MSGID: 1:317/3 627201cc   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    How alcohol cravings get stronger after drinking during withdrawal   
      
      
     Date:   
         May 3, 2022   
     Source:   
         Scripps Research Institute   
     Summary:   
         A new finding in an animal study could eventually lead to improved   
         treatments to minimize cravings in people with alcohol use disorder.   
      
      
      
   FULL STORY   
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   For some people with alcohol use disorder, it might be the sight of a   
   familiar bar or a favorite bottle; for others, it might be the feeling   
   of leaving the office after a stressful day at work or stepping into a   
   crowded party. Most people who struggle with drug or alcohol addiction   
   have particular cues that set off their cravings.   
      
      
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   Now, scientists at Scripps Research have discovered how, in rats dependent   
   on alcohol, environmental cues that become associated with drinking   
   during withdrawal are much more powerful than those learned during the   
   early phases of alcohol use, leading to more irresistible cravings. The   
   new findings, published online in the British Journal of Pharmacology,   
   could eventually lead to new treatments to minimize cravings in people   
   with addictions.   
      
   "We already knew that the craving produced by environmental stimuli   
   typically intensifies over time in severe alcohol use disorder,"   
   says Friedbert Weiss, PhD, a professor at Scripps Research, "but no   
   one had teased apart, at both a behavioral and neurobiological level,   
   why that is until now."  An estimated 14.5 million people in the United   
   States have alcohol use disorder, which encompasses a range of unhealthy   
   drinking behaviors. Like other drug addictions, alcohol addiction is   
   characterized by cycles of withdrawal, abstinence and relapse. Cravings   
   set off by environmental stimuli -- like those present when driving past   
   a local bar -- are powerful drivers for relapse.   
      
   Similarly, rats that have learned to associate a particular smell with   
   alcohol will seek out alcohol when exposed to the smell.   
      
   In the new work, Weiss and his colleagues sought to understand whether   
   the experience of repeatedly drinking alcohol during withdrawal --   
   rather than just the length of time or severity of the addiction --   
   helps strengthen the learned associations that lead to cravings. They   
   conditioned rats that were not dependent on alcohol to associate an   
   anise or orange scent with alcohol. Then, a subset of those animals   
   went through cycles of withdrawal, during which they were conditioned   
   to associate a different scent with alcohol consumption.   
      
   "This allowed us to separate, for the first time, the learning that   
   happens during the original, non-dependent state, and the learning that   
   happens during withdrawal," says Weiss.   
      
      
      
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   When all the animals were then tested to see what lengths they would   
   go to for alcohol in the presence of a conditioned scent, Weiss' group   
   discovered that cues learned during withdrawal were far stronger at   
   eliciting a reaction. In other words, the experience of learning how   
   alcohol relieves negative withdrawal symptoms led to even stronger   
   cravings than the original experience of learning alcohol's feel-good   
   effects.   
      
   "It is commonly thought that people drink because it makes them feel   
   good. But in people who have developed dependence, the 'feel-good'   
   sensation that the drug produces is actually a reversal of feeling   
   terrible," says Weiss. "When this reversal of feeling terrible is   
   experienced repeatedly, then environmental cues that become associated   
   with this experience produce a much more powerful craving than the   
   initial 'feel-good' craving."  Rats that had learned to associate a   
   scent with alcohol during withdrawal were much more persistent in the   
   presence of that scent; during a 30-minute time period, they pressed a   
   lever attempting to obtain alcohol twice as many times as animals that   
   had only been conditioned during early alcohol drinking while not yet   
   dependent. This persistence remained even when they received a small   
   electric shock upon pressing the lever, or when the task of lever pressing   
   was made increasingly more difficult.   
      
   "If an alcoholic comes home from work and there's nothing in the   
   refrigerator, what lengths will they go to for alcohol? Will they run   
   next door to the liquor store? What if it's snowing outside and the store   
   is a five-mile walk away?  What we're seeing is that in rats, they'll   
   work much harder to overcome obstacles and are willing to endure adverse   
   consequences if they've been conditioned with cues during withdrawal,"   
   says Weiss.   
      
   Moreover, the team found that the new conditioning actually weakened older   
   cues that had been learned before the animal became alcohol dependent. If   
   an animal originally associated alcohol with an anise scent, but was   
   later made dependent and conditioned to associate alcohol with an orange   
   scent while drinking during withdrawal, the anise scent was no longer as   
   strong a cue for setting off alcohol-seeking behaviors compared to the   
   second scent that was associated with alcohol drinking during withdrawal.   
      
      
      
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   The researchers then studied the amygdala, the part of the brain   
   associated with drug and alcohol addiction in humans and rats, to see   
   how it changed during each conditioning experiment. Different areas,   
   they discovered, were activated depending on whether rats were learning   
   a scent during initial alcohol exposure while not dependent, or during   
   withdrawal after having been made dependent.   
      
   "Identifying how learned associations between drug and environment are   
   instantiated in the brain was the really exciting part of this paper for   
   me," says one of the authors, Hermina Nedelescu, PhD, a Scripps Research   
   staff scientist. "Once we can narrow in on which circuits in the brain   
   are responsible for this withdrawal-associated learning, we can start   
   thinking about how to target them with therapeutics."  The group is   
   now planning future experiments to more specifically identify the exact   
   groups of neurons involved.   
      
   In addition to Weiss and Nedelescu, authors of the study, "Compulsive   
   Alcohol Seeking and Relapse: Central Role of Conditioning Factors   
   Associated with Alleviation of Withdrawal States by Alcohol," include   
   Olga Kozanian and Peter Kufahl of Scripps Research; and Mark Mayford of   
   UC San Diego.   
      
   This work was supported by funding from the National Institute of Alcohol   
   Abuse and Alcoholism (AA023183, AA027555 and T32AA007456).   
      
      
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   Story Source: Materials provided by Scripps_Research_Institute. Note:   
   Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Olga O. Kozanian, Hermina Nedelescu, Peter R. Kufahl, Mark Mayford,   
         Friedbert Weiss. Compulsive alcohol seeking and relapse: Central   
         role of conditioning factors associated with alleviation of   
         withdrawal states by alcohol. British Journal of Pharmacology,   
         2022; DOI: 10.1111/bph.15854   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220503190218.htm   
      
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