Multiple neurochemical action of clozapine: A quantitative autoradiographic study of DA 2, opiate and benzodiazepine receptors in the rat brain after long-term treatment

Abstract

The atypical neuroleptic clozapine has clinical and behavioral properties that differ not only from the typical compounds, but also from atypical ones. It interacts with the dopaminergic systems, but also produces effects on the serotoninergic, GABA-ergic, cholinergic systems. In spite of the amount of papers devoted to its study, the profile of the neurochemical action of this drug is still confuse. In this paper we investigated the DA2-, opiate- and benzodiazepine-receptor modifications induced by the long term (21 days) treatment with clozapine 20 mg/kg/day in the rat brain. We found a decrease of DA2 receptor density in the target areas of the mesolimbocortical system (ventral n. caudate-putamen, cerebral cortex except for the anterior cingulate at the most anterior level and the n. accumbens) and a decrease of opiate and benzodiazepine receptors in the cerebral cortex and in the olfactory tubercle. Opiate receptors increase in the patches of the striatum. We also compared these effects with those produced by long-term (21 days), low-dosage (0.5 mg/kg day) haloperidol.

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

“…In the present study, we failed to replicate these results, since no regional differences in BDZ V T were observed between patients on or off neuroleptics. Thus our results do not support alteration of BDZ receptors density associated with longterm neuroleptic exposure, a conclusion consistent with preclinical studies (Gavish et al 1988;Giardino et al 1991).…”

“…Patient clinical evaluation at intake included the Positive and Negative Symptoms Scales (PANS) (Kay et al 1987), a scale that includes the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962), and the AIMS (Munetz and Benjamin 1988). Since BDZ receptor density is not consistently affected by chronic antipsychotic administration (Gavish et al 1988;Giardino et al 1991), neuroleptic withdrawal was not required for this study.…”

Effects of clozapine on the δ‐ and κ‐opioid receptors and the G‐protein‐activated K+ (GIRK) channel expressed in Xenopus oocytes

“…Clozapine has high affinity for the D 4 dopamine, 5‐hydroxytryptamine 2A (5‐HT 2A ), 5‐HT 2C , 5‐HT 6 , 5‐HT 7 , M 1 muscarinic receptors and α 1 adrenoceptors (Meltzer, 1994), as well as the ability to modulate the release of dopamine, 5‐HT and acetylcholine (Moghaddam & Bunney, 1990; Yamamoto et al , 1994; Parada et al , 1997). Furthermore, previous studies showed that clozapine inhibited the binding of [ 3 H]‐Met 5 ‐enkephalin to synaptosome fractions prepared from rat brain with an IC 50 value of 28.5 μ m (Somoza et al , 1981) and chronic treatment with clozapine altered the density of opioid receptors (Giardino et al , 1991; Zhang et al , 1995), and the level of dynorphin (Nylander & Terenius, 1986) and proenkephalin mRNA (Angulo et al , 1990; Zhang et al , 1995) in certain areas of the brain, suggesting the interaction of clozapine with the opioid system. However, the molecular mechanisms underlying the effect of clozapine on the opioid system remain unknown.…”

Pharmacological actions of the atypical antipsychotic drug clozapine: A review

“…The chronic administration (1, 8, or 12 months) of CLOZ (via drinking water) does not alter the KD or B,,, of GAB% or benzodiazepine receptor binding in the rat striatum of nucleus accumbens (Rupniak et al, 1987;See et al, 1990). However, Giardino et al (1991) reported that the chronic administration of CLOZ (20 mgkg/day for 21 days) produces a significant decrease in 3H-flunitrazepam binding in the medial, dorsal, and lateral cortices, but not in the striaturn or nucleus accumbens of the rat brain.…”