Various hypothesis have been proposed to explain the properties of atypical as compared to classical antipsychotics (APDs): blockade of 5-HT2A receptors, high dissociation rate of drug - D2 receptor complex, mesolimbic selectivity, etc. We hypothesized that the atypical properties of different classes of APDs are the result of different mechanisms not only pharmacodynamic but also pharmacokinetic in nature. In order to test this hypothesis, we first studied by in vivo microdialysis the effects of various APDs on the extracellular dopamine (DA) in different areas of the rat brain: the prefrontal cortex (PFCX), the nucleus accumbens (NAc) shell and the NAc core. We administered different doses of haloperidol, clozapine, raclopride, chlorpromazine, risperidone, olanzapine, quetiapine amisulpride and levosulpiride. All the typical and atypical APDs tested significantly and dose dependently increased extracellular DA output in dialysates from the NAc shell, but after atypical APDs the increase was preferential or depending on the drug selective in the NAc shell as compared to the NAc core. All atypical APDs, except the benzamides raclopride, amisulpride and levosulpiride, increase DA output in dialysates from the PFCX. The benzamides also showed major differences in the time-course of the effects: while raclopride produced a sharp but short lasting increase of DA, levosulpiride and amisulpride elicited long lasting increase, producing the latter a slower effect. These observations suggest that different mechanisms might underlie the atypical properties of ADPs. Among drugs with rapid penetration into the brain compartments, such as haloperidol, chlorpromazine, clozapine and raclopride, atypical properties, as in the case of clozapine and quetiapine, critically depend from rapid D2 receptor dissociation. Conversely, among drugs with slow D2 receptor dissociation, as haloperidol, chlorpromazine, risperidone, olanzapine, raclopride, amisulpride and levosulpiride, atypical properties depend from slow penetration of the blood brain barrier. Within this frame, blockade of 5-HT2A receptors may be important for atypical aspect unrelated to extrapiramidal side effects and to clinical positive symptoms. Moreover, in order to evaluate the effects on motor behavior, we tested the antipsychotics in an animal model for motor coordination disturbances. Thus, we administered drugs to rats trained on a rotarod (8, 12, 16 rpm) and evaluated the latency to fall. No differences in vehicle, clozapine or amisulpride treated rats were observed whereas haloperidol and raclopride elicited significant deficits after all rpm and doses tested.
Typical and atypical antipsychotics: effects on motor behavior and differential responsiveness of shell/core/prefrontal cortex dopamine transmission
DE LUCA, MARIA ANTONIETTA;VALENTINI, VALENTINA;
2008-01-01
Abstract
Various hypothesis have been proposed to explain the properties of atypical as compared to classical antipsychotics (APDs): blockade of 5-HT2A receptors, high dissociation rate of drug - D2 receptor complex, mesolimbic selectivity, etc. We hypothesized that the atypical properties of different classes of APDs are the result of different mechanisms not only pharmacodynamic but also pharmacokinetic in nature. In order to test this hypothesis, we first studied by in vivo microdialysis the effects of various APDs on the extracellular dopamine (DA) in different areas of the rat brain: the prefrontal cortex (PFCX), the nucleus accumbens (NAc) shell and the NAc core. We administered different doses of haloperidol, clozapine, raclopride, chlorpromazine, risperidone, olanzapine, quetiapine amisulpride and levosulpiride. All the typical and atypical APDs tested significantly and dose dependently increased extracellular DA output in dialysates from the NAc shell, but after atypical APDs the increase was preferential or depending on the drug selective in the NAc shell as compared to the NAc core. All atypical APDs, except the benzamides raclopride, amisulpride and levosulpiride, increase DA output in dialysates from the PFCX. The benzamides also showed major differences in the time-course of the effects: while raclopride produced a sharp but short lasting increase of DA, levosulpiride and amisulpride elicited long lasting increase, producing the latter a slower effect. These observations suggest that different mechanisms might underlie the atypical properties of ADPs. Among drugs with rapid penetration into the brain compartments, such as haloperidol, chlorpromazine, clozapine and raclopride, atypical properties, as in the case of clozapine and quetiapine, critically depend from rapid D2 receptor dissociation. Conversely, among drugs with slow D2 receptor dissociation, as haloperidol, chlorpromazine, risperidone, olanzapine, raclopride, amisulpride and levosulpiride, atypical properties depend from slow penetration of the blood brain barrier. Within this frame, blockade of 5-HT2A receptors may be important for atypical aspect unrelated to extrapiramidal side effects and to clinical positive symptoms. Moreover, in order to evaluate the effects on motor behavior, we tested the antipsychotics in an animal model for motor coordination disturbances. Thus, we administered drugs to rats trained on a rotarod (8, 12, 16 rpm) and evaluated the latency to fall. No differences in vehicle, clozapine or amisulpride treated rats were observed whereas haloperidol and raclopride elicited significant deficits after all rpm and doses tested.
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