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The Development and Maintenance of Drug Addiction - BLOG NOW

Dr Koob states "the allostasis-like changes in the reward system that I consider compulsive-like are generally evident only in animal models with the extended-access paradigms associated with escalation in drug intake". The LgA model has gained dominance in the field as one of the best animal models of addiction. Granted, we cannot make rats stand in bus shelters smoking crack. But this should not deter us from asking how well the LgA model reflects reality. With this model, animals are exposed daily to continuously high brain levels of drug for weeks, sometimes months on end. As Dr Koob argues, 'allostasis-like changes in the reward system' preferentially occur in these rats. But is this how addicts take drugs? For several reasons easy to imagine, it is rather unlikely that addicts maintain high brain levels of drug on a nearly continuous basis. Some clinical researchers who have taken the time to study the temporal patterns of drug use, in particular for cocaine, find that cocaine addicts use intermittently—and do so willingly. As argued and illustrated by Dave Roberts' group, it might be time to pay attention to this, and revisit the LgA model to see if it truly captures how addicts expose their brains to drug. Because if this is not how addicts do it, then it is not how our rats should do it either.
Anne-Noël Samaha
Posted: Aug 29, 2014 9:03 AM
Perhaps the antagonists are describing two sides of the one coin. Is the alleviation of withdrawal rewarding? Does the "dark side" make reward de-escalate more rapidly? We see people totally detoxed but then relapse upon return to their usual haunts at the first cue. Is this driven by Koob's prolonged motivational withdrawal or is it an example of Wise's reinforced compulsive use. Or both.
Simon Holliday
Posted: Aug 03, 2014 7:57 AM
Thank you for taking the time to write. We are happy to take suggestions for future articles. I personally encourage ACNP members to take a more active role in their journal by taking the time to share their ideas of what types of articles they would like to see. Hopefully this is the first of many Circumspectives pieces that stimulate collegial discussion on matters of great importance to the college.
Bill Carlezon
Posted: Jan 25, 2014 9:51 AM
ACNP used to be, and should continue to be, the setting for translational research on psychiatric and addictive disorders. I am currently mentoring two neuroscience graduate students who are working in our clinical research laboratories in studies of recovery and relapse in alcohol dependent and opioid dependent patients in 90-120 day supervised extended care. While the patients do not have the types of addiction "careers" of Don Klein's Lexington patients, both students have commented how much more complex the issues of addiction recovery and risk of relapse are in patients compared with the rodent models with which they have become familiar. What is missing from your "debate" is the complexity that one finds in clinical research-and the failure of either "reward" or "the dark side" to fully account for risk of addiction or risk of relapse in real patients. As opposed to other areas of research in psychiatry, the addiction field does have robust animal models that enable researchers to examine addiction related phenomena in the brain-and at the level of epigenetic changes in relevant brain regions. What is missing from your debate is the opportunity to bring this back to the human condition and the clinical research laboratory. The animal models have not been especially robust in predicting the possible efficacy of medications in the treatment of various addictive disorders (see various putative predictors of medications to treat cocaine dependence that "worked" in animal models and failed in patients.) The stories of "drug reward" and "the dark side" as explanations of addiction are not new stories-nor even a debate. Both issues are important, but insufficient explanations of risk of addiction and risk of relapse. The addictions field should be leading the way to new frontiers of translational research-and ACNP and its journal should be the venue. Sadly, your "debate" lacks the insights or experience of many talented clinical investigators. And ACNP is increasingly losing its relevance to those with that kind of interest and experience. In a symbolic way, the absence of the clinical investigator from this "debate" is symptomatic of ACNP's descent into a mini (and less relevant) Society for Neuroscience. How unfortunate that the College and its Journal have voluntarily given up our roots in clinical research, especially when the rest of medicine is emphasizing the importance of translational research (a term that explicitly includes clinical investigation).
Roger Meyer
Posted: Jan 24, 2014 4:32 PM
My experience with human heroin addiction stems from 1953 to 1955. Having one whole year as a psychiatric resident at Creedmoor State Hospital, I transferred to the USPHS Narcotic Hospital at Lexington Kentucky. I was placed in charge of the admission service, the 70 bed withdrawal service, the 200 bed women's service and the women's sick call. I also did psychiatric evaluations upon all admissions which averaged about 10 to 15 a week. My ideas about heroin addiction stemmed from psychoanalytic readings. My expectations were that these were orally regressed depressed patients who on deprivation of their essential narcissistic supplies provided by heroin would plunge into psychotic depression. Fortunately there were very skilled nurses at the hospital who suggested that I had a lot to learn-- on the other hand there were a very skilled psychoanalytic staff that did not contribute anything useful. The methadone withdrawal was carried out very skillfully in liquid form. 30 to 50 mg methadone daily, as a start, supplemented by 200 mg of pentobarbital at night --the entire weaning process was usually completed within a week. The patients were examined daily both physically and mentally with particular attention to the Himmelbach's signs as indicators of uncompensated withdrawal. During withdrawal the patients largely stayed in bed. On rounds they had a litany of physical complaints but nothing very major. When withdrawal was complete they were transferred to the Lexington Hospital,which was a medium security federal penitentiary, which consisted of 1000 beds, about 800 males and 200 females. The volunteer patients, about 15%, signed up for a 45 day withdrawal, but could leave at any time which was usually about 7 to 10 days. They often referred to their stay at Lexington as cheapening the habit. The rest of the inmates were federal prisoners almost all of them convicted of mail theft. They had prison sentences usually about five years long. The big surprise was the status of the patients after withdrawal. There was little or no signs of depression although there was plenty of complaint about being stuck in prison. The women who I knew best had a fair degree of emotional lability that ranged between sulky complaints about pelvic inflammatory disease to good-natured fooling around laughing and telling jokes. Patients communicated with each other by means of a covert kite line that security knew all about. These letters were regularly monitored for signs of severe depression or talk about suicide. In that case they were brought to me for review and then the patient was interviewed. In each case their tone was of exasperation and the hope that they would be given special privileges. In the two years that I was there , there were no suicides. You understand this was well before the use of antidepressants. Naturally we were very interested in the onset of addiction. The women were almost entirely prostitutes which actually anteceded their addiction. Prior to the prostitution career they had been sexually very active and popular with high self-esteem. The story that I heard repeatedly was that some friend would point out to them that they were sitting on a gold mine. What they were giving away for free could really bring them close to the big money. Otherwise the potential economic career was dismal. However, the career of a freelance prostitute is difficult because of their need for protection, which then put them on the string of a pimp. On the whole their relationship with the pimps was mutually gratifying as he provided customers, made sure that they were not robbed, split the intake with them, rarely roughed them up and most surprising held out the promise of a one-on-one relationship where they could live in reasonable retirement and sexual gratification.. These women were very hardheaded and cynical , yet on this particular point they were utterly unwilling to be critical. The entry into addiction occurred sometime after the entry into prostitution and was often supported by the pimp and their colleagues. This was often the happiest time and was referred to as the honeymoon. They thoroughly enjoyed heroin and rarely experienced any distressing withdrawal effects. Prior to discharge there were frequent fantasies of returning to addiction and not being straight. However some few said they were fed up and afraid of jail. They often said they had stayed clean for some time but somehow or other had bumped into the possibility and could not withstand temptation. Abe Wikler MD believed that they were suffering from a subclinical conditioned withdrawal that drove them back to addiction. This was not obvious since during this period they did not report excess lacrimation or rhinorrhea or preoccupation. With regard to not becoming an addict despite using heroin , it was reported that many could “chip” shooting up on weekends and able to avoid the addict’s life. I don’t know what the data is here-if any. It was clear that the introduction to an addict’s life was not simply the pleasures of heroin but part of a major role shift anteceding heroin. I don’t know if conduct disorder was a still earlier stage. Contempt for being straight was general. That they stayed addicts for fear of withdrawal did not seem the case, at least then. There was no trouble volunteering for Lexington or Fort Worth and undergoing methadone withdrawal which most said was no worse than a mild flu. Rodent heroin dependency seems a limited model of the human process.
Dr. Donald F. Klein, D.Sc.,M.D.
Posted: Jan 22, 2014 10:05 PM
I congratulate the journal for developing this innovative Circumspectives format. It is helpful that two giants of addiction research share their perspective on the disorder, place their work into the broader context of this perspective, and identify areas where their thinking diverges. It seems to me that the central disagreement between the authors on the contribution of positive or negative reinforcement as the driving force in addiction can only be resolved from observations in human addicts rather than modeling in rodents. Most notably, as our understanding of the genetics of addiction increases, it will be interesting to see which process - positive or negative reinforcement - is most impacted by genetic variation than contributes to addiction vulnerability.
Paul Kenny
Posted: Jan 18, 2014 12:45 PM