ABSTRACT
Buspirone, a partial agonist of 5-hydroxytryptaminelA autoreceptors, preferentially blocks the presynaptic rather than the postsynaptic D2 dopamine (DA) receptors. Behavioural effects of a wide dose range of buspirone were therefore studied in mice. Buspirone at 0.625 to 5 mg/kg ip induced stereotyped cage climbing behaviour which was antagonized by pretreatment with haloperidol, alpha-methyl-p-tyrosine and small doses of apomorphine. Buspirone at 10, 20 and 40 mg/kg ip induced catalepsy and antagonized oral stereotypies induced by high doses of apomorphine and methamphetamine and apomorphine-induced cage climbing behaviour. The findings indicate that buspirone at 0.625 to 5 mg/kg selectively blocks the presynaptic mesolimbic D2 DA autoreceptors and releases DA which stimulates the postsynaptic mesolimbic D2 and D1 DA receptors and induces cage climbing behaviour. Buspirone, at 10, 20 and 40 mg/kg blocks the postsynaptic striatal and mesolimbic D2 and D1 DA receptors. Pretreatment with 1-tryptophan, dexfenfluramine and fluoxetine antagonized buspirone induced cage climbing behaviour and potentiated buspirone induced catalepsy. Pretreatment with trazodone, mianserin and p-chlorophenylalanine potentiated buspirone induced cage climbing behaviour and antagonized buspirone induced catalepsy. The results indicate that drugs which influence the activity of central serotonergic systems modulate the intensity of buspirone induced cage climbing behaviour and catalepsy.
Subject(s)
Animals , Anti-Anxiety Agents/administration & dosage , Buspirone/administration & dosage , Catalepsy/chemically induced , Dose-Response Relationship, Drug , Haloperidol/administration & dosage , Male , Mice , Receptors, Dopamine D2/antagonists & inhibitors , Serotonin Receptor Agonists/administration & dosage , Stereotyped Behavior/drug effects , Tryptophan/administration & dosageABSTRACT
Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.
Subject(s)
Animals , Apomorphine/pharmacology , Buspirone/pharmacology , Catalepsy/chemically induced , Dextroamphetamine/pharmacology , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Haloperidol/pharmacology , Male , Rats , Rats, Wistar , Receptors, Dopamine D1/antagonists & inhibitors , Receptors, Dopamine D2/antagonists & inhibitors , Stereotyped Behavior/drug effectsABSTRACT
Non-ulcer dyspepsia is a common clinical disorder characterised by reduced gastric motility. Safety concerns have restricted use of currently available prokinetic drugs. Itopride is a new safer prokinetic drug with dopamine D2 antagonism and acetylcholinesterase inhibitory actions. The ENGIP-II study was conducted to investigate the efficacy, and safety of itopride in patients of non-ulcer dyspepsia. There were significant reductions in upper abdominal pain, heartburn frequency, gastro-oesophageal regurgitation, nausea, bloating, early satiety after meals at day 3 only; whereas significant improvements were noted in belching, anorexia at day 6 and in vomiting at day 9. Thus, ENGIP-II study shows that itopride was well tolerated patients and appears to be the drug of choice in patients with non-ulcer dyspepsia.
Subject(s)
Acetylcholinesterase/drug effects , Adult , Benzamides/pharmacology , Benzyl Compounds/pharmacology , Dyspepsia/drug therapy , Female , Gastrointestinal Motility/drug effects , Humans , Male , Middle Aged , Receptors, Dopamine D2/antagonists & inhibitors , Safety , Treatment OutcomeABSTRACT
1. Radio-ligand binding study has demonstrated that flunarizine has a high affinity for the rat striatal D 2 dopamine (DA) receptors. 2. In the present behavioural study conducted in rats it was observed that flunarizine, unlike the postsynaptic striatal D 2 DA receptor agonist apomorphine, did not induce stereotyped behaviour (SB) in rats. This indicates that flunarizine does not act as an agonist at the postsynaptic striatal D 2 DA receptors. 3. Flunarizine however, like the postsynaptic striatal D 2 DA receptor antagonist haloperiodal, inhibited the conditioned avoidance response, induced catalepsy and antagonized the SB induced by the DA agonists apomorphine and methamphetamine. 4. Our findings indicate that flunarizine acts as a postsynaptic striatal D 2 DA receptor antagonist.