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.     

Buspirone improves haloperidol-induced Parkinson disease in mice through 5-HT(1A) recaptors

BACKGROUND AND THE PURPOSE OF THE STUDY: The available literatures show that 5-HT(1A) receptors are widely distributed throughout the basal ganglia, and their activation facilitate dopamine release. Neuroleptic drugs such as haloperidol induce Parkinson-like syndrome through blocking brain D(2) receptors. This study aimed to investigate effect of buspirone, a partial agonist of 5HT(1A) receptor, on motor dysfunctions induced by haloperidol and involvement of 5HT(1A) receptors in this regard. METHODS: Study was performed on the male mice weighing 25-30 g. Animals were divided randomly to groups of 10 animals. Motor dysfunction was induced by intraperitoneal (i.p.) injection of haloperidol (1 mg/kg). Catalepsy was assayed by bar-test method 5, 60, 120 and 180 minutes after drug administration and motor imbalance was studied by rotarod test. RESULTS AND MAJOR CONCLUSION: Results showed that buspirone (20 mg/kg, i.p.) decreased significantly haloperidol-induced catalepsy and balance disorder in a dose dependent manner. Furthermore, 8-OH-DPAT (10 mg/kg, i.p.), as an agonist of 5-HT(1A) receptor, decreased haloperidol-induced catalepsy and balance disorder. The effect of buspirone (20 mg/kg, i.p.) on haloperidol-induced motor disorders was abolished by NAN-190 (10 mg/kg, i.p.), as a 5-HT(1A) receptor antagonist. From the results it may be concluded that buspirone improves haloperidol-induced catalepsy and balance disorder through activation of 5-HT(1A) receptors.     

Rice bran oil prevents neuroleptic-induced extrapyramidal symptoms in rats: Possible antioxidant mechanisms

Tardive dyskinesia (TD) is one of the serious side effects of long-term antipsychotic treatment. Chronic treatment with neuroleptic leads to the development of abnormal oral movements called vacuous chewing movements (VCMs). The oxidative stress hypothesis of TD is one of the possible pathophysiologic models for TD. Preclinical and clinical studies of this hypothesis indicate that neurotoxic free radical production is likely to be a consequence of antipsychotic medication and is related to occurrence of TD. Oxidative stress is implicated in the pathophysiology of TD. Rats chronically treated with haloperidol orally at a dose of 0.2 mg/kg/day for a period of 5 weeks developed VCMs, which increased in a time-dependent manner as the treatment continued for 5 weeks. Motor coordination impairment started after the 1^st week and was maximally impaired after 3 weeks and gradually returned to the 1^st week value. Motor activity in an open field or home cage (activity box) not altered. Administration of rice bran oil (antioxidant) by oral tubes at a dose of 0.4 mL/ day prevented the induction of haloperidol-elicited VCMs as well impairment of motor coordination. The results are discussed in the context of a protective role of antioxidant of rice bran oil in the prevention of haloperidol-induced extrapyramidal symptoms.     

Possible mechanism of action in melatonin attenuation of haloperidol-induced orofacial dyskinesia

Tardive dyskinesia (TD) is a late complication of prolonged neuroleptic treatment characterized by involuntary movements of the oral region. In spite of high incidence and much research, the pathophysiology of this devastating movement disorder remains elusive. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats, referred to as vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of TD. Rats chronically treated with haloperidol (1.5 mg/kg ip) significantly developed VCMs and tongue protrusions. Melatonin dose-dependently (1, 2, and 5 mg/kg) reversed the haloperidol-induced VCM and tongue protrusions frequencies. Biochemical analysis reveals that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the forebrain glutathione (GSH) levels in the rats. Chronic haloperidol-treated rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Coadministration of melatonin (1, 2, and 5 mg/kg) along with haloperidol significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic haloperidol treatment, and significantly reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. However, a lower dose of melatonin (1 mg/kg) failed to reverse chronic haloperidol-induced decreases in forebrain GSH, SOD, and catalase levels. In conclusion, melatonin could be screened as a potential drug candidate for the prevention or treatment of neuroleptic-induced orofacial dyskinesia.     

Excitatory mechanisms in neuroleptic-induced vacuous chewing movements (VCMs): possible involvement of calcium and nitric oxide

Tardive dyskinesia (TD) is a serious motor side-effect of chronic neuroleptic therapy. Chronic treatment with neuroleptics leads to the development of oral abnormal movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats have been widely accepted as an animal model of tardive dyskinesia. Chronic blockade of D2 inhibitory dopamine (DA) receptors localized on glutamatergic terminals in the striatum leads to the persistent enhanced release of glutamate that kills the striatal output neurons. The object of the present study was to explore the role of glutamatergic modulation on the neuroleptic-induced VCMs. Rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to produce VCMs. The neuroleptic-induced VCMs viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5 min observation period. Dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, dose dependently (0.02 and 0.05 mg/kg) reduced haloperidol-induced VCMs. Felodipine (5 and 10 mg/kg), an L-type calcium-channel blocker, also significantly reduced the VCM count. N-omega-nitro-L-arginine methyl ester (L-NAME) (25 and 50 mg/kg), a nitric oxide synthase inhibitor, also reduced the VCM count in an L-arginine-sensitive manner. In conclusion, the findings of the present study indicated NMDA receptor involvement in haloperidol-induced VCMs, and also suggested the possible involvement of calcium and nitric oxide in haloperidol-induced VCMs.     

Inhibition of restraint-induced neuroendocrine and serotonergic responses by buspirone in rats

The effects of buspirone (0.5 mg/kg) on the neuroendocrine and serotonergic responses to stress were monitored in rats. Exposure to 2-h of restraint stress increased circulating levels of corticosterone, noradrenaline and glucose. The metabolism of 5-hydroxytryptamine (5-HT; serotonin) increased in the brain. Prior administration of buspirone did not alter levels of corticosterone, noradrenaline and glucose in unrestrained rats, but inhibited stress-induced increase in the activity of hypothalamic-pituitary-adrenal (HPA) axis and circulating levels of glucose. Restraint-induced rise in brain 5-HT and 5-hydroxyindole-acetic acid (5-HIAA) was also attenuated by buspirone. Unrestrained animals injected with buspirone also exhibited a decrease in brain 5-HIAA concentration. The findings are discussed in the context of the role of somatodendritic 5-HT(1A) receptors in responses to stress.     

Relationship of orofacial movements to behavioural repertoire as assessed topographically over the course of 6-month haloperidol treatment followed by 4-month withdrawal

Rationale Late-onset vacuous chewing movements (VCMs) arise in a significant proportion of rats treated chronically with conventional antipsychotic drugs. Given their common action to block dopamine D₂-like receptors, VCMs may be related to changes in dopaminergic function; if so, other typical dopamine-mediated behaviours might be altered also.Objective To examine this hypothesis, behavioural repertoire was studied topographically over the course of chronic treatment and withdrawal.Methods Animals were injected with haloperidol decanoate 28 mg/kg IM, or vehicle, every 3 weeks for 27 weeks, and then maintained without treatment for a further 18 weeks. Immediately before each injection and during withdrawal, VCMs and other topographies of behaviour were assessed.Results In both control and haloperidol-treated rats, exploratory behaviours declined over the study, indicating habituation effects. Conversely, VCMs emerged after 6 weeks of treatment with haloperidol and persisted after withdrawal; VCM and locomotion were not related, indicating that in treated rats, increased VCMs are not an artifact of reduced locomotion. Treated animals with VCMs evidenced increases in buccal tremor and grooming behaviour relative to those without VCMs, although no clear relationship to the emergence of VCMs was established; there were no material differences in any other topographies of behaviour.Conclusion The effect of long-term treatment with haloperidol to induce VCMs is not reflected in fundamental changes in dopamine-mediated behavioural topography but, rather, appears to affect neural mechanisms involved in orofacial movement preferentially.     

Neuroleptic-induced vacuous chewing movements in rodents: incidence and effects of long-term increases in haloperidol dose

Rats treated chronically with neuroleptics develop vacuous chewing movements (VCMs), similar in some respects to tardive dyskinesia (TD) in man. The VCM syndrome was used as a model of TD to examine the ability of increased neuroleptic doses to produce long-term suppression of dyskinetic movements. The incidence and persistence of the VCM syndrome in individual rats were also assessed to look for affected and unaffected subgroups. Rats were initially treated for 15 weeks with haloperidol decanoate. For the next 21 weeks, half the group received a 50–150% increase in dose while the other half continued to receive the same dose. Animals were also followed during a 28-week withdrawal period. Total VCM ratings showed a skewed distribution, with some rats exhibiting few movements while others developed marked and persistent movements. Increasing doses did not suppress VCMs, nor did they exacerbate movements during the withdrawal period. To the extent that the VCM syndrome models TD, the absence of long-term suppression of the VCM syndrome suggests that, at this dosage range, increasing depot neuroleptic doses may not be a useful long-term strategy for TD suppression.     

Effect of melanotropin release inhibiting factor on changes by haloperidol and centbutindole in cerebral cortical 5-hydroxytryptamine receptors

The effect of melanotropin release inhibiting factor (Pro-Leu-Gly-NH2, MIF) was determined on changes induced by two neuroleptics, haloperidol and centbutindole, in cerebral cortical 5-hydroxytryptamine (5-HT) receptors. Male Sprague-Dawley rats were injected daily i.p. with vehicle, haloperidol (1.0 mg/kg) or centbutindole (0.5 mg/kg), respectively, for 21 days. On day 22, these 3 groups were further divided into 2 subgroups and injected with either vehicle or MIF (2.0 mg/kg, i.p.) daily for 3 days. 3H-5-HT was used to study 5-HT1 receptors, and 3H-spiroperidol to label 5-HT2 receptors in the cerebral cortex. Chronic administration of haloperidol significantly increased (39.7%) the maximal binding capacity (Bmax) of 3H-5-HT binding to 5-HT1 receptors. Dissociation constant (Kd) values did not change. Centbutindole had no effect on 5-HT1 receptors. MIF had no effect on 5-HT1 receptors, nor did it alter haloperidol-induced increases in the Bmax of 3H-5-HT binding to 5-HT1 receptors. Chronic administration of centbutindole significantly increased (61.1%) the Bmax of 3H-spiroperidol binding to 5-HT2 receptors. No change occurred in the Kd values. Chronic treatment with haloperidol had no effect on 5-HT2 receptor characteristics. MIF had no effect on 5-HT2 receptors or on the increase in 5-HT2 receptor density induced by centbutindole. The behavioral syndrome induced by 5-hydroxytryptophan (5-HTP) (50, 100 and 200 mg/kg, i.p.) was also measured in rats treated chronically with haloperidol or centbutindole. Haloperidol had no effect on the 5-HTP syndrome, whereas centbutindole stimulated by 24-45% the intensity of the syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)     

8-Hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis

The selective serotonin1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was studied for its ability to reverse haloperidol-induced catalepsy in rats. Given subcutaneously 8-OH-DPAT (0.06-0.5 mg/kg), dose-dependently antagonized the catalepsy induced by 1 mg/kg of haloperidol. Intraventricular injection of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which caused marked depletion of 5-HT in brain, did not change haloperidol-induced catalepsy per se, but completely antagonized the anticataleptic effect of subcutaneously administered 8-OH-DPAT. When injected directly into the median or dorsal raphe nucleus, 8-OH-DPAT, in doses ranging from 0.2 to 5 micrograms/0.5 microliter, reduced the catalepsy induced by haloperidol. The results suggest that the activation of 5-HT1A receptors, probably those located presynaptically on 5-HT-containing cell bodies, reduces the catalepsy induced by haloperidol.     

Co-administration of nitric oxide (NO) donors prevents haloperidol-induced orofacial dyskinesia, oxidative damage and change in striatal dopamine levels

Tardive dyskinesia (TD) has been considered as a major clinical issue in the treatment of schizophrenia. Various animal studies have indicated the role of oxidative stress and nitric oxide pathway in haloperidol-induced TD. The present study investigated the effect of NO donors (molsidomine and l-arginine) in haloperidol-induced TD in rats. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, and facial jerking in rats which was dose dependently inhibited by NO donors. Besides, haloperidol also increased striatal superoxide anion levels and decreased striatal NO and citrulline levels which were prevented by molsidomine and l-arginine. On chronic administration of haloperidol, there was a decrease in the striatal levels of dopamine, which was again reversed by treatment with NO donors. The findings of the present study suggested for the involvement of NO in the development of neuroleptic-induced TD and indicated the potential of NO donors as a possible therapeutic option. Furthermore, a sub-study on a possible schizophrenic phenotype, i.e. a possible clinical worsening in the animals receiving NO donors and neuroleptics will substantiate the clinical utility of the study.     

Chronic imipramine treatment sensitizes 5-HT1A and 5-HT 2 A receptors in the dorsal periaqueductal gray matter: evidence from the elevated T-maze test of anxiety

The dorsal periaqueductal gray matter (DPAG) has been implicated in the mediation of escape, a defensive behavior associated with panic disorder (PD). Chronic treatment with the anti-panic agent imipramine enhances the inhibitory effect on escape evoked by DPAG electrical stimulation of intra-DPAG administration of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the preferential 5-HT 2 A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). In the present study we further explore the hypothesis that sensitization of 5-HT1A and 5-HT 2 A receptors in the DPAG is involved in the anti-panic effect of imipramine. To this end, Wistar rats, subchronically or chronically treated with imipramine, were intra-DPAG injected with 8-OH-DPAT (0.4 or 3.2 nmoles) or DOI (16 nmoles), and tested in the elevated T-maze. In addition to its possible relevance to panic disorder, this test also measures inhibitory avoidance, a behavior that has been associated with generalized anxiety disorder (GAD). The effects of these 5-HT agonists in the DPAG were also investigated in animals chronically injected with buspirone, a drug clinically effective in treating GAD, but not PD. The results showed that intra-DPAG administration of the highest dose of 8-OH-DPAT and of DOI inhibited escape, and this panicolytic-like effect was significantly higher in animals previously treated chronically, but not subchronically, with imipramine. 8-OH-DPAT (0.4 nmole), although not affecting escape in animals systemically treated with saline, had a panicolytic-like effect in those receiving long-term treatment with imipramine. Microinjection of 8-OH-DPAT (3.2 nmoles), but not of DOI, impaired inhibitory avoidance, and this anxiolytic effect did not differ between animals treated with saline or imipramine. Chronic buspirone did not change the effect of 8-OH-DPAT and DOI on inhibitory avoidance and escape. Therefore, chronic imipramine seems to sensitize both 5-HT1A and 5-HT 2 A receptors in the DPAG, strengthening the view that these receptors are involved in the mode of action of anti-panic drugs.     

Neurochemical and behavioral effects of 8-OH-DPAT following exposure to restraint stress in rats

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-hydroxytryptamine 1A (serotonin; 5-HT1A) agonist was used to evaluate the role of somatodendritic and/or postsynaptic 5-HT1A receptors following exposure to restraint stress. Exposure to an episode of 2-h restraint stress decreased 24 h cumulative food intake. Intensity of 8-OH-DPAT-induced 5-HT syndrome monitored next day was smaller in restrained than unrestrained animals. Hyperphagic effects of 8-OH-DPAT were comparable in the two groups. Restrained animals injected with saline exhibited an increase in 5-HT levels in the hippocampus, hypothalamus and cortex but not in the midbrain and striatum. 5-Hydroxyindolacetic acid (5-HIAA) increased in the hippocampus, midbrain and cortex but not in the hypothalamus and striatum. 8-OH-DPAT injected at a dose of 0.25 mg/kg decreased 5-HT and 5-HIAA levels in different brain regions of unrestrained as well as restrained animals. The decreases were greater in restrained than unrestrained animals, suggesting a supersensitivity of somatodendritic 5-HT1A receptors. The results are discussed in the context of a role of 5-HT1A receptor in restraint-induced behavioral deficits.     

Reversal of neuroleptic-induced catalepsy by novel aryl-piperazine anxiolytic drugs

The novel anxiolytic drug, buspirone, reverses catalepsy induced by haloperidol. A series of aryl-piperazine analogues of buspirone and other 5-hydroxytryptaminergic agonists were tested for their ability to reverse haloperidol induced catalepsy. Those drugs with strong affinity for 5-hydroxytryptamine1a receptors were able to reverse catalepsy. Drugs with affinity for other 5-HT receptors or weak affinity were ineffective. However, inhibition of postsynaptic 5-HT receptors neither inhibited nor potentiated reversal of catalepsy and leaves open the question as to the site or mechanism for this effect.     

The 5-HT(1A) receptor agonist F 13640 attenuates mechanical allodynia in a rat model of trigeminal neuropathic pain

It has been reported that the treatment with a tricyclic antidepressant imipramine induces an increase in the sensitivity of 5-HT(1A) receptors and a decrease in the sensitivity of 5-HT(4) receptors in the rat hippocampus. 5-HT(1A) receptor agonists and neuroleptics also affect 5-HT(1A) receptors in different brain areas; therefore, it was of interest to compare their effects on hippocampal 5-HT receptors with the influence of the well-established antidepressant imipramine. We studied the effects of repeated treatment with imipramine, the 5-HT(1A) receptor agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, and the neuroleptics haloperidol and clozapine on the sensitivity of rat hippocampal CA1 neurons to 5-HT(1A)- and 5-HT(4) receptor activation. Imipramine was administered for 21 days (10 mg/kg p.o., twice daily), 8-OH-DPAT for 7 days (1 mg/kg s.c., twice daily) and buspirone for 21 days (5 mg/kg s.c., twice daily). The rats received haloperidol (1 mg/kg) and clozapine (30 mg/kg) for 6 weeks in drinking water. Hippocampal slices were prepared 2 days after the last treatment with imipramine, 8-OH-DPAT or buspirone, and 5 days after the last treatment with the neuroleptics. Using an extracellular in vitro recording, we studied changes in the amplitude of stimulation-evoked population spikes, induced by 5-HT, 8-OH-DPAT and the 5-HT(4) receptor agonist zacopride. Activation of 5-HT(1A) receptors decreased, while activation of 5-HT(4) receptors increased the amplitude of population spikes. Imipramine significantly enhanced the inhibitory effects of 5-HT and 8-OH-DPAT, and attenuated the excitatory effect of zacopride. No other treatment used in the present study changed the sensitivity of hippocampal CA1 neurons to 5-HT(1A) and 5-HT(4) receptors activation. These findings indicate that adaptive changes in the sensitivity of hippocampal neurons to 5-HT(1A) and 5-HT(4) receptors agonists are specific to imipramine and may thus-at least partly-mediate its effects.     

Reversal of haloperidol-induced orofacial dyskinesia by Murraya koenigii leaves in experimental animals

Context: Orofacial dyskinesia (OD) is a late complication of prolonged neuroleptic treatment characterized by involuntary movements of the oral region. Chronic treatment with neuroleptics leads to development of vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of OD.

Objective: To study the effect of Murraya koenigii L. (Rutaceae) leaves on haloperidol-induced OD.

Materials and methods: Effect of alcohol extract of M. koenigii leaves (EEMK) and its alkaloid fraction (AMK) on body weight, locomotor activity, behavioral parameters, such as VCMs, tongue protrusions (TPs), orofacial bursts (OBs), and biochemical parameters such as antioxidant defense enzymes levels [superoxide dismutase (SOD) and catalase (CAT)], glutathione (GSH) levels, and lipid peroxidation (LPO) in the forebrain region was studied in haloperidol-treated rats.

Results: Rats chronically treated with haloperidol (1?mg/kg, i.p., 21 days) significantly decreased locomotion and developed VCMs, OBs, and TPs. Biochemical analysis reveals that chronic haloperidol-treated rats also showed decreased levels of SOD and CAT. Chronic haloperidol treatment significantly induced LPO and decreased the forebrain GSH levels in the rats. Co-administration of EEMK (100 and 300?mg/kg, p.o.) and AMK (30 and 100?mg/kg, p.o.) along with haloperidol significantly reversed the effect on locomotion. EEMK and AMK significantly reversed the haloperidol-induced decrease in forebrain SOD and CAT levels in rats and significantly reduced the LPO and restored the decreased GSH levels by chronic haloperidol treatment.

Conclusion: The study concludes that M. koenigii could be screened as a potential drug for the prevention or treatment of neuroleptic-induced OD.     

Rapid desensitization of somatodendritic 5-HT1A receptors by chronic administration of the high-efficacy 5-HT1A agonist, F13714: a microdialysis study in the rat

BACKGROUND AND PURPOSE: Desensitization of somatodendritic 5-HT(1A) receptors is involved in the mechanism of action of several antidepressants, but the rapidity of this effect and the amount of agonist stimulation needed are unclear. We evaluated the capacity of the high-efficacy 5-HT(1A) agonist, F13714 (3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone) and of the partial agonist, flesinoxan, to desensitize somatodendritic 5-HT(1A) receptors involved in the control of 5-HT release. EXPERIMENTAL APPROACH: Intracerebral microdialysis in the hippocampus of freely moving rats was used to examine the acute and chronic effects of the two compounds (administered by osmotic pumps for 3, 7 or 14 days) on extracellular 5-HT levels, measured by HPLC with electrochemical detection. KEY RESULTS: When given acutely, F13714, flesinoxan and the low-efficacy 5-HT(1A) agonist, buspirone, dose-dependently decreased extracellular 5-HT concentrations (ED(50) values: 0.04, 0.77 and 5.6 mg kg(-1), respectively). The selective 5-HT(1A) antagonist WAY100635 inhibited the effects of the three compounds. F13714 (2.5 mg kg(-1) per day for 3, 7 or 14 days and 0.63 mg kg(-1) for 7 days) significantly attenuated the inhibition of 5-HT release induced by buspirone (10 mg kg(-1)). In contrast, flesinoxan (10 mg kg(-1) per day) failed to alter the response to buspirone at any of the treatment durations. CONCLUSIONS AND IMPLICATIONS: Rat somatodendritic 5-HT(1A) receptors controlling hippocampal 5-HT release were rapidly desensitized by chronic activation with a high-efficacy 5-HT(1A) agonist, but not by chronic activation with a partial agonist. Thus, rapid 5-HT(1A) autoreceptor desensitization by high-efficacy agonists may accelerate the onset of the therapeutic effects of antidepressants.     

Effect of 5-HT1A and 5-HT2A/2C receptor modulation on neuroleptic-induced vacuous chewing movements.

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. Chronic treatment or rats with neuroleptics leads to the development of abnormal oral movements called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Atypical antipsychotics such as clozapine and rispiridone are associated with a lower incidence of extrapyramidal side effects and tardive dyskinesia. The present study was aimed to explore the role of 5-HT1A, 5-HT2A/2C receptors in the expression of neuroleptic-induced orofacial dyskinesia. In the present study rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to elicit vacuous chewing movements. The neuroleptic-induced vacuous chewing movements, viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5-min observation period. Acute treatment with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, dose-dependently (0.05, 0.1 and 0.2 mg/kg, i.p.) reduced the haloperidol-induced vacuous chewing movements and headshakes. Both acute and chronic administration of seganserin, ketanserin and ritanserin, 5-HT2A/2C receptor antagonists, also reduced haloperidol-induced vacuous chewing movements in a dose-dependent (0.05, 0.1 and 0.2 mg/kg, i.p.) manner. In acute studies a higher dose of ritanserin (1 mg/kg) but not ketanserin (1 mg/kg) increased vacuous chewing movements, whereas a higher dose of seganserin (1 mg/kg) did not have any effect on vacuous chewing movements. All the drugs reduced haloperidol-induced headshakes in a dose-dependent fashion. These findings indicate that the serotonergic system, and particularly 5-HT1A and 5-HT2A/2C receptors, may be involved in haloperidol-induced orofacial dyskinesia, and that 5-HT receptors may provide novel targets for the development of drugs that can be used to reverse or prevent the extrapyramidal side effects associated with long-term antipsychotic treatment.     

Effects of xylamidine on peripheral 5-hydroxytryptamine-induced anorexia

Rats injected peripherally with 5-hydroxytryptamine (5-HT) showed a dose-dependent decrease in food intake following overnight fasting. The peripheral 5-HT-2 antagonist xylamidine had no effect on food intake when administered alone, but antagonised 5-HT-induced anorexia. However, at the highest dose of 5-HT (5 mg/kg), both doses of xylamidine (1.0 and 2.0 mg/kg) displayed the same degree of antagonism to the anorectic effect, but failed to block it completely. The results are discussed in terms of 5-HT receptor subtypes, and it is suggested that non-5-HT-2 receptors may be partially responsible for the mediation of peripheral 5-HT-induced anorexia.     

Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors

In animals given citalopram (10 mg/kg) twice daily for 14 days a further dose of 1 mg/kg, administered 24 h after the last dose, markedly increased cortical dialysate serotonin (5-hydroxytryptamine, 5-HT), but had no effect in control animals. The effect on dialysate 5-HT in the dorsal raphe was not increased by the chronic treatment. At 25 μg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin, an agonist at 5-HT_1A receptors, reduced cortical 5-HT output in controls but not in animals treated chronically with citalopram whereas 50 μg/kg reduced 5-HT output in both groups. These findings suggest that somatodendritic 5-HT_1A receptors are desentisized after chronic treatment with citalopram and this results in facilitation of its effect on cortical dialysate 5-HT. These results also agree with the concept that the effect of 5-HT re-uptake inhibitors on increasing 5-HT output in the frontal cortex is attenuated by their simultaneous ability to activate somatodendritic 5-HT_1A receptors via an increase of endogenous 5-HT in the raphe region.