Ventral Tegmental Area Gap Junctions Mediate Opiate Dependence Development

In substance dependence, drugs are sought not for their pleasurable qualities but, rather, for their ability to alleviate withdrawal. For example, smokers often report that they do not like cigarettes but that they, nevertheless, want them. This transition from drug-liking to drug-wanting is by no means limited to nicotine dependence; it is a hallmark of addiction. What remains a mystery, however, is how exactly the brain determines whether a substance will produce pleasure, discomfort or merely alleviate withdrawal. This is precisely what I am investigating.

The ventral tegmental area (VTA) is a brainstem region that dictates whether we seek or avoid a stimulus. Long-term drug use initiates a series of molecular events in this region that alter our experience and, therefore, the very reason we seek the drug. Our lab has pinpointed the biochemical events that elicit withdrawal. We have shown that artificially inducing these events via pharmacological or genetic manipulations is sufficient to produce feelings of withdrawal in rodents with no prior exposure to the drug. We use an assay that can explain why the animal seeks morphine: for the buzz or to overcome withdrawal. Our most recent work demonstrates that a population of inhibitory neurons in the VTA contain a protein that serves as an enhancer of electrical conductance between these cells, thereby facilitating the spread of electrical signals from one neuron to the next. We have shown that this protein - called connexin-36 - has to be expressed for animals to become drug-dependent. Blocking these electrically conductive links by injecting a drug directly into the VTA reverts drug dependent rats to a drug-nondependent state wherein opiates are sought for their pleasurable qualities, rather than withdrawal alleviation. Furthermore, mice lacking the connexin-36 gene are perpetually drug-nondependent: they never experience withdrawal and the rewarding properties of opiates never diminish. We are currently studying the events that unfold downstream of the VTA when electrical coupling is prevented. Our data suggest that two different pathways can be activated in response to drugs: a drug-liking and a drug-wanting pathway. The latter pathway is never active in mice lacking connexin-36, thereby explaining their dependence-resistance.

All in all, these experiments suggest that the VTA needs to transmit synchronous signals with minimal electrical impedance to trigger withdrawal and, consequently, dependence.