Serotonergic involvement with neuroleptic catalepsy

Costall, B.; Fortune, David H.; Naylor, R.J.; Marsden, C. D.; Pycock, Christopher J.

doi:10.1016/0028-3908(75)90114-8

Cited by 145 publications

(25 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As in previous studies (Costall et al, 1975;Invernizzi et al, 1988), 1 mg/kg haloperidol caused maximal cataleptic response in rats and this effect was associated with Effect of idazoxan on basal and haloperidol-induced rise of extracellular DA in the striatum. Haloperidol (HAL; 1 mg/kg) or vehicle (VEH) was injected once basal extracellular concentrations of DA were stable (first arrow).…”

Section: Discussionsupporting

confidence: 75%

The α2-Adrenoceptor Antagonist Idazoxan Reverses Catalepsy Induced by Haloperidol in Rats Independent of Striatal Dopamine Release: Role of Serotonergic Mechanisms

Invernizzi

Garavaglia

Samanin

2002

Neuropsychopharmacol

View full text Add to dashboard Cite

The a 2 -adrenoceptor antagonist idazoxan may improve motor symptoms in Parkinson's disease and experimental Parkinsonism. We studied the effect of idazoxan on haloperidol-induced catalepsy in rats, an animal model of the drug-induced extrapyramidal side effects in man. Catalepsy was induced by a subcutaneous (s.c.) injection of haloperidol (1 mg/kg) and measured by the bar test for a maximum of 5 min. At 3 h after haloperidol, rats were given 0.16-5.0 mg/kg s.c. idazoxan, and descent latency was measured 1 h later. Idazoxan potently reversed haloperidol-induced catalepsy with an ED 50 of 0.25 mg/kg. This effect was mimicked by the selective a 2 -adrenoceptor antagonist RS-15385-197 (0.3 and 1 mg/kg orally). We assessed how dopaminergic mechanisms were involved in the anticataleptic effect of idazoxan by studying its effect on dopamine (DA) release in the striatum, with the microdialysis technique in conscious rats. Idazoxan (0.3 and 2.5 mg/kg) had no effect on extracellular DA and did not modify the rise of extracellular DA induced by haloperidol, indicating that changes of striatal DA release were not involved in the reversal of catalepsy. The anticataleptic effect of 2.5 mg/kg idazoxan (haloperidol+vehicle 288 7 8 s, haloperidol+idazoxan 47 7 22 s) was attenuated in rats given an intraventricular injection of 150 mg of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (haloperidol+vehicle 275 7 25 s, haloperidol+idazoxan 137 7 28 s). The 5-HT 1A receptor antagonist WAY100 635 (0.1 mg/kg s.c.) did not affect the anticataleptic effect of idazoxan. The results suggest that idazoxan reversed haloperidol-induced catalepsy by a mechanism involving blockade of a 2 -adrenoceptors and, at least in part, 5-HT neurons.

show abstract

Section: Discussionsupporting

confidence: 75%

The α2-Adrenoceptor Antagonist Idazoxan Reverses Catalepsy Induced by Haloperidol in Rats Independent of Striatal Dopamine Release: Role of Serotonergic Mechanisms

Invernizzi

Garavaglia

Samanin

2002

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…5,11,33,36 Preclinical studies show that 5HT2A receptor antagonists attenuate cataleptic effects of D2 receptor antagonists. [38][39][40][41] These data suggest that the 5HT2A receptor antagonism may contribute to the low EPS liability of risperidone and olanzapine, and also the recently introduced drugs quetiapine and ziprasidone.…”

Section: Potential Relationships Between D2 and 5ht2 Receptor Occupanmentioning

confidence: 88%

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

1999

View full text Add to dashboard Cite

Available evidence indicates that clozapine is the most effective antipsychotic currently used for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advantageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and serotonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer 'atypical' antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resistant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experience with the newer 'atypical' antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia.Keywords: clozapine; olanzapine; risperidone; ziprasidone; quetiapine; antipsychotic; schizophrenia; dopamine; NMDA The introduction of clozapine for the pharmacotherapy of schizophrenia represented a significant advance in the treatment of this devastating mental illness. Clozapine is superior to typical neuroleptic drugs (eg haloperidol) in treating positive and negative symptoms, and is effective in many patients who are refractory to typical antipsychotics. [1][2][3] In addition, clozapine does not induce the extrapyramidal side effects (EPS) commonly caused by the typical agents. Because of these properties, clozapine was termed atypical and represents the prototype drug of this class. Although clozapine is the most efficacious antipsychotic currently available, serious side effects induced by the drug, including agranulocytosis, impose substantial limitations on its use. Concerted research and development efforts have been made to produce an antipsychotic drug with the therapeutic advantages of clozapine, without the properties contributing to its serious side effects. However, the specific pharmacological characteristics of clozapine that confer its therapeutic properties are poorly understood. Clozapine binds to a diverse number of neurotransmitter receptors (see Table 1) but it is unclear whether actions at specific serotonin, dopamine, or adrenergic receptors, alone or in combination, account for its clinical efficacy.A number of specific hypotheses concerning mechanisms of action of clozapine have directed drug discovery efforts and led to clinical trials of drugs with widely different receptor-binding characteristics. The clinical experience with drugs whose development was inspired by clozapine will be briefly reviewed and then actions of clozapine and other antip...

show abstract

“…The 'atypical' nature of their effects relates to a greatly reduced incidence of EPS as compared to agents such as haloperidol and, at least for clozapine and thioridazine, this may relate to a concomitant 5-HT2 and muscarinic cholinoceptor blockade (see Costall et al, 1975). It remains clear that the atypical neuroleptic agents have a consistent profile to antagonize directly or indirectly the behaviourally inhibitive effects of 5-HTP in the rodent models.…”

Section: Discussionmentioning

confidence: 99%

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Costall

Naylor

1995

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

1 The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2 The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test.3 The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents, spiperone, haloperidol and benperidol, and the atypical neuroleptic agent, clozapine, when administered alone failed to modify mouse or rat behaviour. In contrast, when administered alone, sulpiride in rats and mice and thioridazine in rats disinhibited behaviour. 4 Methysergide, RP62203, ketanserin, ritanserin and MDL11939 antagonized the inhibitory effects of 5-hydroxytryptophan or reversed the inhibitory effects to one of disinhibition. 5 Low doses of spiperone (but not haloperidol or benperidol) also antagonized the inhibitory effects of 5-hydroxytryptophan in the rat but not the mouse. Higher doses of the three neuroleptic agents caused locomotor depression in both rats and mice which obscured any specific changes in behavioural responding to the aversive situations. 6 The disinhibitory profile of sulpiride in both mice and rats and thioridazine in rats was evident during their interaction with 5-hydroxytryptophan. Thioridazine in the mouse and clozapine in rats and mice also reversed the inhibitory effects of 5-hydroxytryptophan to one of disinhibition. 7 In summary, we present evidence that the atypical neuroleptic agents, thioridazine and clozapine, with their known affinity for the 5-HT2 receptors, can mimic the actions of reference 5-HT2 receptor antagonists to antagonize the inhibitory effects of 5-hydroxytryptophan in rodent models of anxiety. The results are intepreted in terms of drug action on different 5-HT2 and other 5-HT receptor subtypes. In addition, thioridazine and sulpiride have disinhibitory effects in their own right which remain to be explained.

show abstract

Serotonergic involvement with neuroleptic catalepsy

Cited by 145 publications

References 18 publications

The α2-Adrenoceptor Antagonist Idazoxan Reverses Catalepsy Induced by Haloperidol in Rats Independent of Striatal Dopamine Release: Role of Serotonergic Mechanisms

The α2-Adrenoceptor Antagonist Idazoxan Reverses Catalepsy Induced by Haloperidol in Rats Independent of Striatal Dopamine Release: Role of Serotonergic Mechanisms

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Contact Info

Product

Resources

About