Chronic methylphenidate treatment during early life is associated with greater ethanol intake in socially isolated rats

Abstract

Background: Methylphenidate (MPH) is a stimulant prescribed to treat attention-deficit/ hyperactivity disorder. Its primary mechanism of action is in the dopamine system, alterations of which are associated with vulnerability to alcohol abuse. There are concerns that juvenile MPH treatment may influence adult drinking behavior. This study examined the interaction of MPH treatment and environmental rearing conditions, which are known to independently influence ethanol (EtOH) drinking behavior, on anxiety-like behavior and vulnerability to alcohol abuse in a juvenile rodent model.

Methods: Male Sprague-Dawley rats were housed in enriched, standard, or isolated conditions for 4 weeks, starting at postnatal day 21. Rats were concurrently treated with 8 mg/kg/d MPH or saline, delivered via osmotic minipump. Anxiety-like behavior was determined at the end of the treatment session, and 5 weeks later. After MPH treatment, rats were exposed to a 2-bottle choice EtOH drinking procedure that lasted 3 weeks.

Results: Early life chronic MPH treatment was associated with greater EtOH intake and greater EtOH preference, but only in socially isolated animals. Isolated animals had greater levels of anxiety-like behavior than standard-housed or enriched animals after 4 weeks of exposure to the housing conditions, a difference that persisted even after all animals had been individually housed for an additional 5 weeks and exposed to EtOH.

Conclusions: These results suggest that early life MPH treatment may increase vulnerability to EtOH drinking in adulthood in a subset of the population. Additionally, this study highlights the importance of early rearing condition for establishing long-lasting behavioral phenotypes. Environmental histories should be considered when prescribing MPH treatment to young children.

Keywords: Ethanol Drinking; Methylphenidate; Rearing Environment; Social Isolation.

Figure 1. Post-natal days and study timeline

Figure 2. Daily g/kg EtOH intakes

MPH- and saline-treated animals within the enriched (A) and pair-housed (B) groups did not differ in their daily intakes of an EtOH/sucrose solution over a three-week drinking period. MPH-treated isolated animals had significantly greater average EtOH/sucrose intakes than saline-treated isolated animals (C).

Figure 3. Ethanol Preference in Isolated Animals

MPH-treated isolated animals had significantly greater EtOH preference over water than saline-treated isolated animals.

Figure 4. Elevated Plus Maze Behavior

In the Pre-EtOH run, there was a main effect of housing condition, but no effect of MPH and no interaction between MPH and housing on open arm time (A), and there were no effects of housing, MPH and no interactions on closed arm entries (B). In the Post-EtOH run, there was still a main effect of housing condition, as well as an effect of MPH, but no interaction (C). Again, there were no effects of housing, MPH, and no interactions on closed arm entries (D).

Figure 5. Blood Ethanol Concentrations

BECs taken on two separate drinking days correlated with g/kg EtOH intake on that day. Animals were consuming measurable quantities of EtOH.

Figure 6. Sucrose drinking

There was a main effect of day, a main effect of housing condition and a main effect of MPH treatment on sucrose intake over a three-day sucrose preference test (A–C). Enriched animals drank significantly more sucrose than isolated animals. MPH-treated animals consumed more sucrose than saline-treated animals. Animals drank significantly greater amounts of sucrose on Day 3 than on Day 1. There was no interaction between housing and MPH treatment. * p < 0.05.