Figure 10. Reduced GABAa receptor levels with meth dependence.

A map of the brain (side view) showing regions (blackened areas) where levels of normal GABAa receptors are lower in the brain of a patient with meth dependence versus a normal individual (Agi-Darbham, 1998).

What Does It All Mean?
As is the case with many diseases, scientists have not yet provided final answers to the questions of what causes addiction to meth or what leads to the very unpleasant symptoms that result when those dependent on methamphetamine try to stop using these agents.  However, we do have quite a bit of information about the changes in the brain that underlie these problems:

1. The initial rewarding effects of drugs that are abused involve increased activity in the dopamine system and changes in this system (reduced numbers of dopamine receptors) that occur with long-term abuse and dependence probably result in the requirement for increasing drug doses to achieve rewarding effects.
   
   
2. Dependence on meth and the unpleasant symptoms (e.g., anxiety, insomnia, irritability, dysphoria) that occur when people try to abstain from them probably involve the GABAergic system and may result from a change in the type of GABAa receptors made by brain cells. These altered receptors may be less effective than normal GABAa receptors in carrying out the calming effect of GABA on
   the brain.

While our growing understanding of the roles of dopamine and GABA in methamphetamine dependence and withdrawal has permitted us to forge strong links between changes in the brain and behavior characteristic of these conditions, there may be more to this story. 

HORMONES IN THE BRAIN AND HOW THEY MAY INFLUENCE METHAMPHETAMINE DEPENDENCE
AND WITHDRAWAL
Hormones are molecules similar to neurotransmitters that are made in many parts of the body, including the kidney, adrenal glands, testes, ovary, and other organs. These molecules have long been known to alter the activity of nerve cells in the brain and scientists now know that many brain cells have receptors for hormones that are very much like those for neurotransmitters. Experiments in animals and humans carried out over the last 20 years have shown that one hormone called allopregnanolone may interact with the GABAa receptors described in the preceding section and influence how the brain responds when people try to stop abusing methamphetamine (N-Wihlback, 2006; Follesa, 2006; Finn, 2004; Leskiewicz, 2003). 

Allopregnanolone, GABAa Receptors and Meth Withdrawal
Allopregnanolone, also referred to as THP, is found in many portions of the brain. Under normal circumstances, allopregnanolone binds to GABAa receptors and enhances their calming effects on the brain
(Figure 11) (McCarthy, 2007).