Drugs of abuse are taken because they produce pleasure by increasing dopamine, invoking the involvement of the limbic areas. How do we explain that in many instances, the drug is not even pleasurable, and yet the addicted patients could not stop taking it.

Soudabeh said:

Drugs of abuse are taken because they produce pleasure by increasing dopamine, invoking the involvement of the limbic areas. How do we explain that in many instances, the drug is not even pleasurable, and yet the addicted patients could not stop taking it.

The mechanism of drug abuse is really complicated. It cannot be done in a day or improvised by a mere command of the will, there is a long way to go. Regarding the above question, it can be explained that without the drug that is not even pleasurable, people will suffer something.

Soudabeh said:

Drugs of abuse are taken because they produce pleasure by increasing dopamine, invoking the involvement of the limbic areas. How do we explain that in many instances, the drug is not even pleasurable, and yet the addicted patients could not stop taking it.

I suggest the loss of pleasure is due to too many increased receptors. I think drugs of abuse work in the same manner as growth and development of the brain. This growth and development is designed to increase absorption of molecules which result in growth and development. When this starts, the large impulse of these molecules, directed by the location of action of the drugs, causes "pleasure."

It is my hypothesis that this mechanism involves DHEA, the molecule of growth and development. That is, drugs of abuse act by stimulating a part of the brain which then stimulates DHEA for activation. As drugs are continued, the receptors for DHEA continue to develop but the production of DHEA cannot keep pace with it. Therefore, the available DHEA eventually cannot cause sufficient stimulation for the "pleasure" response.

I think all drugs of abuse, either stimulants or depressants, all act via this DHEA recruitment mechanism. Therefore, there will be cross-over in the effects of these drugs.

Harris and colleagues (Psychopharmacology (Berl). 2002 Aug;162(4):396-405. Epub 2002 Jun 27.) support your hypothesis for MDMA users. Wilkins and colleagues (Psychoneuroendocrinology. 2005 Jan;30(1):18-28.) found that increased endogenous DHEA during cocaine withdrawal predicted success in abstinence, suggesting that elevated DHEA gives the brain at least some of what it wants during withdrawal. However, Shoptaw and colleagues (Exp Clin Psychopharmacol. 2004 May;12(2):126-35.) found that 100 mg/day of DHEA only made things worse for cocaine addicts in recovery. Romieu and colleagues (J Neurosci. 2003 May 1;23(9):3572-6.) found that exogenous DHEA seems to enhance the rewarding aspect of cocaine in mice. Mendelson and colleagues (Psychoneuroendocrinology. 2002 Jan-Feb;27(1-2):71-82.) reported exactly what you predicted, that cocaine induces a rise in DHEA. HOWEVER...

This effect is not observed when opiates are used. In fact, when Obut and colleagues (Bull Exp Biol Med. 2003 Mar;135(3):231-3.) blocked the opioid signaling process, DHEA quit working as a reducer of steress. Here's what I think this means: DHEA is released in response to sympathetic stimulation such as occurs when MDMA, cocaine, and other "uppers" are ingested. DHEA feels so good because it increases endogenous opioid activity.

In fact, most addictions involve opioids at some level. Even rats allowed ad lib access to 10% sucrose solution will go into a state very similar to opiate withdrawal when opioid signaling is blocked (Pomonis and colleagues, Am J Physiol Regul Integr Comp Physiol. 2000 Mar;278(3):R712-9.). Alcoholics no longer find alcohol rewarding when their opioid signaling is blocked (e.g., Drobes et al, Alcohol Clin Exp Res. 2004 Sep;28(9):1362-70.). The same applies to users of benzodiazepines (Swift et al, Psychopharmacology (Berl). 1998 Feb;135(3):256-62.).

So..."uppers" increase DHEA levels, which in turn increase opioid levels, which reinforce the drug use. "Downers" do not predictably affect DHEA levels, but they still increase opioid levels, which reinforce drug use. Sucrose, which many non-scientists describe as addivtive, increases opioids, which reinforces consumption of more sucrose. Of course opiates are themselves directly reinforcing without DHEA involvement.

That's my take on it. I don't specialize in substance use disorder research, but the work I did in my doctoral program was funded by NIDA because there was so much overlap with substance dependence.

Don

So sugar is addicting?

physically addicting?

no it is not