Effects of 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine on alcohol consumption in Long-Evans rats

Abstract

The objectives of this study were to determine alcohol consumption after administration of (R)(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) or naltrexone in Long-Evans rats, and to assess the effectiveness of these treatments based on individual differences in alcohol consumption. Adult male Long-Evans rats (N = 16) were given opportunities to orally self-administer a 20% (v/v) ethanol (EtOH) solution using an intermittent access, two-bottle (vs. tap water) choice procedure in their home cages. EtOH consumption and preference, total fluid consumption and food intake were measured. Last, we assessed the effects of naltrexone (1 mg/kg; subcutaneous) and (R)(-)-DOI (0.1-1 mg/kg; subcutaneous) on EtOH intake and preference using a quartile analysis. Rats showed stable EtOH (20%) intake and preference after 15 EtOH access sessions. Naltrexone produced a transient decrease in EtOH intake, but an inconsistent effect on EtOH preference, whereas DOI dose-dependently reduced EtOH intake and preference for at least 24 h. Subsequent quartile analyses revealed that rats with the highest EtOH intake during the first 60 min of access to EtOH showed greater reductions in EtOH intake and preference after DOI treatment. This is the first report to show that DOI-elicited reductions in EtOH intake and preference in rats depend on baseline EtOH intake, perhaps supporting a 'baseline dependency' hypothesis of effectiveness with phenethylamine psychedelics on EtOH consumption. If so, individuals with greater potential to develop severe AUDs may be particularly responsive to the positive motivational changes produced by treatment with psychedelics that target the 5-HT2 receptor family.

Fig. 1

Intermittent access to 20% ethanol (EtOH) in Long-Evans rats lead to an escalation in (A) EtOH intake (g/kg/24 hrs), reaching a stable, average EtOH intake of 5.19 g/kg/24 hrs, and (B) EtOH preference, reaching a stable, average EtOH preference of 47.89%. There was a statistically significant decrease in water intake (open symbols) across EtOH access sessions, while EtOH intake (filled symbols) increased over time (C). Aside from a few instances in which total fluid intake differed between water days (open symbols) compared to EtOH days (filled symbols), there was no consistent difference in total fluid intake across two-bottle choice sessions (D). The values are expressed as mean EtOH intake (g/kg/24 hrs), preference (ratio of EtOH over total fluid intake), fluid intake (ml/kg/24 hrs), or total fluid intake (ml/kg/24 hrs) ± SE at each access session. Error bars are contained within the point for some data. *p < 0.05 compared to EtOH intake (C) or between the type of fluid at a specified two-bottle choice session (D) according to Holm-Šídák multiple comparisons tests. n = 14-16; on water days 1 and 2, the water bottles spilled water in 1-2 of the animals’ home cages, so their data on these days are omitted from D. Numbers near symbols indicate the sample size.

Fig. 2

Naltrexone (1 mg/kg; sc) generally decreases EtOH intake during 0-60 min of EtOH access (A), but shows differential effects that varied by EtOH concentration during the 61-240 min (B), and 24 hr cumulative (C) measurement periods using an intermittent-access to EtOH (5-40%; v/v) drinking procedure in Long-Evans rats. Naltrexone administration also interacted with EtOH concentration to alter EtOH preference during the 0-60 min (D), 61-240 min (E), and 24 hrs (not cumulative) (F) measurement periods. The values are expressed as mean EtOH intake (g/kg) or (g/kg/hr), or preference (ratio of EtOH over total fluid intake). * p < 0.05 naltrexone (filled symbols) compared to saline (open symbols) at each EtOH concentration according to Holm-Šídák multiple comparisons tests. n = 11-16; some subjects did not consume EtOH or water during an EtOH access measurement period, precluding computation of an EtOH preference. Numbers near symbols indicate the sample size.

Fig. 3

2,5-Dimethoxy-4-iodoamphetamine (DOI; 0.1-1 mg/kg; sc) decreases 20% EtOH intake during the 0-60 min (A) and 24 hr cumulative (C) measurement periods, but not the 61-240 min measurement period (B). DOI administration reduces EtOH preference during both the 0-60 min (D) and 24 hr period (F), and the largest dose of DOI reduces EtOH preference for at least 24 hrs after ethanol access (F). DOI did not affect EtOH preference during the 61-240 min period (E). S = saline (open circles), NTX = 1 mg/kg naltrexone (filled circles), and DOI is indicated by dose (filled diamonds). * p < 0.05 compared to saline, # p < 0.05 compared to 0.1 mg/kg DOI, & p < 0.05 compared to 1 mg/kg DOI according to Tukey’s multiple comparisons tests. n = 12-16; some subjects did not consume either fluid, precluding computation of an EtOH preference. In addition, one animal died within 24 hrs after 1.0 mg/kg DOI, so its data are omitted from all plots and analyses.

Fig. 4

DOI administration produced a persistent decrease in food intake across measurement periods (A, B, C) with effects lasting for at least 24 hrs. DOI administration did not reduce total fluid intake during the 0-60 min period (D), increased total fluid intake during the 61-240 min period (E), and 0.32 mg/kg DOI reduced total fluid intake at the 24 hr cumulative measurement period (F).; abbreviations and indications of statistical significance as in Figure 3.