Cel To determine the role of dopaminergic systems in attentional processes in animals;- To determine the role of dopaminergic systems in latent inhibition, which indexes organisms' capacity to ignore stimuli that predict no significant consequences;- To elucidate the neural circuitry of latent inhibition;- To establish an animal model of schizophrenia and of antipsychotic drug action;- To establish a screening test for drugs with antipsychotic activity.Results- Latent inhibition is known to be disrupted by systemic administration of drugs that increase dopaminergic transmission (amphetamine, nicotine), and potentiated by drugs that block dopaminergic transmission (neuroleptics, i.e. haloperidol), which also antagonise amphetamine-induced disruption of latent inhibition. Our work yielded several important findings in this context: First, the atypical neuroleptic, clozapine, has been shown to act in the latent inhibition model like typical neuroleptics. Second, the locus of action of dopaminergic agents is in the conditioning stage, when the stimulus that was previously inconsequential, comes to signal an event of consequence (reinforcement). Third, dialysis studies showed that in order to abolish LI, dopaminergic antagonists must provoke impulse (calcium)-dependent DA release in the nucleus accumbens.- Latent inhibition is disrupted by electrolytic lesions of the shell but not the core subterritory of the nucleus accumbens. Shell-lesion induced disruption of latent inhibition is prevented by systemic treatment with haloperidol.- The functional dissociation obtained between the two subterritories of the nucleus accumbens with respect to latent inhibition led to the hypothesis that shell is necessary for LI expression whereas core is necessary for LI disruption. This was supported by the finding that whereas shell lesion abolishes LI, a large nucleus accumbens lesion which includes the same shell lesion, restores the phenomenon.- Latent inhibition is disrupted by transection of the subiculo-accumbens pathway, and this disruption is prevented by systemic treatment with haloperidol. Since latent inhibition is disrupted by shell but not core lesion, and afferents to the shell arise primarily from ventral subiculum, it appears that the critical portion of the subiculo-accumbens projection subserving latent inhibition is that from the ventral subiculum to the shell.- Latent inhibition is not affected by electrolytic or excitotoxic lesions to the medial prefrontal cortex or electrolytic lesions of the basolateral amygdala, which provide major inputs to the nucleus accumbens. Direct manipulation of dopamine within the medial prefrontal cortex using infusion of dopaminergic agonists and antagonists, were also ineffective in altering LI.- Latent inhibition is not affected by electrolytic lesions to the dorsal striatum.- Intra-accumbens manipulations of dopamine showed that the dopaminergic innervation of the nucleus accumbens subserves both the disruption and the potentiation of latent inhibition. Destruction of dopaminergic terminals in the nucleus accumbens by means of 6 OHDA lesions as well as dopaminergic blockade in this structure by means of intra-accumbens injection of haloperidol, potentiate the latent inhibition effect, and reverse the disruption of latent inhibition caused by systemic amphetamine or nicotine administration. Importantly, both the latent inhibition-enhancing and amphetamine or nicotine-reversing effects of intra-accumbens haloperidol injection are obtained when the injection is confined to the time of conditioning. Latent inhibition is disrupted by intra-accumbens injection of amphetamine during conditioning if preceded by a systemic amphetamine injection (which by itself is insufficient to disrupt it).Follow up- Assessment of the effects of amphetamine on latent inhibition in animals with combined shell-core lesion. Since the combined shell-core lesion was effective in preventing shell lesion- induced disruption of latent inhibition, we will test whether this lesion will also prevent amphetamine- induced disruption;- Assessment of the effects of quinolinic acid lesions to the shell or the core subterritory, and tests of the effects of haloperidol in shell lesioned animals, and of amphetamine in core lesioned animals;- Assessment of the effects of dopamine depletion in the medial prefrontal cortex and dorsal striatum on latent inhibition. If these lesions have an effect on latent inhibition, the effects of amphetamine and haloperidol will be tested in the lesioned animals;- Assessment of changes in structures "down-stream" to nucleus accumbens, including the ventral pallidum and sensory regions of neocortex, where GABA and excitatory amino-acids changes will be measured using dialysis following manipulations of dopaminergic transmission in the nucleus accumbens. In addition, the effects of intra-pallidal injections of GABAergic agonists and antagonists on latent inhibition will be measured.- Measurement of latent inhibition after systemic administration of drugs that affect dopaminergic transmission;- Measurement of latent inhibition after intracerebral administration of drugs;- Measurement of latent inhibition after experimental lesioning of brain pathways/regions related to dopaminergic system;- Measurement by in vivo microdialysis of extra-cellular levels of dopamine during latent inhibition. Program(-y) IC-ISC C - Activity (Euratom, EEC) on cooperation in science and technology, 1984- Temat(-y) Data not available Zaproszenie do składania wniosków Data not available System finansowania CSC - Cost-sharing contracts Koordynator Institute of Psychiatry Wkład UE Brak danych Adres De Crespigny Park Camberwell SE5 8AF London Zjednoczone Królestwo Zobacz na mapie Koszt całkowity Brak danych
