The brain dopaminergic system. Pharmacological, behavioural and electrophysiological studies.

The kindling phenomenon is a good example of the effect of multiplicity on response increment processes in the nervous system. The electrical potentiation resembles pharmacological sensitization. An intermittent regimen is essential for a progressive augmentation of the behavioural response in both conditions. Nigro-striatal dopaminergic sensitization by on and off anti-dopaminergic drugs has been suggested as a model for development of tardive dyskinesia (TD) and sensitization of the meso-limbic dopaminergic system either by repeated stimulation with agonists or by environmental stressors has been proposed to model psychotic development in schizophrenia. The present thesis addresses the implications of intermittent influences on the brain dopaminergic systems for the development of pathological behaviours. For this purpose new rat models have been developed both for studying the effects of the treatment schedule of neuroleptics on the development of oral hyperactivity and for studying the effects of intermittent electrical stimulations of the ventral tegmental area (VTA) housing the meso-limbic dopamine (DA) cells. A long-lasting/permanent kindling-like sensitization to the dyskinetic inducing side-effects of classical neuroleptic drugs following intermittent opposed to continuous treatment has been demonstrated. This sensitization is proposed to represent an animal model for TD. The significance of receptor profiles, the effects of pharmacological interventions and the possible relation to the GABAergic and cholinergic systems are discussed. Intermittent electrical activation of the cells in the VTA resulted in a syndrome characterized by a hypersensitive response to electrical or pharmacological dopaminergic provocation combined with abnormal social interactions. This new animal model may have implications for the understanding of the pathogenesis of schizophrenia. Hypotheses are proposed for the meaning of dopaminergic sensitization both in the development of persisting dyskinetic side-effects related to neuroleptic treatment and in the development of schizophrenia.