Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia

A. C. Lahti, M. Weiler, A. Carlsson, C. A. Tamminga

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The aminotetralin derivative (+)-UH232 is a dopamine-receptor antagonist with complex pharmacological properties, including a 4:1 selectivity for the D3 vs. D2 receptor and a preference for the autoreceptors. Its behavioral profile differs markedly from that of other dopamine antagonists in exhibiting both stimulant and inhibitory features. In an effort to elucidate the role of different dopamine receptor subtypes in psychosis, we administered (+)-UH232 to drug-free schizophrenic patients. Six patients received single doses of (+)-UH232 over a dose range of 80 to 180 mg in a rising-dose, double-blind placebo-controlled design. Efficacy and safety were assessed over 8 hours after a single dose. In none of the patients at any of the doses was there an indication of a symptomatic psychosis improvement in response to (+)-UH232. On the contrary, an examination of individual cases revealed symptomatic worsening, such as increases in unusual thought content, anxiety, activation and hostility in four patients. No extrapyramidal movements were noted. Safety assessments were benign. These preliminary data suggest that putative dopamine D3 antagonism, in combination with preferential autoreceptor antagonism, does not alleviate but rather tends to worsen psychosis, at least following a single-dose regimen. However, the possibility cannot be excluded that a 5-HT2-receptor agonistic action of (+)-UH232, suggested by some animal data, has played a role in this treatment outcome. Replication with more selective agents and multiple dose regimens is necessary.

Original languageEnglish (US)
Pages (from-to)719-734
Number of pages16
JournalJournal of Neural Transmission
Volume105
Issue number6-7
DOIs
StatePublished - 1998

Fingerprint

Autoreceptors
Dopamine Antagonists
Schizophrenia
Psychotic Disorders
Safety
Hostility
Dopamine Receptors
Dopamine
Anxiety
Placebos
Pharmacology
Pharmaceutical Preparations

Keywords

  • Antipsychotic
  • D3 antagonist
  • Dopamine
  • Schizophrenia
  • UH232

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia. / Lahti, A. C.; Weiler, M.; Carlsson, A.; Tamminga, C. A.

In: Journal of Neural Transmission, Vol. 105, No. 6-7, 1998, p. 719-734.

Research output: Contribution to journalArticle

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