Skip to main content
SpringerLink
Log in

Discriminative stimulus properties of the atypical antipsychotic clozapine and the typical antipsychotic chlorpromazine in a three-choice drug discrimination procedure in rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The atypical antipsychotic drug (APD) clozapine elicits a robust discriminative cue that is generally selective for other atypical APDS in two-choice drug discrimination (DD) procedures.

Objectives

The present study determined whether a three-choice DD procedure with the atypical APD clozapine (CLZ) versus the typical APD chlorpromazine (CPZ) versus vehicle (VEH) could provide greater selectivity between atypical and typical APDs.

Methods

Sprague-Dawley rats were trained to discriminate 5.0 mg/kg CLZ from 1.0 mg/kg CPZ from VEH in a three-lever DD task with an FR30 food reinforcement schedule.

Results

Generalization testing with CLZ produced CPZ-appropriate responding at lower doses (ED50=0.103 mg/kg) and CLZ-appropriate responding at higher doses (ED50=1.69 mg/kg). Generalization testing with the atypical APD olanzapine produced similar results. In contrast, the atypical APD risperidone and the typical APDs CPZ and haloperidol produced only CPZ-appropriate responding. The muscarinic antagonist scopolamine produced CPZ-appropriate responding at lower doses and CLZ-appropriate responding at higher doses in a manner similar to CLZ and olanzapine. The co-administration of haloperidol (0.00625 mg/kg) with scopolamine shifted the dose–response curve for CLZ-appropriate responding to the left. The 5-HT2A/2C antagonist ritanserin and the H1 histamine antagonist pyrilamine did not substitute for either CLZ or CPZ. The α1 adrenergic antagonist prazosin did not substitute for CLZ, but produced full substitution for CPZ.

Conclusions

The three-choice DD procedure clearly distinguished the atypical APDs CLZ and olanzapine from the typical APDs CPZ and haloperidol; however, the stimulus properties of the atypical APD risperidone were similar to CPZ, but not to CLZ. These findings further suggest that CLZ, as well as CPZ, elicits a compound cue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Arnt J, Skarsfeldt T (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 18:63–101

    Article  CAS  PubMed  Google Scholar 

  • Bolden C, Cusack B, Richelson E (1992) Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther 260:576–580

    CAS  PubMed  Google Scholar 

  • Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wong DT (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87–96

    Article  CAS  PubMed  Google Scholar 

  • Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, McKinzie DL (2003) Muscarinic mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 27:1125–1143

    Article  CAS  PubMed  Google Scholar 

  • Carey GJ, Bergman J (1997) Discriminative-stimulus effects of clozapine in squirrel monkeys: comparison with conventional and novel antipsychotic drugs. Psychopharmacology 132:261–269

    Article  CAS  PubMed  Google Scholar 

  • Dekeyne A, Iob L, Millan MJ (2003) Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist, MDL100,907. Neuropharmacology 44:604–615

    Article  CAS  PubMed  Google Scholar 

  • Extance K, Goudie AJ (1981) Inter-animal olfactory cues in operant drug discrimination procedures in rats. Psychopharmacology 73:363–371

    CAS  PubMed  Google Scholar 

  • Fiorella D, Helsley S, Rabin RA, Winter JC (1995) The interactions of typical and atypical antipsychotics with the (−)2, 5,-dimethoxy-4-methamphetamine (DOM) discriminative stimulus. Neuropharmacology 34:1297–1303

    Article  CAS  PubMed  Google Scholar 

  • Friedman RL, Sanders-Bush E, Barrett RL (1985) Clozapine blocks disruptive and discriminative stimulus effects of quipazine. Eur J Pharmacol 106:191–193

    Article  Google Scholar 

  • Gauvin DV, Goulden KL, Holloway FA (1994) A three-choice haloperidol–saline–cocaine drug discrimination task in rats. Pharmacol Biochem Behav 49:223–227

    Article  CAS  PubMed  Google Scholar 

  • Goas JA, Boston JE Jr (1978) Discriminative stimulus properties of clozapine and chlorpromazine. Pharmacol Biochem Behav 8:235–241

    Article  CAS  PubMed  Google Scholar 

  • Goldstein A (1964) Biostatistics: an introductory text. MacMillan, New York

    Google Scholar 

  • Goodwin AK, Baker LE (2000) A three-choice discrimination procedure dissociates the discriminative stimulus effects of d-amphetamine and (±)-MDMA in rats. Exp Clin Psychopharmacol 8:415–423

    Article  CAS  PubMed  Google Scholar 

  • Goudie AJ, Smith JA (1999) Discriminative stimulus properties of antipsychotics. Pharmacol Biochem Behav 64:193–201

    Article  CAS  PubMed  Google Scholar 

  • Goudie A, Taylor A (1998) Comparative characterisation of the discriminative stimulus properties of clozapine and other antipsychotics in rats. Psychopharmacology 135:392–400

    Article  CAS  PubMed  Google Scholar 

  • Goudie AJ, Smith JA, Taylor A, Taylor MA, Tricklebank MD (1998) Discriminative stimulus properties of the atypical neuroleptic clozapine in rats: tests with subtype selective receptor ligands. Behav Pharmacol 9:699–710

    CAS  PubMed  Google Scholar 

  • Goudie AJ, Baker LE, Smith JA, Prus AJ, Svensson KA, Cortes-Burgos LA, Wong EH, Haadsma-Svensson S (2001) Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms. Behav Pharmacol 12:303–315

    CAS  PubMed  Google Scholar 

  • Goudie AJ, Smith JA, Millan MJ (2004) Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine. Psychopharmacology 171:212–222

    Article  CAS  PubMed  Google Scholar 

  • Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY (1993) Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry 34:702–712

    Article  CAS  PubMed  Google Scholar 

  • Hoenicke EM, Vanecek SA, Woods JH (1992) The discriminative stimulus effects of clozapine in pigeons: involvement of 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors. J Pharmacol Exp Ther 263:276–284

    CAS  PubMed  Google Scholar 

  • Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    CAS  PubMed  Google Scholar 

  • Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 27:1081–1090

    Article  CAS  PubMed  Google Scholar 

  • Kelley BM, Porter JH (1997) The role of muscarinic cholinergic receptors in the discriminative stimulus properties of clozapine in rats. Pharmacol Biochem Behav 57:707–719

    Article  CAS  PubMed  Google Scholar 

  • Mariathasan EA, Stolerman IP, White J-AW (1999) AND and AND–OR drug mixture discriminations in rats: generalization to single drugs and drug mixtures. Psychopharmacology 143:54–63

    Article  CAS  PubMed  Google Scholar 

  • Matz R, Rick W, Thompson H, Gershon S (1974) Clozapine—a potential antipsychotic agent without extrapyramidal manifestations. Curr Ther Res Clin Exp 16:687–695

    CAS  PubMed  Google Scholar 

  • McElroy JF, Stimmel JJ, O’Donnell JM (1989) Discriminative stimulus properties of haloperidol. Drug Dev Res 18:47–55

    CAS  Google Scholar 

  • Melkersson KI, Dahl M-L (2003) Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses. Psychopharmacology 170:157–166

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY (1992) The mechanism of action of clozapine in relation to its clinical advantages. In: Meltzer HY (ed) Novel antipsychotic drugs. Raven, New York, pp 1–13

    Google Scholar 

  • Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255

    CAS  PubMed  Google Scholar 

  • Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246

    CAS  PubMed  Google Scholar 

  • Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S (2003a) Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60:82–91

    CAS  PubMed  Google Scholar 

  • Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003b) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:1159–1172

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Schreiber R, Dekeyne A, Rivet JM, Bervoets K, Mavridis M, Sebban C, Maurel-Remy S, Newman-Tancredi A, Spedding M, Muller O, LaVielle G, Brocco M (1999) S 16924 ((R)-2-{1-[2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties. II. Functional profile in comparison to clozapine and haloperidol. J Pharmacol Exp Ther 286:1356–1373

    Google Scholar 

  • Moore NA, Tye NC, Axton MS, Risius FC (1992) The behavioral pharmacology of olanzapine, a novel “atypical” antipsychotic agent. J Pharmacol Exp Ther 262:545–551

    CAS  PubMed  Google Scholar 

  • Nielsen EB (1988) Cholinergic mediation of the discriminative stimulus properties of clozapine. Psychopharmacology 94:115–118

    CAS  PubMed  Google Scholar 

  • Palumbo PA, Winter JC (1994) Interactions of clozapine with the stimulus effects of DOM and LSD. Pharmacol Biochem Behav 49:115–120

    Article  CAS  PubMed  Google Scholar 

  • Philibin SD, Pehrson AL, Prus AJ, Porter JH (2003) Two-lever drug discrimination with the typical antipsychotic clozapine in C57BL/6 mice. Program number 858.8. 2003 Abstract Viewer/Itinerary Planner. Society for Neuroscience, Washington

    Google Scholar 

  • Porter JH, Strong SE (1996) Discriminative stimulus control with olanzapine: generalization to the atypical antipsychotic clozapine. Psychopharmacology 128:216–219

    Article  CAS  PubMed  Google Scholar 

  • Porter JH, Covington HE, Varvel SA, Vann RE, Warren TA (1998) Chlorpromazine as a discriminative stimulus in rats: generalization to typical and atypical antipsychotics. Drug Dev Res 48:38–44

    Article  Google Scholar 

  • Porter JH, Villanueva HF, Rosecrans JA (1999) Role of D1 and D2 dopamine receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine in rats. Drug Dev Res 46:139–147

    Article  CAS  Google Scholar 

  • Porter JH, McCallum SE, Varvel SA, Vann RE (2000a) The discriminative stimulus properties of the atypical antipsychotic olanzapine in rats. Psychopharmacology 148:224–233

    Article  CAS  PubMed  Google Scholar 

  • Porter JH, Varvel SA, Vann RE, Philibin SD, Wise LE (2000b) Clozapine discrimination with a low training dose distinguishes atypical from typical antipsychotic drugs in rats. Psychopharmacology 149:189–193

    Article  CAS  PubMed  Google Scholar 

  • Prus AJ, Baker LE, Meltzer HY (2004) Discriminative stimulus properties of 1.25 mg/kg and 5.0 mg/kg doses of clozapine in rats: further examination of the role of dopamine, serotonin and muscarinic receptor mechanisms. Pharmacol Biochem Behav 77:199–208

    Article  CAS  PubMed  Google Scholar 

  • Richelson E, Souder T (2000) Binding of antipsychotic drugs to human brain receptors: focus on newer generation compounds. Life Sci 68:29–39

    Article  CAS  PubMed  Google Scholar 

  • Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124:57–73

    Google Scholar 

  • Schreiber R, Brocco M, Millan MJ (1994) Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the ‘atypical’ antipsychotics, clozapine and risperidone. Eur J Pharmacol 264:99–102

    Article  CAS  PubMed  Google Scholar 

  • Smith JA, Goudie AJ (2002) Discriminative stimulus properties in rats of the novel antipsychotic quetiapine. Exp Clin Psychopharmacol 10:376–384

    Article  CAS  PubMed  Google Scholar 

  • Stolerman IP, Mariathasan EA, White J-AW (1994) Implications of mixture research for discrimination of single drugs. Behav Pharmacol 5(Suppl):18

    Google Scholar 

  • Stolerman IP, White J-AW, Mariathasan EA (1996) Generalizations between mixtures of drugs under “AND” and “AND–OR” discrimination procedures in rats. In: Harris LS (ed) Problems of drug dependence 1995. NIDA Research monograph 162. US Government Printing Office, Washington, p 214

    Google Scholar 

  • Tang AH, Franklin SR, Himes CS, Smith MW, Tenbrink RE (1997) PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties. J Pharmacol Exp Ther 281:440–447

    CAS  PubMed  Google Scholar 

  • Walker EA, Picker MJ, Dykstra LA (2001) Three-choice discrimination in pigeons is based on relative efficacy differences among opioids. Psychopharmacology 155:389–396

    Article  CAS  PubMed  Google Scholar 

  • White JM, Holtzman SG (1983) Three-choice drug discrimination: phencyclidine-like stimulus effects of opioids. Psychopharmacology 80:1–9

    CAS  PubMed  Google Scholar 

  • Wiley JL, Porter JH (1992) Serotonergic drugs do not substitute for clozapine in clozapine-trained rats in a two-lever drug discrimination procedure. Pharmacol Biochem Behav 43:961–965

    Article  CAS  PubMed  Google Scholar 

  • Young CR, Longhurst JG, Bowers MB Jr, Mazure CM (1997) The expanding indications for clozapine. Exp Clin Psychopharmacol 5:216–234

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychology, Virginia Commonwealth University, PO Box 842018, 808 West Franklin Street, Richmond, VA 23284-2018, USA

    Joseph H. Porter, Adam J. Prus, Robert E. Vann & Stephen A. Varvel

Authors
  1. Joseph H. Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam J. Prus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert E. Vann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen A. Varvel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph H. Porter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Porter, J.H., Prus, A.J., Vann, R.E. et al. Discriminative stimulus properties of the atypical antipsychotic clozapine and the typical antipsychotic chlorpromazine in a three-choice drug discrimination procedure in rats. Psychopharmacology 178, 67–77 (2005). https://doi.org/10.1007/s00213-004-1985-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-004-1985-5

Keywords

Search

Navigation