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). Addictions are conceived to be primarily mediated by obsessive behaviors sustained by reward-SEEKING circuits in the case of psychostimulant abuse, and also powerful consummatory-PLEASURE responses in the case of opioid abuse, which in turn capture SEEKING circuits. Both forms of addiction, as well as others, eventually deplete reward-SEEKING resources, leading to a state of dysphoria which can only temporarily be reversed by drugs of abuse, thereby promoting a negative affect that sustains addictive cycles. In other words, the opponent affective process - the dysphoria of diminished SEEKING resources - that can be aroused by sustained over-arousal of separation-distress (PANIC/GRIEF) as well as direct pharmacological over-stimulation and depletion of SEEKING resources, may be a common denominator for the genesis of both depression and addiction. Envisioning the foundation of such psychiatric problems as being in imbalances of the basic mammalian emotional systems that engender prototype affective states may provide more robust translational research strategies, coordinated with, rather than simply focusing on, the underlying molecular dynamics. Emotional vocalizations might be one of the best ways to monitor the underlying affective dynamics in commonly used rodent models of psychiatric disorders.

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. We hypothesized that NMDA receptor stimulation in the VTA is necessary for the acquisition by a CS to both produce conditioned approach and activate dopamine terminal regions. Rats were tested in a conditioned approach protocol that consisted of light stimulus-food conditioning sessions (30 randomly presented light stimulus-food pellet pairings), a session with no stimuli or food and 1 session with only light stimulus (CS-only) presentations. Food trough head entries during the CS and just prior to the CS were recorded and a CS/pre-CS ratio indicating the conditioned approach response was calculated. Brain tissue was harvested after the CS-only session and processed for c-fos expression in prefrontal cortex area 2, nucleus accumbens core and shell and medial and lateral caudate. When bilateral intra-VTA microinjections of AP-5 (0, 0.25 or 0.5 µg) were made prior to each of the conditioning sessions the 0.5 µg AP-5 dose prevented the acquisition of conditioned approach; when 0.5 µg AP-5 injections were made prior to the CS-only test they failed to affect expression of the response. Also, 0.5 µg AP-5 prior to conditioning significantly reduced c-fos expression in response to the CS in nucleus accumbens core. These results suggest that VTA NMDA receptor stimulation is necessary for both the acquisition of reward-related learning and acquisition by the CS to activate dopamine terminal regions.

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. Our model suggests that NMDA receptor stimulation in the VTA allows originally weak glutamate signals carrying information about environmental stimuli, coincident with strong excitation correlated with primary rewards, to be strengthened and thereby acquire the ability to activate VTA neurons in themselves, producing approach. Furthermore, once synaptic strengthening occurs, the model suggests that NMDA receptor stimulation in VTA is not necessary for the expression of reward-related learning. In this review we survey evidence that VTA cells respond to cues associated with primary rewards, that this responding is acquired, and that the VTA possesses the attributes to function as a site of integration of signals of primary and conditioned stimuli.

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. Animals received microinjections of AP-5 or vehicle immediately before sessions 1-4 and 10. AP-5 impaired acquisition of lever pressing during sessions 1-4 (but not when injected dorsal to the VTA). All groups increased lever pressing across sessions 5-9. On session 10, lever pressing was not affected regardless of treatment. In separate experiments, AP-5 failed to reduce free feeding, food reward or motor activity, suggesting that impairment in acquisition was not due to reduced food motivation or activity. NMDA transmission in the VTA thus appears to be necessary for the acquisition, but not expression, of reward-related learning.