Methamphetamine self-administration reduces alcohol consumption and preference in alcohol-preferring P rats

Abstract

Subclinical levels of polysubstance use are a prevalent and understudied phenomenon. Alcohol is a substance commonly co-used with other substances of other drug classes. These studies sought to determine the consumption effects of combining alcohol drinking and methamphetamine (MA) self-administration. Male alcohol-preferring P rats had continuous access to a two-bottle alcohol drinking procedure in the home cage. Control rats remained alcohol naïve. Rats were also surgically implanted with intra-jugular catheters and trained to self-administer saline (control) or MA in daily 2-hour sessions. We first measured the acquisition and maintenance of MA intake in alcohol-consuming or control rats. MA intake was initially enhanced by alcohol consumption on a fixed ratio 1 schedule of reinforcement, but this effect did not prevail as the difficulty of the schedule (FR5 and progressive ratio) was increased. We next measured both alcohol consumption and preference before, during and after MA (or saline) self-administration. MA self-administration significantly reduced alcohol intake and preference ratios, a robust effect that persisted across several experimental variations. Interestingly, alcohol consumption rebounded following the cessation of MA self-administration. The effects of MA self-administration were specific to alcohol intake because it did not alter total fluid consumption or consumption of sucrose. MA self-administration did not impact blood-alcohol concentrations or alcohol-induced loss of righting reflex suggesting no effect of MA intake on the alcohol metabolism or sensitivity. Together, the results suggest that MA intake disrupts alcohol consumption and preferences but not the reverse in alcohol-preferring P rats.

Keywords: ethanol; polydrug use; psychostimulant.

Figure 1

Alcohol consumption enhances methamphetamine (MA) self‐administration on a fixed ratio 1 (FR1) schedule of reinforcement. (a) Timeline illustrating the schedule of combining the 24‐hour two‐bottle choice procedure, daily 2‐hour self‐administration sessions and extinction sessions. (b) Average number of MA infusions (± SEM; 0.1 mg/kg/100 µl infusion) for each session of self‐administration under a FR1 and fixed ratio 5 (FR5) schedule of reinforcement. Alcohol consuming animals (n = 31) had significantly greater number of infusions during a FR1 schedule of reinforcement compared with water consuming animals (n = 16). However, this effect was not evident when MA self‐administration was conducted with an FR5 schedule of reinforcement. (c) Average number of drug‐paired and inactive lever responses (± SEM) for each session of self‐administration under a FR1 and FR5 schedule of reinforcement. Active, drug‐paired lever responses were greater than inactive lever responses, but no group effects were observed between the water and alcohol consumption groups. (d) Average number of MA infusions and total drug‐paired lever responses on the progressive ratio (PR) schedule of reinforcement. No significant group effects were observed over the three sessions of PR schedule testing. (e) There were no differences in the average number of active and inactive lever presses during extinction between alcohol and water consuming animals. *Significant from water‐drinking control (p < 0.05)

Figure 2

Concurrent methamphetamine (MA) self‐administration decreases alcohol preference and consumption but not total consumption. (a) Average daily alcohol preference during pre‐MA baseline, MA co‐use and post‐MA extinction phases are shown for the 10 percent ethanol group in Experiment 1. Average preference during the MA co‐use phase (40.8 ± 2.2 percent; indicated by rose shading) was significantly reduced compared with both pre‐MA baseline (60.5 ± 3.7 percent) and post‐MA extinction (70.1 ± 5.3 percent). (b) Average daily alcohol intake during pre‐MA baseline, MA co‐use and post‐MA extinction phases are shown for the 10 percent ethanol group in Experiment 1. Average intake during the MA co‐use phase (2.36 ± 0.1 g/kg/day; indicated by rose shading) was significantly reduced compared with both pre‐MA baseline (3.94 ± 0.3 g/kg/day) and post‐MA extinction (4.00 ± 0.3 g/kg/day). (c) Total fluid consumption during the three phases was not altered. * Significant from pre‐MA baseline and post‐MA extinction (p < 0.001)

Figure 3

Methamphetamine (MA) self‐administration reduces 10 and 20 percent alcohol consumption and preference. (a) Timeline illustrating the schedule of combining the two‐bottle choice procedure with daily 2‐hour self‐administration sessions and extinction sessions. The preference for (b) 10 percent and (d) 20 percent alcohol was significantly reduced during MA self‐administration (rose shading). Similarly, intake of (c) 10 percent and (e) 20 percent alcohol was also significantly reduced during MA self‐administration (rose shading). The red symbols indicate significance between MA and saline self‐administration groups on that day (p < 0.05); n = 9–21/group

Figure 4

Methamphetamine (MA) self‐administration reduces alcohol consumption and preference after prolonged alcohol consumption. (a) Timeline illustrating schedule of combining the 24‐hour two‐bottle choice procedure and daily 2‐hour self‐administration sessions and extinction sessions. (b) Preference and (c) intake of alcohol after prolonged alcohol consumption were both significantly reduced during MA self‐administration (rose shading). The red symbols indicate significance between MA and saline self‐administration groups on that day (p < 0.05); n = 10–14/group

Figure 5

Initiating methamphetamine self‐administration prior to concurrent alcohol consumption procedures reduces initial alcohol consumption and preference. (a) Timeline illustrating the schedule of combining the 24‐hour two‐bottle choice procedure and daily 2‐hour self‐administration sessions and extinction sessions. (b) Average number of MA infusions (± SEM; 0.1 mg/kg/100 µl infusion) during each 2‐hour session over the 5 days prior to alcohol consumption and the 10 days concurrent with alcohol consumption (rose shading). (c) Average number of drug‐paired lever presses for each 2‐hour session during the three‐day extinction procedure. Prior self‐administration of methamphetamine reduces (d) preference and (e) intake of 10 percent alcohol during the beginning of the co‐use phase (rose shading) but not during the later days of the co‐use phase. The red symbols indicate significance between MA and saline self‐administration groups on that day (p < 0.05); n = 9–11/group

Figure 6

Temporally dissociating prior methamphetamine (MA) self‐administration from two‐bottle alcohol procedure has no lasting impact on subsequent alcohol consumption or preference. (a) Timeline illustrating the schedule of combining the 24‐hour two‐bottle choice procedure and daily 2‐hour self‐administration sessions. (a) Prior MA self‐administration did not significantly alter alcohol (b) preference or (c) intake when MA and alcohol were not administered concurrently; n = 10–11/group

Figure 7

Methamphetamine (MA) self‐administration does not alter blood alcohol concentrations or alcohol intoxication. Blood was collected 30 minutes following oral administration of 1.0 g/kg alcohol in animals that self‐administered MA (n = 7) or saline (n = 7) for 14 days in daily 2‐hour self‐administration sessions. (a) No significant differences were detected between the two self‐administration groups. Similarly, the loss and regain of the righting reflex was measured following administration 3.0 mg/kg alcohol (i.p.) in animals that self‐administered MA (n = 7) or saline (n = 5) for 14 days in daily 2‐hour self‐administration sessions. (b) No significant differences in either measure were observed between the self‐administration groups

Figure 8

Methamphetamine (MA) self‐administration has no effect on sucrose consumption or preference. (a) Timeline illustrating the schedule of combining the 24‐hour two‐bottle choice procedure and daily 2‐hour self‐administration sessions. MA self‐administration did not alter sucrose preference (b) or intake (c). (d) Total fluid consumption during the three phases was not altered. The rose colored area indicates concurrent MA self‐administration and two‐bottle sucrose procedures; n = 10/group