Behavioral and neurochemical effects of the preferential dopamine D3 receptor agonist cis-8-OH-PBZI.
In the present study we investigated the in vivo pharmacological profile of the benz[e]indole cis-8-hydroxy-3-(n-propyl)],2,3a,4,5,9b-hexahydro-1H-benz[e]indole (cis-8-OH-PBZI), which has been described as a preferential dopamine D3 receptor agonist in vitro. The compound inhibited spontaneous locomotor activity in mice, an effect which was antagonized by the dopamine D3 receptor antagonist 5,6-dimethoxy-2-(di-u-propylamino) indan (U99194A). Moreover, cis-8-OH-PBZI inhibited conditioned avoidance responding in rats, a preclinical test indicative of antipsychotic efficacy, at doses which did not induce catalepsy. Doses of cis-8-OH-PBZI (6 and 12 mg/kg) that inhibited spontaneous locomotor activity in rats did not affect interstitial levels of dopamine and dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens or dorsolateral striatum. In contrast to the effect of the dopamine receptor agonist (+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphythalene (7-OH-DPAT), cis-8-OH-PBZI did not induce locomotor activity in reserpinized mice. In conclusion, cis-8-OH-PBZI exhibits a pharmacological profile that suggests it has antipsychotic activity but lacks the motoric side effects often associated with antipsychotic medication. The data suggest a mechanism requiring the activation of postsynaptic dopamine D3 receptors and support the hypothesis that these receptors mediate inhibitory behavioral effects.
Fink-Jensen
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A
Health Care Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark. afj@novo.dk
Nielsen
E B
EB
Hansen
L
L
Scheideler
M A
MA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D012110:Reserpine / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects
C111033:8-hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz(e)indole; D018759:Adrenergic Uptake Inhibitors; D018491:Dopamine Agonists; C493594:Drd3 protein, mouse; C493595:Drd3 protein, rat; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D015102:3,4-Dihydroxyphenylacetic Acid; D012110:Reserpine; D004298:Dopamine