Animal models of affective psychopathology : depression and reward
One approach to the clinical problem of defining the neural substrates of human depressive disorders is to model discrete aspects of affective psychopathology in animals. Two major methodological problems have hindered the development of valid animals models of depression. First, individual responses to the manipulations commonly used to model depression are highly variable. Second, reliable and valid measures of hedonic state remain elusive. This thesis describes experimental work which addresses these methodological concerns. Selective breeding based on individual responses to cholinergic challenge has resulted in a putative genetic model of depression, the Flinders Sensitive Line hypercholinergic rat (FSL). An examination of the affective status of the FSL described in this thesis confirms that selective breeding can generate interesting behavioural and neurochemical phenomena, but does not support the FSL's validity as a model of anhedonia. Problems of measurement of hedonic responsivity are considered both in the description of a novel dependent measure derived from an operant food reward paradigm; and also in an evaluation of the reliability and validity of standard measurement techniques employed with the 'chronic unpredictable mild stress model' (CMS) of anhedonia. Initial validating studies suggest that the food reward paradigm may represent a useful method for assessment of affective state. Manipulation of environmental stimuli to induce CMS led to a partial replication of the target behavioural phenomena. However, the effects were not independent of metabolic consequences that seriously confound the interpretation of experiments employing this procedure. It is concluded that future advances in the development of valid models of depression will require a shift of emphasis towards combined manipulations of genetic predisposition and of specific critical environmental stimuli.