Pharmacology Biochemistry and Behavior, Vol. 60, No. 1, pp. 133–141, 1998 © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/98 $19.00 + .00 PII S0091-3057(97)00594-7 133 Antipsychotic-Like Profile of Alstonine L. COSTA-CAMPOS,*† D. R. LARA,* D. S. NUNES‡ AND E. ELISABETSKY*† *Laboratório de Etnofarmacologia, Depto. de Framacologia, UFRGS, Porto Alegre, Brazil, †Curso de Pós Graduação em Biologia, Fisiologia, Depto de Fisiologia, UFRGS, and ‡Laboratório de Química, UFPa, Belém, Pará, Brazil Received 28 March 1997; Revised 10 September 1997; Accepted 30 September 1997 COSTA-CAMPOS, L., D. R. LARA, D. S. NUNES AND E. ELISABETSKY. Antipsychotic-like profile of alstonine. PHARMACOL BIOCHEM BEHAV 60(1) 133–141, 1998.—Although recently developed drugs have brought significant im- provement, the treatment of psychotic disorders still presents serious drawbacks. Because inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This article reports pharmacological properties of alstonine, a heteroyohim- bine-type alkaloid, which exhibited an antipsychotic-like profile, inhibiting amphetamine-induced lethality, apomorphine- induced stereotypy, and potentiating barbiturate-induced sleeping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D 1 , D 2 and 5-HT 2A receptors, classically linked to antipsy- chotic mechanism of action. © 1998 Elsevier Science Inc. Alstonine Antipsychotic Serpentine alkaloids Dopamine THE recent accretion of a considerable body of knowledge has challenged the classic dopamine centered understanding of the pathophysiology of schizophrenia (3). However, the still limited comprehension of psychotic disorders constrains rational drug design and motivates innovative approaches in the search for antipsychotics. Typical antipsychotics have ap- parent therapeutic limitations, especially concerning effec- tiveness on the so-called negative symptoms and induction of autonomic and extrapyramidal side effects (13,14). It has long been established that typical antipsychotic (Fig. 1) clinical po- tency is dependent on their ability to block dopamine D 2 re- ceptors (8,25). In contrast, atypical antipsychotics (Fig. 1), such as clozapine and risperidone, which have proved more effective in controlling positive and negative symptoms, as well as presenting diminished extrapyramidal side effects (4), are associated with a less potent blockade of D 2 receptors, combined with 5-HT 2 antagonism (17). The multiple mecha- nism of action of clozapine as well as its clinical advantages have been well documented (7). Natural products are inextricably linked to the history of schizophrenia. In 1931, the use of Rauwolfia serpentina in the treatment of insanity was reported (27). Reserpine (Fig. 1) is a major alkaloid in the plant root and was developed as the first antipsychotic drug. Amphetamine, a congener of ephedrine, the active compound of the Chinese drug Ma Huang , was the basis for the first model of psychosis (1). Ethnopharmacology has been defined as “the interdiscipli- nary scientific exploration of biologically active agents tradition- ally employed or observed by men” (11). In Nigeria, two-thirds of health practitioners are traditional healers (20), the medical setting is pluralistic, and there are distinct categories of healers including traditional birth attendants, traditional psychiatrists, herbalists, and traditional pharmacists (19,20,21,23, 28), An eth- nopharmacological study in Nigeria has lead to the investiga- tion of a plant-based extract used by traditional psychiatrists with anecdotal antipsychotic-like effects. This extract was later found to bear an antipsychotic-like profile (Elisabetsky et al., unpublished results) using a behavioral approach simi- lar to the present study. Phytochemical studies have identified alstonine as one of the major components of this extract. The following study investigates the putative antipsychotic profile of alstonine using behavioral and neurochemical strat- egies. METHOD Animals Male Swiss albino adult (20–35 g) mice (CS 1 strain) and male Wistar adult rats were used for behavioral and binding exper- iments, respectively. Animals were housed at 22  2 ° C with food and water ad lib and 12 L:12 D cycles. Behavioral exper- Requests for reprints should be addressed to Elaine Elisabetsky, Caixa Postal 5072, 90041-970, Porto Alegre, RS, Brazil.