To take the example of dopaminergic involvement in depression, one could begin to deconstruct this idea by pointing out that “anhedonia” in depression is often misinterpreted or mislabeled by clinicians (Treadway and Zald, 2011). Several studies show that depressed people often learn more have a relatively normal self-rated experience of encounters with pleasurable stimuli and that, over and above any problems with the experience of pleasure, depressed people appear to have impairments in

behavioral activation, reward-seeking behavior, and exertion of effort (Treadway and Zald, 2011). Indeed, most depressed people suffer from a crippling constellation of motivational impairments that include psychomotor retardation, anergia, and fatigue (Demyttenaere et al., 2005; Salamone et al., 2006), and considerable evidence implicates DA in these symptoms (Salamone et al., 2006, 2007). These observations, coupled with the literature indicating that there is not a simple correspondence between DA activity and hedonic experience (e.g., Smith et al., 2011) and the studies linking DA to behavioral activation Ferroptosis tumor and exertion of effort (Salamone et al., 2007;

see discussion below), lead one to conclude that dopaminergic involvement in depression seems to be more complicated than the simple story would have allowed. Similarly, it is clear that a substantial body of research on drug dependence and addiction does not comply with the traditional tenets of the DA hypothesis of reward. Several studies have shown that blockade of DA

receptors or inhibition of oxyclozanide DA synthesis does not consistently blunt the self-reported euphoria or “high” induced by drugs of abuse (Gawin, 1986; Brauer and De Wit, 1997; Haney et al., 2001; Nann-Vernotica et al., 2001; Wachtel et al., 2002; Leyton et al., 2005; Venugopalan et al., 2011). Recent research has identified individual differences in behavioral patterns shown by rats during Pavlovian approach conditioning, which are related to the propensity to self-administer drugs. Rats that show greater response to conditioned cues (sign trackers) display different patterns of dopaminergic adaptation to training as compared to animals that are more responsive to the primary reinforcer (goal trackers; Flagel et al., 2007). Interestingly, the rats that show greater Pavlovian conditioned approach to an appetitive stimulus and show greater incentive conditioning to drug cues, also tend to show greater fear in response to cues predicting shock and greater contextual fear conditioning (Morrow et al., 2011). Additional research has challenged some long held views about the neural mechanisms underlying addiction, as opposed to the initial reinforcing characteristics of drugs.