The complexity of the dopaminergic system and its role in addicition behavior

The field of Optogenetics is fast growing in popularity and effectiveness in the field of Neuroscience. It allows experimenters to activate certain types of cell channels and cause a corresponding inhibition or excitation of neuronal firing in response to channel activation through light stimulus. This method allows scientist to further define the role of certain cell populations as well as their function. It gives scientist a more direct way of determining evidentiary support for the correlation or causation of certain neurons or nueronal pathways. Because of the value of this extraordinary work, amazing advances have been made in understanding the complexity of brain circuitry, such as the the dopaminergic system. I had the pleasure of getting the chance to listen to Dr. Steidle present his paper, which is currently under review, twice.

In his paper, he examines a very small subset of cell in the laterodorsal tegmental nucleus (LDTg) with cholinergic and glutamatergic inputs into the ventral tegmental area (VTA). He studied this dopaminergic pathway and hopes of achieving a greater understanding of its role in addicition and its role as a behavioral reinforcement. The dopaminergic system is known to be involved with reward behavior. It has projections that spread throughout the brain. Some drugs such as cocaine are known to directly cause activation of dopamine neurons. In the VTA, the population of dopaminergic neurons receive input from cells of the LTDg, which are either cholinergic, glutamaterigc, or GABAergic. He first identifies the brain areas affected by dopamine, then activates them through pairing of a reward to a cue, that thus results in a craving by the subject. The VTA receives input from multiple brain regions, and Dr. Steidle looks at the LDTg as well as pedunculopontene (PPTg). He artificially activates the two pathways that feed into the VTA using optogenetics. In this he uses a recombinase (CAMKII) and a rhodopsin to genetically insert a protein that activates or inhibits in response to certain wavelengths of light. He does this in tandem by activating on type of proteins and inhibiting another since both proteins are found to overlay one another.  This way he can measure protein and neurotransmitter specific effects of LDTg on the VTA. This is concluded with behavioral study of artificially stimulating the same neurons activated in reward reinforcement with mice and lever pressing paired with cocain, or paired with light. This was also shown when mice that had been preconditioned to show preference for one lever to indicate reward stimulation showed a reverse preference for the lever when the previous reward stimulus became dormant and the other lever that they previously showed no preference for triggered an activation of the dopamingergic (DA) neurons. This was also true and stronger corresponding to longer stimulation of DA neurons but only up to 5 ms. They see that it is similar and LDTg in necessary. The same was also observed by artificially stimulating those neurons in a place preference test. To go further, he looked at the type of neurotransmitter release (GABA, Glutamate, or Cholinergic). Although it was found that cholinergic neurons are important, it could not be determined their contributions to LDTg.

A recent paper by Susana Pecina and Kent Berridge also looked at the reward circuitry in the DA system and how the level of cravings vary. They also used a controlled stimulus(CS) setting where animals were cued to reward and later experimentally inserted amphetamine rostral shell which was thought to be specific and the caudal area that could have diffused to other areas compared to those that received it and compared them to the received sugar as a cue when trained with the CS. Their results seemed to implicate the Nucleus Accumbens as the source responsible when given stimuli of varying degrees for relaying that information to the mesolympic system, but how this is exactly done is still largely unknown.

There is a lot of resources going into studying addiction and every day advances are made in the field. The dopaminergic system is incredibly difficult to study and has been implicated in a variety of psyschiatric conditions such as depression and some nuerodegenerative diseases like parkinsons as well. Because this system is responsible for so much, it is innervated all throughout the brain and that makes it very difficult to study each level of input and output and the corresponding function at every level of its circuity. Because many of these studies are still trying to figure out the function of theses neurons and pathways, research is limited and aids for diseases are only at the treatment level and will likely remain so for many years to come, however it is still important because each step in treatment has the potential to tell us more and do more for patients.

Resources:

Steidl, Stephan, and Kevin Veverka. "Optogenetic excitation of LDTg axons in the VTA reinforces operant responding in rats." Brain research 1614 (2015): 86-93.

Peciña, Susana, and Kent C. Berridge. "Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue‐triggered ‘wanting’for reward: entire core and medial shell mapped as substrates for PIT enhancement." European Journal of Neuroscience 37.9 (2013): 1529-1540.