Affective neuroscientific and neuropsychoanalytic approaches to two intractable psychiatric problems: why depression feels so bad and what addicts really want.

The affective foundations of depression and addictions are discussed from a cross-species - animal to human - perspective of translational psychiatric research. Depression is hypothesized to arise from an evolutionarily conserved mechanism to terminate protracted activation of separation-distress (PANIC/GRIEF) systems of the brain, a shutdown mechanism which may be in part mediated by down-regulation of dopamine based reward-SEEKING resources. This shutdown of the brain's core motivational machinery is organized by shifts in multiple peptide systems, particularly increased dynorphin (kappa opioids).

The effects of VTA NMDA receptor antagonism on reward-related learning and associated c-fos expression in forebrain.

The mechanisms whereby reward-associated stimuli come to function as conditioned stimuli and acquire the capacity to activate the same neural regions activated by primary rewards (i.e., dopamine terminal regions) is not fully understood.

How conditioned stimuli acquire the ability to activate VTA dopamine cells: a proposed neurobiological component of reward-related learning.

The ability to learn about conditioned stimuli (CS) associated with rewards is a crucial adaptive mechanism. Activity in the mesocorticolimbic dopamine (DA) system, as well as in the ventral tegmental area (VTA), is correlated with responding to and learning about CSs. The mechanism by which VTA neurons become activated by signals associated with conditioned stimuli is not fully understood.

NMDA receptor antagonism in the ventral tegmental area impairs acquisition of reward-related learning.

Mechanisms underlying reward-related learning presumably involve neural plasticity integrating signals representing unconditioned and conditioned stimuli in regions mediating reward. The ventral tegmental area (VTA) receives such signals and shows synaptic plasticity which is NMDA receptor-dependent. To test the hypothesis that NMDA receptor stimulation in the VTA is necessary for the acquisition of food-reinforced appetitive learning, Long-Evans male rats were prepared with bilateral VTA cannulae and tested in operant chambers with the opportunity to lever press for food for 10 sessions.