Suppression of dopamine level in the rhinal cortex resulted in monkeys losing their ability to understand work for reward, working intently all the time, a finding that may have implications for patients with disorders including depression and obsessive compulsive disorder, which are marked by distortions in the link between reward and urge to work, according to an article published online August 9th by the Proceedings of the National Academy of Sciences (USA).

The researchers used a new molecular genetic technique to temporarily block production of a key dopamine receptor in the rhinal cortex. Monkeys that had worked harder as they neared their reward (learning that an increasingly intense band on a computer screen meant they were nearing the reward point) lost the ability to link work and reward and began to work at full intensity all the time.

"The gene makes a receptor for a key brain messenger chemical, dopamine," explained Barry Richmond, MD, lead author. "The gene knockdown triggered a remarkable transformation in the simian work ethic. Like many of us, monkeys normally slack off initially in working toward a distant goal. They work more efficiently - make fewer errors - as they get closer to being rewarded. But without the dopamine receptor, they consistently stayed on-task and made few errors, because they could no longer learn to use visual cues to predict how their work was going to get them a reward."

The team trained monkeys to release a lever when a spot on a computer screen turned from red to green. The animals knew they had performed correctly when the spot turned blue. A visual cue - a gray bar on the screen - got brighter as they progressed through a succession of trials required to get a juice treat. Though never punished, the monkeys couldn't graduate to the next level until they had successfully completed the current trial.

As in a previous study (http://www.nimh.nih.gov/Press/prrewardsignal.cfm) using
the same task, the monkeys made progressively fewer errors with each trial as the reward approached, with the fewest occurring during the rewarded trial. Previous studies had also traced the monkeys' ability to associate the visual cues with the reward to the rhinal cortex, which is rich in dopamine. There was also reason to suspect that the dopamine D2 receptor in this area might be critical for reward learning. To find out, the researchers needed a way to temporarily knock it out of action.

The researchers fashioned an agent that, when injected directly into the rhinal cortex of four trained monkeys, caused the cells to turning off D2 expression for several weeks. This depleted the area of D2 receptors, impairing the monkeys' reward learning. For a few months, the monkeys were unable to associate the visual cues with the workload - to learn how many trials needed to be completed to get the reward.

"The monkeys became extreme workaholics, as evidenced by a sustained low rate of errors in performing the experimental task, irrespective of how distant the reward might be," said Richmond. "This was conspicuously out-of-character for these animals. Like people, they tend to procrastinate when they know they will have to do more work before getting a reward."

To make sure that it was, indeed, the lack of D2 receptors that was causing the observed effect, the researchers played a similar recombinant decoy trick targeted at the gene that codes for receptors for another neurotransmitter abundant in the rhinal cortex: NMDA (N-methlD-aspartate). Three monkeys lacking the NMDA receptor in the rhinal cortex showed no impairment in reward learning. The researchers also confirmed that the DNA treatments actually affected the targeted receptors by measuring receptor binding following the intervention in two other monkeys' brains.

"This new technique permits researchers to, in effect, measure the effects of a long-term, yet reversible, lesion of a single molecular mechanism," said Richmond. "This could lead to important discoveries that impact public health. In this case, it's worth noting that the ability to associate work with reward is disturbed in mental disorders, including schizophrenia, mood disorders and obsessive-compulsive disorder, so our finding of the pivotal role played by this gene and circuit may be of clinical interest," suggested Richmond.

"For example, people who are depressed often feel nothing is worth the work. People with obsessive compulsive disorder work incessantly; even when they get rewarded they feel they must repeat the task. In mania, people will work feverishly for rewards that aren't worth the trouble to most of us."