, 2011), and electrophysiological recordings during free operant responding (Nishino et al., 1987; Kosobud et al., 1994). Cacciapaglia et al. (2011) reported that click here fast phasic DA release in nucleus accumbens as measured by voltammetry occurred during onset of a cue that signaled reinforcer availability, as well as lever press responding, and that the excitatory effects of this phasic release on accumbens neurons were blunted by inactivation of burst firing in ventral tegmental DA neurons. Furthermore, a substantial body of electrophysiology research has identified some of the conditions that activate burst firing in putative ventral tegmental DA neurons, including

presentation of stimuli that are associated with buy Trametinib the primary reinforcer, as well as conditions that have a higher reinforcement value relative to the expectation generated by previous experience (Schultz et al., 1997). The later observation has led to the hypothesis that DA neuron activity could represent the kind of prediction error signal described by some models of learning (e.g., Rescorla and Wagner, 1972). This pattern of activity in putative DA neurons has provided a formal theoretical basis for the involvement of fast phasic DA signaling in reinforcement learning models (Schultz et al., 1997; Bayer and Glimcher, 2005; Niv, 2009;

Schultz, 2010). Although the primary focus of the present paper is on the effects of dopaminergic manipulations on distinct aspects of motivation, it

is useful to consider the importance of fast phasic and slow phasic (i.e., “tonic”) signaling for interpreting the effects of conditions that interfere with DA transmission. The different timescales of dopaminergic activity could serve very different functions, and therefore, the effects of a particular manipulation could below very much depend upon whether it is altering fast or slow phasic activity or baseline levels of DA. Researchers have used various pharmacological or genetic manipulations to differentially affect fast phasic DA activity versus DA release on slower time scales (Zweifel et al., 2009; Parker et al., 2010; Grieder et al., 2012) and have reported that these manipulations can exert distinct behavioral effects. For example, Grieder et al. (2012) showed that selective interference with phasic DA activity prevented the expression of conditioned place aversions to withdrawal from a single acute dose of nicotine, but not to withdrawal from chronic nicotine. In contrast, blockade of D2 receptors impaired the expression of conditioned aversion during chronic, but not acute withdrawal. Zweifel et al. (2009) reported that selective genetic inactivation of NMDA receptors, which blunted burst firing in VTA DA neurons, impaired the acquisition of cue dependent appetitive learning but did not disrupt the behavior of working for food reinforcement on a progressive ratio schedule.