Muhammad Abdul Haleem

Somatodendritic and postsynaptic serotonin-1A receptors in the attenuation of haloperidol-induced catalepsy.

The mechanism by which stimulation of somatodendritic and/or postsynaptic 5-hydroxytryptamine (5-HT, serotonin)-1A receptor could attenuate acute Parkinsonian-like effects of typical antipsychotics is investigated by comparing the anticataleptic and neurochemical effects of 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT) and buspirone in rats injected with haloperidol. Cataleptic effects of a submaximal dose (1 mg/kg) of haloperidol were attenuated more by prior administration of 8-OH-DPAT (0.25 mg/kg) than buspirone (1 mg/kg). Striatal 5-HT metabolism decreased more in buspirone- than 8-OH-DPAT-injected animals. Administration of haloperidol did not alter 5-HT metabolism in saline-, 8-OH-DPAT- or buspirone-injected animals. Dopamine decreased and its metabolite homovanillic acid (HVA) increased in the striatum of rats injected with buspirone. Effects of 8-OH-DPAT on dopamine metabolism were not significant. Haloperidol-induced increases of dopamine metabolites were attenuated by prior administration of 8-OH-DPAT, but not buspirone. The mechanism by which stimulation of somatodendritic as well as postsynaptic 5-HT-1A receptors could attenuate haloperidol-induced catalepsy is discussed. The findings have potential implications in the treatment of schizophrenia and motor behavior.

Reversal of haloperidol-induced tardive vacuous chewing movements and supersensitive somatodendritic serotonergic response by buspirone in rats

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the pathogenesis and treatment of TD because repeated administration of haloperidol resulted in an increase in the effectiveness of 5-HT-1A receptors while drugs with agonist activity at 5-HT-1A receptors could attenuate haloperidol-induced VCMs. The present study was designed to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-HT-1A receptors by the coadministration of buspirone could reverse the induction of VCMs and supersensitivity at 5-HT-1A receptors by haloperidol. Rats treated with haloperidol at a dose of 1 mg/kg twice a day for 2 weeks displayed VCMs with twitching of facial musculature that increased in a time dependent manner as the treatment continued to 5 weeks. Coadministration of buspirone attenuated haloperidol-induced VCMs after 2 weeks and completely prevented it after 5 weeks. The intensity of 8-hydroxy-2-di (n-propylamino) tetralin (8-OH-DPAT)-induced locomotion was greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. 8-OH-DPAT-induced decreases of 5-HT metabolism were greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. It is suggested that an impaired somatodendritic 5-HT-1A receptor dependent response is a major contributing factor in the pathophysiology of TD and a normalization of the somatodendritic response by drugs may help extending therapeutics in schizophrenia.

Reversal of haloperidol-induced extrapyramidal symptoms by buspirone: a time-related study.

Effects of coadministration of buspirone were investigated on the time course of haloperidol-induced extrapyramidal symptoms in rats. Rats treated with haloperidol at a dose of 1 mg/kg exhibited impaired motor coordination and a decrease in exploratory activity. Coadministration of buspirone at a dose of 1 mg/kg attenuated haloperidol-induced deficits of motor coordination but no effect was produced on the deficits of exploratory activity, possibly because of a ‘floor effect’. Long-term administration of haloperidol (1 mg/kg) twice a day for 5 weeks did not produce tolerance to haloperidol-induced deficits of exploratory activity. The deficits of motor coordination were attenuated after 4–5 weeks of drug administration. Coadministration of buspirone for 3–5 weeks attenuated and reversed haloperidol-induced deficits of exploratory activity. Deficits of motor coordination were smaller in rats cotreated with buspirone after 1 week but not after 2–5 weeks. Administration of haloperidol for 2 weeks elicited vacuous chewing movements with twitching of facial musculature that increased in a time-dependent manner as the treatment continued to 5 weeks. Animals cotreated with buspirone exhibited a gradual reversal of the response during 2–5 weeks of treatment. The mechanism involved in the attenuation/reversal of haloperidol-induced extrapyramidal symptoms by buspirone is discussed. Prior administration of buspirone for 2 weeks may be of help in the improvement of extrapyramidal symptoms induced by antipsychotic drugs.

Inhibition of immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion by injected leptin in rats

Leptin, originally identified as an anti-obesity hormone, also has an important role in the regulation of mood and emotion. The present study was designed to monitor effects of injected leptin on immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion in rats. Exposure to 2 h immobilization stress decreased food intake and body weight in saline-injected animals. Animals exposed to open field, elevated plus maze, and light–dark transition tests the day following immobilization exhibited anxiety-like behavior. Leptin injected at doses of 0.1 and 0.5 mg/kg also decreased food intake and body weight in unstressed animals and elicited anxiolytic effects at dose of 0.5 mg/kg, monitored on the following day. Immobilization-induced decreases in food intake, body weight, as well as stress-induced behavioral deficits in the open field, elevated plus maze, and light–dark transition test were reversed by exogenous leptin in a dose-dependent (0.1–0.5 mg/kg) manner. Acute exposure to 2 h immobilization produced a fourfold rise in plasma levels of corticosterone. Animals injected with leptin at a dose of 0.1 mg/kg, but not at dose of 0.5 mg/kg, exhibited a marginal increase in plasma corticosterone. Immobilization-induced increases of plasma corticosterone were reversed by leptin injected at doses of 0.1 or 0.5 mg/kg. The data suggest that exogenous leptin can reduce stress perception, resulting in an inhibition of stress effects on the activity of hypothalamic-pituitary-adrenal axis and behavior. The reported pharmacological effects of leptin represent an innovative approach for the treatment of stress-related disorders.

Enhancement and inhibition of apomorphine-induced sensitization in rats exposed to immobilization stress: Relationship with adaptation to stress

Stress increases vulnerability to addiction while drugs of abuse impair coping responses and pre-dispose to depression. Pre-clinical research shows that stress exposure augments locomotor sensitization effects of drugs of abuse and impairs behavioral tolerance to repeated stress. The present study investigates relationship between behavioral tolerance to repeated immobilization stress and apomorphine-induced sensitization. Apomorphine was injected either before exposure or after the termination of immobilization, daily for 5 days, to monitor drug-induced behavioral sensitization and tolerance in immobilization stress-induced anorexia. We find that apomorphine-induced sensitization is enhanced and tolerance to repeated immobilization is impaired if the drug is administered before exposure to stress episode. Conversely, apomorphine-induced sensitization is inhibited and adaptation to stress is facilitated if the drug is administered after the termination of stress episode. It shows that apomorphine, if experienced during stress, produces greater sensitization and impairs stress tolerance. Conversely, sensitization effects of apomorphine are blocked and tolerance to stress is facilitated in animals receiving drug after the termination of stress episode. It is suggested that additive effects of stress and apomorphine on mesocorticolimbic dopamine neurotransmission and 5-HT-1A influences on dopamine neurotransmission may have a role in the modulation of apomorphine sensitization and tolerance to repeated immobilization stress. The results may help develop potential pharmacotherapies when substance abuse/dependence disorder and depression occur together.

Role of serotonin-1A receptors in restraint-induced behavioral deficits and adaptation to repeated restraint stress in rats.

8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-hydroxy-tryptamine (5-HT; serotonin)-1A agonist was used to evaluate the role 5-HT-1 A receptors in restraint-induced behavioral deficits and adaptation to repeated restraint stress in rats. Animals were injected with 8-OH-DPAT at a dose of 0.25 mg/kg 1 h before exposing to an episode of 2 h/day restraint stress daily for 5 days. Effects of drug administration and restraint stress on 24 h cumulative food intakes were monitored daily. Intensity of 8-OH-DPAT-induced serotonin syndrome was also monitored each day before submitting animals to the episode of stress. Exposure to the first episode of 2 h restraint stress resulted in a decrease in 24 h cumulative food intake and an attenuation of 8-OH-DPAT-induced serotonin syndrome monitored next day. The deficits attenuated following 2nd and 3rd 2 h/day restraint were not observed following the 4th and 5th 2 h/day restraint. The decreases of food intake following 1st and 2nd day restraint sessions were smaller in 8-OH-DPAT than saline-injected animals. Administration of 8-OH-DPAT on day 6 elicited comparable serotonin syndrome in unrestrained and repeatedly restrained groups. Brain 5-HT metabolism decreased in unrestrained but not repeatedly restrained animals. The results suggest that a decrease in serotonergic neurotransmission is involved in restraint-induced behavioral deficits while a normalization of serotonin neurotransmission due to desensitization of somatodendritic 5-HT-1A receptors may help cope with the stress demand to produce adaptation to stress.

Behavioral, hormonal and central serotonin modulating effects of injected leptin.

Leptin is viewed as an important target for developing novel therapeutics for obesity, depression/anxiety and cognitive dysfunctions. The present study therefore concerns behavioral, hormonal and central serotonin modulating effects of systemically injected leptin. Pharmacological doses (100 and 500 μg/kg) of leptin injected systemically decreased 24h cumulative food intake and body weight in freely feeding rats and improved acquisition and retention of memory in Morris water maze test. Potential anxiety reducing, hormonal and serotonin modulating effects of the peptide hormone were determined in a separate experiment. Animals injected with 100 or 500 μg/kg leptin were tested for anxiety in an elevated plus maze test 1h later. A significant increase in the number of entries and time passed in open arm of the elevated plus maze in leptin injected animals suggested pronounced anxiety reducing effect. Moreover, circulating levels of leptin correlated significantly with anxiety reducing effects of the peptide hormone. Serum serotonin increased and ghrelin decreased in leptin injected animals and correlated, positively and negatively respectively, with circulating leptin. Corticosterone increased at low dose and levels were normal at higher dose. Serotonin metabolism in the hypothalamus and hippocampus decreased only at higher dose of leptin. The results support a role of leptin in the treatment of obesity, anxiety and cognitive dysfunctions. It is suggested that hormonal and serotonin modulating effects of leptin can alter treatment efficacy in particularly comorbid conditions.

Long-term consumption of sugar-rich diet decreases the effectiveness of somatodendritic serotonin-1A receptors.

Abstract 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a 5-hydroxytryptamine (5-HT)-1A selective agonist was used to investigate a possible role of somatodendritic serotonin-1A receptors in the precipitation of hyperphagia and decreases of 5-HT metabolism associated with long-term consumption of sugar rich-diet. In the first part of study, dose-related hyperphagic effects of 8-OH-DPAT were monitored in freely feeding rats. In the second part of study, rats were fed freely on a sugar-rich diet (prepared by mixing standard rodent diet with table sugar in the ratio of 3:1 [w/w]) for 5 weeks. Hyperphagic effects of 8-OH-DPAT were monitored in sugar-rich diet and normal diet treated rats by injecting the drug at a dose of 0.25 mg/kg body weight, a dose that produced significant hyperphagia. Effects of 8-OH-DPAT on decreasing 5-HT metabolism in the hypothalamus were also investigated in the two groups. Results showed that administration of 8-OH-DPAT at a dose of 0.25 mg/kg body weight elicited hyperphagia and decreased 5-HT metabolism in normal diet treated animals but the effects in sugar-rich diet treated animals were smaller and not significant suggesting a decrease in the effectiveness of somatodendritic 5-HT-1A receptors, which provide a feedback control over the synthesis and release of 5-HT in terminal region. A possible mechanism involved in sugar-diet induced decreases of 5-HT metabolism is discussed.

Inhibition of apomorphine-induced conditioned place preference in rats co-injected with buspirone: relationship with serotonin and dopamine in the striatum.

Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist to produce psychostimulant like effects. Currently, apomorphine is used in patients with advanced Parkinson׳s disease, for the treatment of persistent and disabling motor fluctuations, but a constellation of addictive syndromes such as excessive over use of medication, compulsive behaviors, and disturbances of impulse control are noticed in certain patients. Research on rodent models using conditioned place preference (CPP) paradigm also shows that the drug is rewarding. Previously we have shown that repeated administration of apomorphine produces behavioral sensitization which is prevented in rats co-injected with a low (1.0mg/kg) but not higher (2.0mg/kg) dose of buspirone. The present study shows that rewarding effects of apomorphine (1.0mg/kg) in a CPP paradigm are also blocked in rats co-injected with a low (1.0mg/kg) but not higher (2.0mg/kg) dose of buspirone. The levels of serotonin and its metabolite are decreased in the caudate as well as nucleus accumbens of rats exhibiting CPP and the decreases do not occur in animals co-injected with low or higher dose of buspirone. The levels of dopamine and its metabolites are not affected in animals exhibiting CPP; administration as well as co-administration of higher dose of buspirone decreased dopamine metabolism in the caudate as well as nucleus accumbens. The findings suggest a critical role of serotonin in the rewarding effects of apomorphine and imply that co-use of buspirone at low doses can help to control addictive syndromes in Parkinson׳s disease patients on apomorphine therapy.

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed. O dozi ovisni učinci klozapina i risperidona na metabolizam serotonina i dopamina u pojedinim područjima mozga i na ekstrapiramidalne nuspojave u štakora Cilj rada bio je procjena ponašanja i neurokemijskog profila klozapina i risperidona u ovisnosti o dozi nakon primjene na štakorima. Pokusnim životinjama intraperitonealno je injiciran klozapin (2,5, 5,0 i 10,0 mg kg-1) ili risperidon (1,0, 2,5 i 5,0 mg kg-1). Nakon jednog sata životinje su žrtvovane i uzeti su uzorci mozga. Nakon primjene lijeka ili fiziološke otopine praćeni su hipolokomotorički učinci (aktivnost u kavezu i katalepsija). Oba lijeka su pri visokim dozama značajno smanjila (p < 0,01) lokomotoričku aktivnost, a smanjenje je ovisilo o dozi. Maksimalni (100%) kataleptički učinak postignut je visokom dozom risperidona (5,0 mg kg-1). Neurokemijske procjene provedene su pomoću HPLC s elektrokemijskom detekcijom. Oba lijeka su pri svim dozama značajno (p < 0,01) povećala koncentraciju homovanilinske kiseline (HVA), metabolita dopamina (DA), u striatumu. Koncentracija dihidroksifeniloctene kiseline (DOPAC) u striatumu bila je povećana, a u ostatku mozga smanjena, posebno nakon primjene klozapina. Koncentracija 5-hidroksiindol octene kiseline (5-HIAA), najvažnijeg metabolita serotonina, značajno (p < 0,01) se smanjila u striatumu. 5-Hidroksitriptamin (5-HT) značajno se povećao (p < 0,01) nakon risperidona, a smanjio nakon klozapina u ostalim dijelovima mozga. Risperidon je značajno smanjio triptofan (TRP) u striatumu (p < 0,01), a povećao njegovu koncentraciju u ostalim dijelovima mozga. Također je povećao omjer HVA/DA u striatumu, dok je metabolizam 5-HT ostao nepromijenjen u ostalim dijelovima mozga. Rezultati upućuju na to da je interakcija ispitivanih lijekova s D2/5-HT1A receptorima uključena u nisku incidenciju ekstrapiramidalnih nuspojava. Razmatrana je uloga 5-HT1A receptora u terapiji šizofrenije.