by attenuating stress-induced behavioral deficits, if experienced after stress.

Neurochemical and behavioral effects of midazolam: A dose related study.

In the present study we have monitored dose dependent effects of midazolam; a benzodiazepine (CNS depressant). It is the primary drug of choice for procedural sedation, preoperative sedation, and in emergency departments. Repeated administration of this drug is reported to have abuse potential and may cause this by increasing dopaminergic neurotransmission. Since an important role of 5-hydroxy tryptamine (5-HT) is there in the pathophysiology of anxiety and addiction, administration of midazolam may involve altered 5-HT metabolism as well. Present study was designed to monitor dose-dependent effects of midazolam and select the optimum dose for further experiments. Effects of midazolam were monitored on food intake, growth rate, activities in familiar and novel environments, light dark box activity, hot plate test, forced swim test and levels of dopamine, 5-HT and their metabolites. Midazolam was administered orally (0mg/kg, 2.5mg/kg, 5.0mg/kg and 10mg/kg) and behaviors were monitored post single midazolam administrations. Rats were decapitated and whole brain samples were collected and stored at -70°C until neurochemical analysis by HPLC-EC. Findings from the present study could be implicated to increased therapeutic utility of midazolam and related benzodiazepines.

Apomorphine-induced sensitization in rats exposed to restraint stress: Relationship with adaptation to stress.

Drug abuse and impaired adaptation to stress are inter-related. Drug abuse is more potentiated upon exposure to stress and an impairment to cope with stress may lead to depression. On the other hand, use of addictive compounds increase the vulnerability to depression by inhibiting the adaptation to stress. Present study investigates relationship between behavioral tolerance to repeated restraint stress and apomorphine-induced sensitization. Apomorphine was injected either before or after the restraint stress episode, to monitor drug-induced behavioral sensitization and place preference. Apomorphine-induced sensitization and place preference were enhanced if the drug is experiencing during restraint stress. Conversely, apomorphine-induced sensitization and place preference were attenuated if the drug is experiencing after restraint stress. It shows that apomorphine, if experienced during restraint stress, produces greater sensitization Conversely, sensitization effects of apomorphine are blocked in animals receiving apomorphine after the termination of restraint stress. The results tend to show that drug of abuse may be effective for the treatment but not prevention of stress-induced depression.

Circulating leptin, cortisol and gender differences associated with anorexia or obesity in depression.

Objectives: To assess the role of circulating cortisol and leptin in depression associated with anorexia or obesity.Methods: Two hundred and fifty depressed patients presenting to the outpatient clinic of a psychiatric hospital and 250 non-depressed healthy volunteers were included in the study. The subjects of both groups were sub-grouped based upon their gender and BMI. Serum cortisol and leptin were determined by using respective ELISA kits.Results: The number of depressed than non-depressed subjects was three-fold higher in obese BMI groups of both genders. There were more depressed than non-depressed subjects in the underweight male BMI groups and in the overweight female BMI groups. There was a BMI-related increase in serum leptin and a decrease in serum cortisol in both genders. Depression in underweight BMI groups of both genders was associated with a decrease in serum leptin and an increase in cortisol. Higher serum leptin in obese BMI group was associated with a decrease in serum cortisol.Conclusions: Obesity is a risk factor for depression. The shift from typical to atypical depression is due to an inhibitory effect of higher circulating leptin on HPA axis activity and subsequent decrease in the lipolytic effects of cortisol.

Targeting Serotonin1A Receptors for Treating Chronic Pain and Depression.

The association of chronic pain with depression is becoming increasingly recognized. Treating both the conditions together is essential for an effective treatment outcome. In this regard, it is important to identify a shared mechanism involved in the association of chronic pain with depression. Central serotonin (5-hydroxytryptamine; 5-HT) neurotransmission has long been known to participate in the processing of signals related to pain. It also plays a key role in the pathogenesis and treatment of depression. Although functional responses to serotonin are mediated via the activation of multiple receptor types and subtypes, the 5-HT1A subtype is involved in the processing of nociception as well as the pathogenesis and treatment of depression. This receptor is located presynaptically, as an autoreceptor, on the perikaryon and dendritic spines of serotonin-containing neurons. It is also expressed as a heteroreceptor on neurons receiving input from serotonergic neurons. This article targets the 5-HT1A receptors to show that indiscriminate activation of pre and postsynaptic 5-HT1A receptors is likely to produce no therapeutic benefits; biased activation of the 5-HT heteroreceptors may be a useful strategy for treating chronic pain and depression individually as well as in a comorbid condition.

Enhancement and impairment of cognitive behaviour in Morris water maze test by methylphenidate to rats.

Methylphenidate (MPD), a psycho-stimulant is a prescription medicine for the treatment of Attention deficit hyperactivity disorder (ADHD). The drug is also being increasingly used by general population for enhancing cognition. Only few preclinical studies have been carried out on the effects of MPD on cognition and these studies show either an enhancement or impairment of memory following the administration of MPD. The present study was designed to evaluate the effects of different doses of methylphenidate on acquisition and retention of memory in Morris water-maze test. Twenty four male Albino Wistar rats (weighing 180-220gm) were randomly assigned to four groups: (1) Control (2) 0.5mg/kg (3) 2.5mg/kg (4) 5 mg/kg methylphenidate. Animals received drug or water orally before training phase. Memory acquisition was monitored 2hrs post drug administration while memory retention was determined next day. It was found that the clinically relevant doses of methylphenidate (0.5mg/kg and 2.5mg/kg) improved memory acquisition and its retention but higher dose (5mg/kg) impaired both. We suggest that MPD-induced increase of catecholamine neurotransmission may have a role in the improvement of water maze performance while agonist activity of the drug for 5HT-1A receptor in the impaired performance at high doses. Food intake and body weight changes were not affected by MPD administration due to short-term administration of the drug. Results may help in improving pharmaco-therapeutic use of MPD for ADHD.

Repeated treatment with a low dose of reserpine as a progressive model of Parkinson's dementia.

Present study was designed to monitor the cognitive profile of the animals upon repeated administration of reserpine, so as to determine that whether these animals should be used as animal models of Parkinson's dementia. In the present study, reserpine was injected daily (once a day for three weeks) at the dose of 0.1mg/kg. Short- and long term memories were assessed using a Morris water maze, on weekly basis. Novel object recognition test was performed after completion of the treatment (day 21). Animals were decapitated on day 21 and brain samples were stored at -70ºC until neurochemical analysis by HPLC-EC. Impairment of short- and long term activities (as monitored in Morris water maze) were not observed until after first week. Long term memory was found to be impaired earlier than the short term memory. Novel object recognition test also exhibited reserpine-induced impairment of working memory. Neurochemical analysis of the whole brain samples by HPLC-EC method showed that repeated administration of reserpine significantly increased DOPAC/ DA ratio (p<0.01). While 5-HIAA/ 5-HT ratio was found to be decreased (p<0.05) in reserpine injected animals. This further confirmed that these neurochemical deficits to be the underlying reason in memory impairment. In conclusion, present study provides evidence that repeated administration of reserpine can be used as a 'progressive' animal model of Parkinson's dementia. Results could be beneficial for face validity and screening of the drugs for the treatment of dementia secondary to Parkinson's and related disorders.

Inhibition of hormonal and behavioral effects of stress by tryptophan in rats.

OBJECTIVES: Stress in known to alter hormonal systems. Pharmacological doses of tryptophan, the essential amino acid precursor of serotonin, increase circulating leptin and decrease ghrelin in normal healthy adults. Because systemically injected leptin inhibits stress-induced behavioral deficits and systemically injected serotonin modulates leptin release from the adipocytes, we used tryptophan as a pharmacological tool to modulate hormonal and behavioral responses in unstressed and stressed rats. METHODS: Leptin, ghrelin, serotonin, tryptophan, and behavior were studied in unstressed and stressed rats following oral administration of 0, 100, 200, and 300 mg/kg of tryptophan. RESULTS: Following oral administration of tryptophan at a dose of 300 mg/kg, circulating levels of serotonin and leptin increased and those of ghrelin decreased in unstressed animals. No effect occurred on 24-hours cumulative food intake and elevated plus maze performance. Exposure to 2 hours immobilization stress decreased 24 hours cumulative food intake and impaired performance in elevated plus maze monitored next day. Serum serotonin decreased, leptin increased, and no effect occurred on ghrelin. Stress effects on serotonin, leptin, food intake, and elevated plus maze performance did not occur in tryptophan-pretreated animals. Tryptophan-induced decreases of ghrelin also did not occur in stressed animals. CONCLUSION: The findings show an important role of serum serotonin, leptin, and ghrelin in responses to stress and suggest that the essential amino acid tryptophan can improve therapeutics in stress-induced hormonal and behavioral disorders.

Dose related effects of buspirone on pain, learning / memory and food intake.

The present study concerned extending the therapeutic use of buspirone for treating pain and improving cognition. Effects of single and repeated administration of buspirone were therefore monitored on pain threshold in the hot plate test and on spatial memory in the water maze test in rats. Effects on cumulative food intake were also monitored. The drug was administered intraperitoneally in doses of 0.1, 0.3, 1.0 and 2.0 mg/kg. We found that single and repeated administration of buspirone in doses of 0.1 mg/kg decreased pain threshold in the hot plate test, while doses of 1.0 and 2.0 mg/kg increased it. Effects of single and repeated administration were not different. A dose of 0.3 mg/kg had no effect. Food intake increased following single as well as repeated administration of 0.1 mg/kg buspirone; higher doses had no effect. Low doses (0.1 and 0.3 mg/kg) improved acquisition and retention of memory in the water maze test, while memory extinction was reduced. Higher doses had either no effect (1.0 mg/kg) or impaired (2.0 mg/kg) performance in this test. The results suggest potential therapeutic use of selected doses of buspirone as an analgesic and nootropic drug.

Serotonin-1A receptor dependent modulation of pain and reward for improving therapy of chronic pain.

Chronic pain conditions such as low back pain and osteoarthritis are the most prominent causes of disability worldwide. Morphine and other opioid drugs are the gold standard treatment for severe pain, including surgical pain, but the use of these drugs for chronic pain is limited largely because long term use of these drugs is associated with drug abuse and hyperalgesia which produces a negative impact on the treatment. Non-addictive treatments for chronic pain are, therefore, highly needed. Commonly used opioid drugs activate mu opioid receptors, resulting in an inhibition of tonic activity of nociceptive neurons. The rewarding effects of opioid drugs are also mediated via activation of mu opioid receptors and inhibition of GABA mediated control of the activity of dopamineregic neurons. Enhanced glutamate release and greater activity of NMDA glutamate receptors is linked to the hyperalgesic effects of opioid drugs. Evidence suggests that activation of serotonin (5-hydroxytryptamine; 5-HT)-1 A receptors modulates dopamine neurotransmission to inhibit rewarding effects of drugs of abuse. Activation of these receptors inhibits glutamate release from the sensory neurons to reduce pain transmission. To help develop strategies for improving therapeutics in chronic pain, and draw research interest in the synthesis of non-addictive opioid drugs which do not predispose to hyperalgesia, the present article concerns the potential mechanism involved in 5-HT-1 A receptor mediated inhibition of pain and reward.

Dopamine and serotonin metabolism associated with morphine reward and its inhibition with buspirone: A study in the rat striatum.

Adaptations within the nucleus accumbens (NAc) and caudate nucleus (CN) dopamine neurotransmission are involved in behavioral sensitization and enhanced incentive motivation towards drug paired stimuli which lead to drug addiction. Serotonin (5-hydroxytryptamine; 5-HT) can modulate dopamine neurotransmission to reduce rewarding effects of drugs of abuse. A recent study from our laboratory shows that rewarding effects of morphine are inhibited in rats co-treated with buspirone. To understand the neurochemical mechanism involved in morphine addiction and its inhibition with buspirone, present study determines the effects of buspirone, morphine and their co-administration on the metabolism of serotonin and dopamine in the NAc and CN. We find that rewarding effects of morphine are associated with an enhancement and attenuation of dopamine metabolism, respectively in the CN and NAc. Serotonin metabolism is enhanced in both regions. Co-administration of buspirone not only prevents rewarding effects of morphine, but its effects on the metabolism of dopamine and serotonin in the NAc and CN are also reversed. Results suggest that 5-HT1A receptor dependent modulation of dopamine neurotransmission in the CN and NAc is involved in the modulation of the rewarding effects of morphine in buspirone co-treated animals. The findings documenting an important role of 5-HT1A receptors in drug addiction suggest that synthetic opioid drugs with agonist activity of 5-HT1A receptors may prove non addictive analgesics.

Effects of single administration of apomorphine on memory and monoamine metabolism: A dose related study.

In the present study, we have monitored dose dependent effects of apomorphine on learning and memory. Behavioral sensitization and craving, which develop upon repeated treatment with dopamine receptor agonist apomorphine, are major limitations of the therapeutic use of apomorphine in Parkinson's patients. Effects of single (intraperitoneal) injection of apomorphine at different doses (i.e., 0.5, 1.0, & 2.0 mg/ml/kg) on locomotion in a familiar environment (Skinner's box) and memory in Morris water maze were investigated. Results show significantly enhanced activity in Skinner's box in a dose dependant manner. Low dose (0.5 mg/ml/kg) of apomorphine impaired both short- as well as long-term memory while both high and moderate doses of the drug (1.0, & 2.0 mg/ml/kg) enhanced the cognitive profile in rats. However, the memory-enhancing effects of apomorphine at moderate (1.0 mg/ml/kg) dose were more pronounced as compared to high (2.0 mg/ml/kg) dose of the drug. Rats were decapitated on day 2. Whole brains of rats were collected and stored at -70°C. Biogenic amines (i.e., 5-Hydroxytryptamine; 5-HT and dopamine) and metabolites (i.e., Dihydroxyphenylacetic acid; DOPAC, Homovanillic acid; HVA & 5-Hydroxyindoleacetic acid; 5HIAA) were estimated by reverse phase High Performance Liquid Chromatography with electrochemical detector (HPLC-EC). Both low (0.5mg/ml/kg) as well as moderate (1.0mg/ml/kg) dose of apomorphine increased levels of dopamine, DOPAC, HVA, 5-HT and 5-HIAA. Whereas, high (4.0 mg/kg) dose of apomorphine increased levels of dopamine, DOPAC and HVA, while decreased 5-HT and 5-HIAA levels. Results would be helpful in elucidating memory enhancing effects of apomorphine at different doses and its implication for extending therapeutics in cognitive disorders.