Compulsive stress coping behaviors linked to brain's dopamine-dependent habit system

By Neha MathurReviewed by Danielle Ellis, B.Sc.Oct 2 2023

In a recent article published in Molecular Psychiatry, researchers performed longitudinal studies in rats to measure the sensitivity of early established versus compulsive polydipsic alcohol (or water) drinking in response to bilateral infusion of α-flupentixol, anterior dorsolateral striatum (aDLS)-dopamine (DA) receptor antagonist. Intra-aDLS infusions of α-flupentixol allowed diffusion of the infused drug or vehicle before each test session. 

Background

All humans have the natural ability to cope with stress through negative reinforcements; however, all use varying emotion regulation strategies. Some give in to shopping, some engage in comfort eating and physical activity, while others succumb to alcohol or drug use. 

Adjunctive behavior is a form of stress-coping displacement behavior prevalent across species; for example, schedule-induced polydipsia (SIP) manifests as polydipsic water intake.

In all species, including humans, non-regulatory polydipsic drinking takes ~1 week to develop and stabilize for prolonged periods; eventually, it decreases stress-related hormones elevated under the influence of intermittent food availability. 

However, given their high impulsivity, some individuals lose control and develop compulsive disorders, e.g., alcohol use disorders. Studies are yet to elucidate the psycho-neural mechanisms underpinning this individual vulnerability. 

Evidence suggests a change in the center of control from the ventral to the aDLS-dependent habit system that works in a DA-dependent manner gives rise to compulsive alcohol use. The mesolimbic DA system mediates the reinforcing properties of alcohol, leading to recreational alcohol use; however, involvement of the aDLS-DA system promotes transitioning to compulsive alcohol and adjunctive polydipsic water drinking behaviors.

About the study

In the present study, researchers used large cohorts of outbred male Sprague Dawley rats to assess the sensitivity of each rat's polydipsic drinking response to bilateral aDLS infusions of α-flupentixol. 

In other words, they tested the functional involvement of the DA-dependent aDLS habit system in compulsive and excessive alcohol or water drinking.

The team carried out four experiments. In Experiment 1, 36 rats underwent surgical bilateral cannulation of their aDLS, and a week later, they were food-restricted and trained in a SIP procedure (a fixed-time 60 s (FT-60 s) schedule) with water (SIPw). After five SIPw sessions, they assessed whether these rats acquired adjunctive water drinking.

In Experiment 2, the team food-restricted 48 rats for a week (to establish hyperdipsia) before they underwent 20 SIPw sessions. Next, these rats underwent surgical implantation of bilateral cannulae targeting their aDLS and were re-baselined under SIPw. Finally, the team assessed the sensitivity to bilateral infusion of α-flupentixol. They also measured to what extent early-established adjunctive alcohol drinking relied on aDLS.

In Experiments 3 and 4, the team tested the stability of water intake levels post-establishment of adjunctive water drinking behavior in rats and the anxiety-controlling properties of polydipsic drinking at the population level under the SIP influence, respectively. 

The time spent in an elevated plus maze (EPM) open arms before and immediately after a SPIw/SIPa training or 20 days of training (EPM 1/2/3) showed the rat's anxiety levels in Experiment 4.

High and low-drinker (HD and LD) rats had an average water consumption over the last three days of training in the upper and lower quartiles of the population, respectively. The researchers replaced water with 10% alcohol 24- hours after the last SIPw session and trained rats for 20 1-hour SIPa sessions, which helped them compute daily alcohol consumption rates (in mL).

Results

Rats developed an adaptive coping response under a SIP procedure; however, exposure to intermittent food delivery activated their hypothalamic-pituitary-adrenal (HPA) axis, increased anxiety, and led to the development of polydipsic water drinking, which remained stable over up to 42 days.

However, within two weeks, some rats progressively lost control over the polydipsic drinking response and developed hyperdipsia, a compulsive stress-coping behavior. In these HD rats, no changes in anxiety levels were seen following SIPw, suggesting compulsive coping behavior remained acutely anxiolytic and mitigated anxiety.

Alcohol coper LD rats learned to drink alcohol under the anxiogenic effects of intermittent food delivery. Moreover, they increased their daily intake of alcohol more rapidly than any other group and eventually developed compulsive coping behavior. It remains unclear why some rats only developed a coping response with alcohol but not water. The anxiolytic properties of alcohol likely facilitated the acquisition of this specific adjunctive response.

Whether drinking water or alcohol, the acquisition of coping response was insensitive to aDLS-DA receptor blockade. Conversely, after prolonged experience, adjunctive drinking became dependent on aDLS dopamine when it was compulsive in vulnerable individuals. 

Conclusions

The study results provide remarkable evidence of the role of negative reinforcement-based habits in the development of compulsive coping behaviors. This data could inform the development of treatments for addiction and other compulsive behaviors.