Cigarette smoking is a debilitating habit; quitters frequently relapse back into smoking, and long-term abstinence often requires pharmacological intervention and/or behavioral therapy. Often, relapses are caused by acute exposure to nicotine or nicotine-associated memories. A new study in rats and humans showed that pharmacological intervention at the stage of smoking-associated memory retrieval (and reconsolidation) can help decrease nicotine craving.
Nicotine addiction is tough to part with. Although most users are aware of the health risks associated with smoking, and express desire to quit, a vast majority of them relapse within a week of trying. Previous research provides us with an explanation for this: nicotine activates reward centers in the brain, resulting in feelings of pleasure. Trying to quit, understandably, results in undesirable outcomes such as irritability, depression, anxiety and attention deficit, among others. Often, the many memories associated with smoking, such as procuring, handling, lighting a cigarette etc. result in the urge to smoke and a subsequent relapse. Researchers call these cues conditioned stimuli. The act of active smoking, on the other hand, is called unconditioned stimuli. After a period of abstinence, exposure to both conditioned and unconditioned stimuli can activate the urge to smoke.
Interestingly, nicotine-associated memories, when reactivated, may undergo the process of reconsolidation, during which time memories become unstable for several hours. Administration of a beta-adrenergic blocker called propranolol during this ‘reconsolidation window’ impairs the process in rats and humans. The end result is decreased craving for a smoke.
Not surprisingly, a lot of studies have tried to make use of this observation; but with limited success. Turns out, an underlying feature of these studies was to expose the participants to nicotine-associated memories, and not nicotine itself. Propranolol under these circumstances interferes and abolishes the association of reward to the specific nicotine-associated cue/memory used in the study and not to nicotine in general. On future exposure to a different cue, the urge to smoke returns, resulting in a relapse.
Promisingly, a new study in JAMA Psychiatry shows that propranolol treatment after acute exposure to nicotine itself (instead of conditioned stimuli such as a memory/cue) resulted in better interference; and significantly decreased the general urge to smoke, in both rats and humans.
The researchers used 156 male rats for the study, and first trained them for what is called a conditioned place preference (CPP). It involves putting individual rats in a three-compartment chamber, with gates that can be opened for animals to freely pass between the compartments. The rat is given a nicotine injection and placed in one of the outer compartments. The following day, the same rat is administered a non-habit forming saline injection and placed in the opposite compartment. Done on a regular basis, and alternating between nicotine and saline, the rat learns to associate a particular chamber to nicotine. On test sessions, if the rat has truly become addicted to nicotine, he spends more time in the nicotine-memory-associated chamber. An ingenious way to determine addiction!
Using this approach, the researchers first addicted rats to nicotine. They subsequently tested whether injection of propranolol after nicotine administration could impair the reconsolidation process, and decrease future nicotine cravings. And the results showed just that. Pharmacological intervention indeed decreased nicotine addiction in these rats, but only when propranolol was administered following nicotine exposure. When the drug was administered to rats following reactivation of specific cue-induced nicotine memories, it decreased addiction only in the specific case of that cue, and not nicotine in general.
The authors then tested whether the observations could be generalized to humans, in a double-blind experimental study involving 69 patients. These were healthy young men between the ages of 18-45, and who have been smoking 10 or more cigarettes a day continuously for the past 12 months. They were asked to abstain from smoking for 8 hours before the experimental sessions, and this short-term abstinence was tested by examining their carbon monoxide levels before the sessions. They were then allowed to smoke two puffs of a cigarette, and given propranolol either 1 hour before, or 6 hours after the smoking session. One day later, researchers took a subjective rating of their craving for cigarettes. In these human chain smokers, pro- administration of propranolol decreased nicotine preference and craving, while a delayed administration, did not have any effect.
Although the results of the study show much promise, researchers point out some caveats. For one, the human study was limited to the subjective measurement of ‘craving’ in a short-term abstinence period in a laboratory setting, which might not be representative of real world situations. The research also needs to be repeated in a much larger clinical study, before drawing strong conclusions. Finally, the study employed only males, and therefore does not tell us whether the observations could be extrapolated to females.
Written By: Debapriya Dutta, PhD