Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra.

Abstract

Antischizophrenic drugs exert their primary effects through blockade of dopamine (DA) receptors in the central nervous system (CNS)1–3. However, because of intricate interconnections between neural pathways, alteration of DA function in the CNS can lead to changes in the function of other neurotrans-mitters. In the basal ganglia, the turnover and utilisation of several neurotransmitters, including γ-aminobutyric acid (GABA)4–6, are indirectly influenced by nigrostriatal DA activity7–10. However, although attention has been focused on changes in DA receptors11,12, relatively little is known about changes in receptors for other transmitters after chronic anti-schizophrenic drug treatment. It is likely that changes occurring one or more synapses removed from the drugs' primary site of action may account for some of the time-dependent changes in the therapeutic and adverse clinical effects of antischizophrenic drugs13,14. In the substantia nigra (SN), a reduction in GABAergic inhibitory tone and a possible increase in the release of excitatory transmitter such as substance P are effects which seem to accompany the acute blockade of striatal DA receptors15. Recent studies have shown that a chronic decrease in GABA function in the SN, through the destruction of stria-tonigral pathways16,17, produces an increase in the number of GABA binding sites in the SN14,45. Therefore, if a relative deficit of GABA transmission in the SN were to be maintained by chronic antischizophrenic drug treatment, an increase in nigral GABA binding might occur. To investigate this possibility, two classical prototype antischizophrenic drugs (chlorpromazine and haloperidol) were examined for their effects on specific GABA binding in the SN and striatum of rats. These effects were compared with those of clozapine, an antischizophrenic drug with an atypical biochemical and clinical profile4,18–23. The data obtained, and reported here, support the hypothesis that chronic blockade of dopamine receptors by classical anti-schizophrenic drugs enhances GABA binding in the SN. This effect may be related to the extrapyramidal side effects associated with classical antischizophrenic drug treatment13.