Modulation of selective processes in learning by neocortical and limbic dopamine : studies of behavioural strategies

Introduction: Damage to the Septum or to the Prefrontal cortex impairs learning and the flexibility of the early attention-related stages of information porocessing. These brain regions are the goals, respectively, of the dopaminergic (DA) mesolimbic and mesocortical pathways emanating from the ventral tegmental A 10 nuclei (VTA). These areas are represented in the "convergent nodes" and "circuit systems" we have described as a basis for the functional influence of DA on integrative function, see Figure 1 and 2, and Oades and Halliday, 1987 Here we elaborate the use of the measurement of a search strategy (for 4 food-holes in a 16 hole board) in rodents as a measure of the influences affecting attention to cues and the establishment of a working memory: in particular we examined the effects of local VTA injections of a DA agonist and antagonist on the stability of the normally consistent sequence of hole visits, and concentrate on the mesolimbic system. We also present preliminary results of the effect of septal 6-OHDA lesions on the conditioned blocking measure of selective attention in a shuttle avoidance task. Methods: Animals were given 10 trials/session, 2 sessions/day for 5 days on a 16-hole board in a closed arena. A food pellet was placed in the same 4 holes on each occasion. Prior to session 4 and 7 the rats received either the DA D2 antagonist spiroperidol (2µg/0.5µl) or the DA agonist apomorphine (2 µg/0.5µl) or the vehicle (saline or pH adjusted tartarate) into the VTA. (Diffusion was restricted to within 1.5 mm.) It would be predicted that local neuroleptic treatment would block local, inhibitory autoreceptors and thus lead to increased DA activity in the terminal regions. Monoamines and their metabolites in the N. accumbens were measured with HPLC. Results: 1/ Neuroleptic, but not other VTA-treatments, increased rearing (3-4 fold), non-food-hole visits / errors (50-100%) and the number of switches away from the preferred hole-visit sequence established on the first 3 sessions. 2/ An increase of DA utilization in the nucleus accumbens was demonstrated in selected animals sacrificed after session 7. 3/ There was a significant correlation for increased DA utilization with the number of errors (of working- and reference-memory type), the amount of rearing, but not with switches away from the preferred search sequence. 4/ Septal-6-OHDA damage did not alter conditioned blocking considered across all test trials - but this masked an initial mild attenuation followed by exaggerated blocking at the end of testing (see Oades et al., 1987 for a full report). Conclusions: On the basis of the disruption of holeboard search by increased DA activity it is postulated that mesolimbic DA is important for the evaluation and temporal coordination of response feedback for the pursuance of task-solving strategies. The changeover from reduced to enhanced conditioned blocking after septal-6-OHDA treatment is discussed in the context of where septal damage induces 'changeovers' in other situations, and seen to be consistent with the interpretation that mesolimbic DA modulates the evaluation of attended stimuli and the formation of working memory templates. (The holeboard work started with investigation of hippocampal lesions and haloperidol treatment as an animal model for schizophrenia, Oades and Isaacson, 1978; Oades, 1981 and continued with studies of the role of the VTA A 10 DA system in Oades, 1981a, 1981b and 1982 ).


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