Dalley, Jeffrey W.; (1992) Typical and atypical neuroleptic drug effects on dopamine and other neurotransmitter functions in rodents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The antischizophrenic effect of neuroleptic drugs probably arises from blockade of central dopamine receptors which also leads to extrapyramidal side effects (EPSEs). The aim of the work described in this thesis was to elucidate how some drugs, the so-called atypical neuroleptics, alleviate the symptoms of schizophrenia without producing marked EPSEs. An intracerebral microdialysis system was developed and used to monitor the acute effects of neuroleptic drugs on dopamine release and metabolism in the caudate putamen (CP), nucleus accumbens (NAc) and medial prefrontal cortex (MPFC) of halothane-anaesthetised rats. Dopamine and its metabolites DOPAC and HVA were estimated in brain dialysates by HPLC with electrochemical detection. In other studies extracellular recording techniques were used to assess the effects of neuroleptics and dopamine agonists on the spontaneous activity of neurons in the CP and MPFC. Both haloperidol (typical neuroleptic) and clozapine (atypical) elevated the efflux of dopamine metabolites in the CP, NAc and MPFC although only clozapine significantly facilitated dopamine efflux and this was restricted to the MPFC. Neither neuroleptic showed any consistent effects on neuronal activity in the CP, however, unlike haloperidol, but similar to the dopamine agonist apomorphine, clozapine both stimulated and inhibited neuronal activity in the MPFC. The ability of these agents to antagonise the effects of apomorphine was also evaluated. Apomorphine produced a dose-dependent inhibition of neuronal activity and efflux of dopamine and metabolites in both the CP and the MPFC. Although fewer cells in the MPFC showed any response to apomorphine compared with those in the CP, those that did, were markedly more sensitive to the inhibitory effects of this agent. The effects of apomorphine were reversed by haloperidol but only partially reduced by clozapine. Since clozapine did not alter the time course of apomorphine appearance in CP dialysates and haloperidol only reduced the appearance at one dose level, it was concluded that the antagonism of apomorphine's actions in the CP and MPFC were directly mediated. The differential effects of haloperidol and clozapine on dopamine function in the CP and MPFC are discussed in respect of their typical and atypical profiles. The weak dopamine (apomorphine) antagonism shown by clozapine in the CP would account for the low incidence of EPSEs seen with this compound although its relatively weak action in the MPFC implies that its antischizophrenic action must stem, at least in part, from other actions. The ability of clozapine to enhance the efflux (release?) of dopamine in the MPFC could explain its efficacy against the negative symptoms of schizophrenia. A possible mechanism to account for the ability of clozapine to alleviate the positive aspects of this disorder (despite weak dopamine receptor antagonism) is also discussed. In other experiments designed to reveal the nature of clozapine's atypical action its effects on 5-HT3 mediated release of dopamine in the NAc as well as on the contraction of guinea-pig ileum in-vitro were studied. It was also compared with other atypical and typical neuroleptics on muscarinic, a-adrenergic and tachykinin receptors in the guinea- pig ileum and rat vas-deferens. The effects of typical and atypical neuroleptics in all these preparations is discussed in an attempt to explain their differential clinical effects.

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