Prior Exposure to Alcohol Has No Effect on Cocaine Self-Administration and Relapse in Rats: Evidence from a Rat Model that Does Not Support the Gateway Hypothesis

Abstract

The gateway hypothesis posits that initial exposure to legal drugs promotes subsequent addiction to illicit drugs. However, epidemiological studies are correlational and cannot rule out the alternative hypothesis of shared addiction vulnerability to legal and illegal drugs. We tested the gateway hypothesis using established rat alcohol exposure procedures and cocaine self-administration and reinstatement (relapse) procedures. We gave Wistar or alcohol-preferring (P) rats intermittent access to water or 20% alcohol in their homecage for 7 weeks (three 24-h sessions/week). We also exposed Wistar rats to air or intoxicating alcohol levels in vapor chambers for 14-h/day for 7 weeks. We then tested the groups of rats for acquisition of cocaine self-administration using ascending cocaine doses (0.125, 0.25, 0.5, 1.0 mg/kg/infusion) followed by a dose-response curve after acquisition of cocaine self-administration. We then extinguished lever pressing and tested the rats for reinstatement of drug seeking induced by cocaine-paired cues and cocaine priming (0, 2.5, 5, 10 mg/kg, i.p.). Wistar rats consumed moderate amounts of alcohol (4.6 g/kg/24 h), P rats consumed higher amounts of alcohol (7.6 g/kg/24 h), and Wistar rats exposed to alcohol vapor had a mean blood alcohol concentration of 176.2 mg/dl during the last week of alcohol exposure. Alcohol pre-exposure had no effect on cocaine self-administration, extinction responding, and reinstatement of drug seeking. Pre-exposure to moderate, high, or intoxicating levels of alcohol had no effect on cocaine self-administration and relapse to cocaine seeking. Our data do not support the notion that alcohol is a gateway drug to cocaine.

Figure 1

Experimental timeline, and age of onset of alcohol exposure, and alcohol pre-exposure. (a) Outline of the experimental procedures. (b) Age of onset of alcohol exposure in Exp. 1–3; the chronological timeline is based on McCutcheon and Marinelli (2009). (c) Left panel: alcohol intake (g/kg) in Wistar rats (Exp.1; n=12 per group) during intermittent home-cage access to 20% alcohol. Middle panel: blood alcohol levels (mg/dl) in Wistar rats (Exp. 2; n=12) during alcohol vapor exposure. Right panel: Alcohol intake (g/kg) in P-rats (Exp. 3; n=15) during intermittent home-cage access to 20% alcohol. Data are presented as mean±SEM.

Figure 2

Acquisition of cocaine self-administration and dose–response after acquisition. Left panel: acquisition of cocaine self-administration with ascending doses of cocaine (3 d per dose) in Exp. 1–3. Right panel: within-session dose–response curve after acquisition of cocaine self-administration in Exp. 1–3. Data are mean±SEM of cocaine infusions per 2 h. Exp. 1: n=10–12 per group; Exp. 2: n=8–11 per group; Exp. 3: n=12–14 per group.

Figure 3

Extinction responding without cue and cue-induced reinstatement. Left panel: extinction responding without cue over nine extinction sessions in Exp. 1–3. Right panel: cue-induced reinstatement in Exp. 1–3. During testing, lever presses led to contingent presentation of the light cue but not cocaine. The No cue data are the mean of the last three extinction sessions without the cue. Data are mean±SEM of active lever presses per 2 h. Exp. 1: n=10–11 per group; Exp. 2: n=8–11 per group; Exp. 3: n=12–14 per group. ^# a significant difference between water and low alcohol intake; * a significant difference between water and high alcohol intake (Exp. 1), p<0. 05.

Figure 4

Extinction responding with cue and drug priming-induced reinstatement. Left panel: extinction responding with cue over 11 extinction sessions in Exp. 1–3. Right panel: priming-induced reinstatement of cocaine seeking (0, 2.5, 5, and 10 mg/kg, IP) in Exp. 1–3. During testing, lever presses led to contingent presentation of the light cue but not cocaine. Data are mean±SEM of active lever presses per 2 h for extinction sessions and per 1 h for priming-induced reinstatement. Exp. 1: n=10–11 per group; Exp. 2: n=8–10 per group; Exp. 3: n=12–14 per group.

Figure 5

Comparison of cocaine-taking and cocaine-seeking behaviors across experiments. (a) Acquisition of cocaine self-administration with ascending doses of cocaine (3 d per dose). (b) Within-session dose–response curve after acquisition of cocaine self-administration. (c) Extinction responding without the cue over nine extinction sessions. (d) Cue-induced reinstatement of cocaine seeking. (e) Extinction responding with cue over 11 extinction sessions. (f) Cocaine priming-induced reinstatement. Data are presented as mean±SEM; comparison between Exp.1–3.