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The effect of serotonergic agents on haloperidol-induced catalepsy
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!EEEPFFKTOFSElWlQ#E IcAmWrSoNHALoPERIm~INmJCEDcAllAIEpm PaulB.Hic&* Scott and White Clinic, 'lkmple,TX 76508 n-redopaminehypothesisofschiz~a~~~that~positive~ [email protected] resultofhypemctivemsoli.&ictimesocortical dapaminergicsystem.Thereis substantialevidence docment*thatmedidl anddorsdlrapheseratonergicneuronsregulatestriatdl,mesolimbicand msocorticaldopmine systems. Thisregulato~effectisthoughttobe predcnninately inhibitory. (Costall,et al., NeWcolcqy 14:859, 1975; Costall, et al., J- Phamacol. 28:523, 1976; Waldmeier, Exoerientia 36: 1092, 1980). lkspitetheknowledgeofthisphysiological and phamacolcgical relationshipbetweenthe semtomqic and dopamimqic sy~therehave~noparadignrsdevelopedfor~~ofpsychosisor neuroleptic-irrducedextra~dalsyndrames which utilize this relationship. The following studies were conducted toevaluatetheeffect of various classes of serotoneryicagents on the haloperidol-induced catalepsy (HIC). Male Sprague-Hawleyrats weighing 200-250 g were used. Catalepsy was assessed by the horizontal bar method. Haloperidolat 0.75 q/kg was administeredsubcutaneaus ly (s.c.) at time zero. At 90 mimrtes the test drugswe.readministereds.c.atthreedoses. Catalep5ywasmonitoredeach 30 minutes for 3 hours. Themaximumc&alepsyscoresforeachtiminterval wereused for statisticalcomparisons. Haloperidol induced catalepsy in all rats at a dose of 0.75 ny/kg S.C. This dosewasused forallsubsequentexperiments. The 5-HlklAreceptoragonists buspirone, ipsapironeand 8-0I-i~DPATallpotentlyreversedHIC. Themixed5XL'-lAand 5-WlB agonist RU 24969 reversed catalepsy at the highest dose only. Thenon-selective 5-HT-1receptorantagonist (-) -prcpranololhadno effectonHICinthedcm?raqetested. A 5-I-P-2agonist (EOI) and the 5W2 antagonist (mesuleryine)both reversed HIC. ICS 205-930, a 5-Hlk3 antagonist,reversedcatalepsyatthetwolawestdoses,lxltnatatthe highestdose. Another 5-I-V-3antagonist,GR 38032F, did not affect HIC. Haloperidol-inducedcatalepsy is mediated primarily thrcugh the nigrostriataldopminesystem. Thisstudyhassub&antiatedprevims reportsthatserotone3qicagentsmdifyHIC. FTeviousstudieshavenot addressed the specificityof semtonergic receptor types in modifying HE. Thepresen tdatasuggestthatboththe5-~1Aard5-~2receptorsare associatedwithmdifyi.ngHIC. Thispredictsthat &=tantreceptortypes semtmeqic agents may be of benefit in treatmfzmtof extrapyramidal reactions induced by neuroleptics. l'kishypothesisissupportedbya primate studywherethenon-selective serotoninantagonists (mianserinand cyprcheptadine)decmased while serotoninuptake inhibitors (paroxetineand OZP 6085A) im=reasedhaloperidol-induceddystonia and psuedo-parkinsonism (Korsgaard,et al., Eur. J. Fharmacol.,118: 245, 1985). The presentdata wmldsuggestthat5-HI'-lAagonists and 5-Hlk2 antagonistsshtidbetested asnovelagents forthetreatmentof acuteextrapyramidal syndromes induced bynewmleptics. The role of specific serotoneqic agents on mesocortical ardmesolimbicdopamine systemareinpmgress.
!EEEPFFKTOFSElWlQ#E IcAmWrSoNHALoPERIm~INmJCEDcAllAIEpm PaulB.Hic&* Scott and White Clinic, 'lkmple,TX 76508 n-redopaminehypothesisofschiz~a~~~that~positive~ [email protected] resultofhypemctivemsoli.&ictimesocortical dapaminergicsystem.Thereis substantialevidence docment*thatmedidl anddorsdlrapheseratonergicneuronsregulatestriatdl,mesolimbicand msocorticaldopmine systems. Thisregulato~effectisthoughttobe predcnninately inhibitory. (Costall,et al., NeWcolcqy 14:859, 1975; Costall, et al., J- Phamacol. 28:523, 1976; Waldmeier, Exoerientia 36: 1092, 1980). lkspitetheknowledgeofthisphysiological and phamacolcgical relationshipbetweenthe semtomqic and dopamimqic sy~therehave~noparadignrsdevelopedfor~~ofpsychosisor neuroleptic-irrducedextra~dalsyndrames which utilize this relationship. The following studies were conducted toevaluatetheeffect of various classes of serotoneryicagents on the haloperidol-induced catalepsy (HIC). Male Sprague-Hawleyrats weighing 200-250 g were used. Catalepsy was assessed by the horizontal bar method. Haloperidolat 0.75 q/kg was administeredsubcutaneaus ly (s.c.) at time zero. At 90 mimrtes the test drugswe.readministereds.c.atthreedoses. Catalep5ywasmonitoredeach 30 minutes for 3 hours. Themaximumc&alepsyscoresforeachtiminterval wereused for statisticalcomparisons. Haloperidol induced catalepsy in all rats at a dose of 0.75 ny/kg S.C. This dosewasused forallsubsequentexperiments. The 5-HlklAreceptoragonists buspirone, ipsapironeand 8-0I-i~DPATallpotentlyreversedHIC. Themixed5XL'-lAand 5-WlB agonist RU 24969 reversed catalepsy at the highest dose only. Thenon-selective 5-HT-1receptorantagonist (-) -prcpranololhadno effectonHICinthedcm?raqetested. A 5-I-P-2agonist (EOI) and the 5W2 antagonist (mesuleryine)both reversed HIC. ICS 205-930, a 5-Hlk3 antagonist,reversedcatalepsyatthetwolawestdoses,lxltnatatthe highestdose. Another 5-I-V-3antagonist,GR 38032F, did not affect HIC. Haloperidol-inducedcatalepsy is mediated primarily thrcugh the nigrostriataldopminesystem. Thisstudyhassub&antiatedprevims reportsthatserotone3qicagentsmdifyHIC. FTeviousstudieshavenot addressed the specificityof semtonergic receptor types in modifying HE. Thepresen tdatasuggestthatboththe5-~1Aard5-~2receptorsare associatedwithmdifyi.ngHIC. Thispredictsthat &=tantreceptortypes semtmeqic agents may be of benefit in treatmfzmtof extrapyramidal reactions induced by neuroleptics. l'kishypothesisissupportedbya primate studywherethenon-selective serotoninantagonists (mianserinand cyprcheptadine)decmased while serotoninuptake inhibitors (paroxetineand OZP 6085A) im=reasedhaloperidol-induceddystonia and psuedo-parkinsonism (Korsgaard,et al., Eur. J. Fharmacol.,118: 245, 1985). The presentdata wmldsuggestthat5-HI'-lAagonists and 5-Hlk2 antagonistsshtidbetested asnovelagents forthetreatmentof acuteextrapyramidal syndromes induced bynewmleptics. The role of specific serotoneqic agents on mesocortical ardmesolimbicdopamine systemareinpmgress.