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Animal models of drug relapse and craving
1. ANIMAL MODELS OF DRUG
RELAPSE AND CRAVING AFTER
VOLUNTARYABSTINENCE
Dr Mohit Kher
Senior Resident
Pharmacology, LHMC
2. OUTLINE
• Addiction
• Reward System
• Pathophysiology of addiction
• Different models of relapse
• Regions of brain involved in relapse
• Conclusion
3. ADDICTION
• Addiction is a treatable, chronic relapsing brain disease involving complex
interaction among brain circuits, genetics, environment and on individual’s life
experiences.
• People with addiction use substances or engage in behaviors that become
compulsive and often continue despite harmful consequences.
• Prevention efforts and treatment approaches for addiction are generally as
successful as those for other chronic diseases.
• American Society of Addiction Medicine (ASAM).
10. HOW MUCH RELAPSE ?
• Addiction outcome studies from NIDA:
40 to 60% will return to use the first year of treatment
60% of those will reuse multiple times in first year.
• CSAT funded study:
50% had sobriety periods of 1 year or longer
29% reused after 3 years
11. Extinction Based Relapse Models
MODELS Number of papers
DRUG PRIMING
Self administration
CPP
Runway
464
187
3
DISCRETE CUES
Self administration 372
DISCRIMINATIVE CUES
Self administration
Runway
58
2
CONTEXT
Self administration 60
STRESS
Self administration
CPP
169
55
12. ABSTINENCE BASED RELAPSE MODELS
MODELS NUMBER OF PAPERS
FORCED ABSTINENCE
A single test during abstinence
Incubation of drug craving
37
67
ADVERSE CONSENQUENCES IMPOSED
ANSTINENCE
Punishment model
Conflict model
9
5
VOLUNTARY ABSTINENCE
Incubation of drug craving 1
15. HOW CONFLICT MODEL IS DIFFERENT FROM
REINSTATEMENT MODEL
• Abstinence in humans often occurs because the drug’s rewarding effects are
outweighed by the aversive consequences of seeking or using them, whereas in
studies using the reinstatement model, abstinence is achieved through experimenter
imposed extinction procedures.
• Human drug-seeking episodes during abstinence often involve a conflict situation—a
choice between experiencing the positive effects of a drug and the aversive
consequences of pursuing it, whereas in the reinstatement model there are no adverse
consequences of drug seeking.
16. CONFLICT MODEL
• To mimic the aversive components of the drug seeking period, a conflict model of
relapse was developed.
• The basic concept of this model is similar to that of the ‘Columbia Obstruction Box’
method.
• In this model, a proportion of rats with an extensive history of exposure to drugs will
continue to engage in drug-taking behavior under adverse conditions that normally
would suppress drug or food-taking responding.
17. PUNISHMENT MODEL
• To have the greatest likelihood of construct validity, an animal model of relapse to drugs should ideally
involve a procedure in which animals become abstinent due to delayed aversive consequences of drug
taking.
• This approach has been to deliver a punishment immediately after drug-taking.
• In this model, lever pressing behavior for drug infusions is suppressed by electric shock delivered
immediately following drug delivery.
• Punishment model may be suitable for modeling human conditions in which abstinence is achieved
because the negative consequences of drug taking exceed the positive consequences.
• Punishment model still does not accurately mimic the human condition.
19. Incubation of methamphetamine craving
• Background
Cue-induced methamphetamine craving increases after prolonged forced (experimenter-
imposed) abstinence.
Here, we determined whether this incubation phenomenon would occur under conditions
that promote voluntary (self-imposed) abstinence.
We also determined the effect of the novel mGluR2 positive allosteric modulator,
AZD8529, on incubation of methamphetamine craving after forced or voluntary
abstinence.
20. • Methods
We trained rats to self-administer palatable food (6 sessions) and then to self-
administer methamphetamine under two conditions: 12 sessions (9-hr/day) or 50
sessions (3-hr/day).
We then assessed cue-induced methamphetamine seeking in extinctions test after 1
or 21 abstinence days.
Between tests, the rats underwent either forced abstinence (no access to the food- or
drug-paired levers) or voluntary abstinence for 19 days (achieved via a discrete
choice procedure between methamphetamine and palatable food; 20 trials per day).
We also determined the effect of subcutaneous injections of AZD8529 (20 and 40
mg/kg) on cue-induced methamphetamine seeking 1 or 21 days after forced or
voluntary abstinence.
21. • Results
Under both training and abstinence conditions, cue-induced
methamphetamine seeking in the extinction tests was higher after 21
abstinence days than after 1 day (incubation of methamphetamine
craving).
AZD8529 decreased cue-induced methamphetamine seeking on day 21
but not day 1 of forced or voluntary abstinence.
22. • Conclusions
We introduce a novel animal model to study the incubation of drug
craving and cue-induced drug seeking after prolonged voluntary
abstinence, mimicking the human condition of relapse after successful
contingency management treatment.
Our data suggest that PAMs of mGluR2 should be considered for relapse
prevention.
23.
24.
25.
26. Effect of AZD8529 on incubation of
methamphetamine craving
• Systemic injections of AZD8529 dose-dependently decreased cue-induced
methamphetamine seeking in the extinction tests on abstinence day 21 but not day
1; this effect occurred after either forced or voluntary abstinence.
• This analysis showed a significant interaction between Abstinence Day and
AZD8529 Dose, reflecting the selective effect of AZD8529 cue-induced
methamphetamine seeking during late but not early abstinence.
• Additional post-hoc analyses showed that the effect of AZD8529 on lever
responding on day 21 extinction test was significant at the 40 mg/kg but not the 20
mg/kg dose.
27.
28. Role of Dorsomedial Striatum Neuronal Ensembles in Incubation of
Methamphetamine Craving after Voluntary Abstinence
• There is a causal role of DMS D1 and D2 family receptors, and DMS neuronal ensembles in “incubated”
methamphetamine seeking.
• Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of
methamphetamine craving).
• The incubated response was associated with increased Fos expression in DMS but not in DLS.
• DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence
days.
• Results demonstrate a role of DMS dopamine D1 and D2 receptors in the incubation of methamphetamine craving
after voluntary abstinence and that DMS neuronal ensembles mediate this incubation.
29. The anterior insular Cortex→Central amygdala glutamatergic
pathway is critical to relapse after contingency management
• The brain mechanisms underlying relapse after cessation of contingency management
are largely unknown, and until recently, an animal model of this human condition did
not exist.
• Activation of monosynaptic glutamatergic projections from anterior insular cortex to
central amygdala is critical to relapse after cessation of contingency management.
• Anterior insular cortex-to-central amygdala projection is a new addiction- and
motivation-related projection and a potential target for relapse prevention.
31. REFERENCES
• Venniro M, Caprioli D, Shaham Y. Novel models of drug relapse and craving after voluntary
abstinence. Neuropsychopharmacology. 2019;44(1):234-235. doi:10.1038/s41386-018-0196-4
• Caprioli D, Venniro M, Zhang M, et al. Role of Dorsomedial Striatum Neuronal Ensembles in Incubation
of Methamphetamine Craving after Voluntary Abstinence. J Neurosci. 2017;37(4):1014-1027.
doi:10.1523/JNEUROSCI.3091-16.2016
• Venniro M, Caprioli D, Zhang M, et al. The Anterior Insular Cortex→Central Amygdala Glutamatergic
Pathway Is Critical to Relapse after Contingency Management. Neuron. 2017;96(2):414-427.e8.
doi:10.1016/j.neuron.2017.09.024
• Cooper A, Barnea-Ygael N, Levy D, Shaham Y, Zangen A. A conflict rat model of cue-induced relapse to
cocaine seeking. Psychopharmacology (Berl). 2007;194(1):117-125. doi:10.1007/s00213-007-0827-7
• Bossert JM, Marchant NJ, Calu DJ, Shaham Y. The reinstatement model of drug relapse: recent
neurobiological findings, emerging research topics, and translational research. Psychopharmacology
(Berl). 2013;229(3):453-476. doi:10.1007/s00213-013-3120-y
32. “ Your Brain has been hooked, hijacked and
hacked.”
THANK YOU
Editor's Notes
NIDA – national institute if drug abuse
CSAT- centre for substance abuse treatment
The conditions under which relapse is studied using the reinstatement model, however, differ from those under which relapse occurs in humans in two important ways.
The degree to which the lack of homology between the reinstatement model and the human condition challenges the validity of the model is subject to an ongoing debate in the addiction field
Both proponents and opponents of the reinstatement model, however, agree that it is important to develop alternative (or complementary) models for the experimental study of relapse to drugs.
We propose an alternative approach suggested by the possibility that, in humans, some aversive events related to drug use might be those that occur during drug seeking, for instance those associated with obtaining money to purchase an illegal drug, and fear of being caught by family members or the police.
It could also be argued that the anticipation of delayed negative consequences of drug relapse is itself an aversive event.
The basic concept of this model is similar to that of the ‘Columbia Obstruction Box’ method, which has been used many years ago to assess rats’ motivation to obtain rewards under different deprivation conditions in the presence of an ‘electric barrier’.
Our model was also inspired by results of more recent studies in which motivation to seek and take drugs was assessed in the presence of aversive stimuli.
The authors of these studies reported that a proportion of rats with an extensive history of exposure to drugs will continue to engage in drug-taking behavior under adverse conditions that normally would suppress drug- or food-taking responding.
However, such a procedure would require training so complex that the model would be, at best, impractical.
They found that in rats that had ceased opiate-taking behavior under these punishment conditions, opiate seeking was reinstated by a priming injection of heroin, which models the human condition of relapse induced by acute re-exposure to heroin during abstinence.
However, the punishment model still does not accurately mimic the human condition, since in humans the major aversive consequences of drug-taking behavior rarely coincide with acute drug intoxication.
We compared incubation of methamphetamine craving after forced or voluntary abstinence following a drug training procedure
Training
We first trained the rats (n=17) to self-administer palatable food pellets (6 days, 3 hr/day; 5 pellets per reward delivery) and then trained them to self-administer methamphetamine (0.1 mg/kg/infusion) for 3 hr/day for 50 days (5 training days per week).
Discrete choice tests
We determined food versus methamphetamine choice in both groups after every five consecutive methamphetamine self-administration sessions (9 choice tests) and during 19 days for the voluntary abstinence group. The day after each choice day during training, we gave the rats a rest day before the next weekly cycle of 5 methamphetamine self-administration training days, 1 choice day, and 1 rest day.
Relapse test
We tested the forced and voluntary abstinence groups for cue-induced methamphetamine seeking under extinction conditions (30 min test session) on abstinence days 1 and 21.
Food and methamphetamine training
The number of food rewards earned remained stable during the 6 food training sessions (p>0.05 for Session effect). The rats increased the number of methamphetamine rewards earned over during the first 10 training days (Fig. 2B), as indicated by a significant effect of Session [F(49,784)=18.1, p<0.01]. During the 9 discrete choice sessions, the rats showed a strong preference for the food (p<0.01, Fig. 2C).
Abstinence phase
During the 3-week abstinence period, the rats in the voluntary abstinence condition, showed a strong preference for food, resulting in either no or minimal methamphetamine intak
Relapse (extinction) tests
Cue-induced methamphetamine seeking in the extinction tests was higher after 21 abstinence days than after 1 day after both forced and voluntary abstinence (Fig. 2E). The statistical analysis of active lever presses included the between-subjects factor of Abstinence Condition, the within-subjects factor of Abstinence Day, and inactive lever-presses as a covariate. This analysis showed a significant main effect of Abstinence Day (F(1,13)=73.9, p<0.01) but not Abstinence Condition or an interaction between the two factors (p values>0.1).
Correlations and frequency distribution
We examined the correlation (Pearson r) between the total number of methamphetamine infusions earned during the training sessions and the total number of lever presses during the extinction tests on abstinence day 21. We found no correlations between these two measures (r=0.06, p>0.1) (Fig. 2G). In Fig. 2F we show the frequency distribution of extinction responding during testing on abstinence day 21 in reference to the mean of day 1 extinction responding.
We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence.
Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation.
We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d).
We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days.
We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests.
Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug rewards to maintain abstinence.
However, when contingency management is discontinued, most addicts relapse to drug use.
