Long-term haloperidol treatment (but not risperidone) enhances addiction-related behaviors in mice: role of dopamine D2 receptors.
The high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol (Hal) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) Hal (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in Hal-withdrawn mice. Ten days after withdrawal from long-term treatment with Hal (but not with Ris or Ris + Hal), a potentiation in AILS was still observed. Only Hal-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as Hal. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon.
Carvalho
Rita C
RC
Department of Pharmacology, Universidade Federal de São Paulo, Rua Botucatu 862, São Paulo-SP, Brazil.
Fukushiro
Daniela F
DF
Helfer
Daniel C
DC
Callegaro-Filho
Donato
D
Trombin
Thaís F
TF
Zanlorenci
Lineane H F
LH
Sanday
Leandro
L
Silva
Regina H
RH
Frussa-Filho
Roberto
R
D019969:Amphetamine-Related Disorders / Q000503:physiopathology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D018491:Dopamine Agonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects / Q000503:physiopathology; D008134:Long-Term Care; D008636:Mesencephalon / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D018967:Risperidone / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D006220:Haloperidol; D018967:Risperidone; D001058:Apomorphine