The Role of the Dorsal and Ventral Striatum in the Therapeutic and Extrapyramidal Side Effects of Neuroleptic Drugs

  • Bart A. Ellenbroek
  • Alexander R. Cools
Part of the Advances in Behavioral Biology book series (ABBI, volume 39)


Ever since their first introduction into clinical practice in the mid 1950s the neuroleptic drugs have been the most effective drugs in various forms of psychoses, most notably the schizophrenic psychosis. Despite their widespread use, however, the neuronal mechanisms giving rise to the therapeutic and side effects is still not completely elucidated. Until the beginning of the sixties it was thought that neuroleptic drugs exert their action by directly blocking the noradrenergic neurotransmission. However, the studies performed by Carlsson & Lindqvist (1963) and van Rossum (1966) clearly showed that blockade of the dopaminergic transmission especially in the caudate nucleus (Cools & van Rossum, 1970) is the primary mode of action of neuroleptics. These findings were extended independently by two groups in 1976. Both Creese et al (1976) and Seeman et al (1976) showed that the potency of neuroleptic drugs for blocking the dopamine receptors was correlated with the clinical dose. Although these data had great impact, some critical comments should be made. First both studies were performed in vitro. This implies that the possible role of metabolites in the therapeutic effect was not taken into account. This is of importance since several neuroleptics, like thioridazine (Axelsson & Marterisson, 1978), fluphenazine (Hitzemann et al, 1984) and trifluoperazine (Javaid et al, 1980) have metabolites with antipsychotic efficacy. Moreover, it has recently been shown that schizophrenic patients resistant to the classical neuroleptic haloperidol show good improvement upon treatment with the atypical (see below) neuroleptic clozapine (Kane et al, 1988). This strongly suggests that clozapine does not work through a blockade of D2 receptors, since haloperidol has a much higher affinity for these receptors than clozapine (Richelson & Nelson, 1984). Although a pharmacokinetic explanation cannot be fully ruled out Wolkin et al (1989) showed that the D2 receptor occupancy was not different between patients responding and those not responding to haloperidol. These data indicate that at least haloperidol and clozapine seem to work through different receptor systems.


Ventral Striatum Dorsal Striatum Neuronal Mechanism Neuroleptic Drug Extrapyramidal Side Effect 
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Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Bart A. Ellenbroek
    • 1
  • Alexander R. Cools
    • 1
  1. 1.Psychoneuropharmacol. Res. UnitCath. University of NijmegenNijmegenthe Netherlands

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