Preclinical Evidence That 5-HT1B Receptor Agonists Show Promise as Medications for Psychostimulant Use Disorders

Abstract

Background: 5-HT1B receptor agonists enhance cocaine intake during daily self-administration sessions but decrease cocaine intake when tested after prolonged abstinence. We examined if 5-HT1B receptor agonists produce similar abstinence-dependent effects on methamphetamine intake.

Methods: Male rats were trained to self-administer methamphetamine (0.1 mg/kg, i.v.) on low (fixed ratio 5 and variable ratio 5) and high (progressive ratio) effort schedules of reinforcement until intake was stable. Rats were then tested for the effects of the selective 5-HT1B receptor agonist, CP 94,253 (5.6 or 10 mg/kg), or the less selective but clinically available 5-HT1B/1D receptor agonist, zolmitriptan (10 mg/kg), on methamphetamine self-administration both before and after a 21-day forced abstinence period during which the rats remained in their home cages.

Results: The inverted U-shaped, methamphetamine dose-response function for intake on the fixed ratio 5 schedule was shifted downward by CP 94,253 both before and after abstinence. The CP 94,253-induced decrease in methamphetamine intake was replicated in rats tested on a variable ratio 5 schedule, and the 5-HT1B receptor antagonist SB 224,289 (10 mg/kg) reversed this effect. CP 94,253 also attenuated methamphetamine intake on a progressive ratio schedule both pre- and postabstinence. Similarly, zolmitriptan attenuated methamphetamine intake on a variable ratio 5 schedule both pre- and postabstinence, and the latter effect was sustained after each of 2 more treatments given every 2 to 3 days prior to daily sessions.

Conclusions: Unlike the abstinence-dependent effect of 5-HT1B receptor agonists on cocaine intake reported previously, both CP 94,253 and zolmitriptan decreased methamphetamine intake regardless of abstinence. These findings suggest that 5-HT1B receptor agonists may have clinical efficacy for psychostimulant use disorders.

Keywords: CP 94,253; addiction; methamphetamine; rodent; zolmitriptan.

Figure 1.

Effects of the 5-HT_1B receptor agonist, CP 94,253 on infusions (A,D), active lever (B,E), and inactive lever (C,F) responses on a FR5 schedule of methamphetamine (0.1 mg/kg, i.v.) reinforcement during pre- and postabstinence tests (left and right panels, respectively). Data are expressed as the mean (± SEM) during the 30-minute test period for each of the methamphetamine doses tested (0.003–0.30 mg/kg, i.v.). Rats (n = 10) were tested twice, receiving pretreatment with vehicle (1 mL/kg, s.c.; open squares) prior to one test and CP 94,253 (5.6 mg/kg, s.c.; filled triangles) prior to the other test, with order of pretreatment counterbalanced. Insets in A-E show a main effect of CP 94,253 averaged across methamphetamine doses. Asterisks (*) represent a difference from vehicle condition (main effect or Tukey’s posthoc test, P<.05).

Figure 2.

Effects of the 5-HT_1B receptor agonist, CP 94,253, on infusions (A), breakpoints (B), active lever (C), and inactive lever (D) responses under a progressive ratio schedule of methamphetamine (0.05 mg/kg, i.v.) reinforcement during pre- and postabstinence tests. Data are expressed as the mean (± SEM) during 4-hour sessions. Rats were pretreated 15 minutes prior to the start of the test sessions with either vehicle (1 mL/kg, s.c.; white bars; n = 7) or CP 94,253 (10 mg/kg, s.c.; black bars; n = 8). Asterisks (*) represent a difference from vehicle at each time point (Tukey’s posthoc test, P<.05).

Figure 3.

Reversing the attenuating effects of CP 94,253 on methamphetamine (0.1 mg/kg, i.v.) self-administration with SB 224,289 during tests that occurred preabstinence. On the first test day, rats (group 1: n=14, group 2: n=17) received a pretreatment of either vehicle (Veh, white bar) or SB 224,289 (SB; 10 mg/kg, i.p., gray bar) 30 minutes before the 2-hour session. They then received a treatment of either vehicle (Veh) or CP 94,253 (CP; 5.6 mg/kg, s.c.; black bar) 15 minutes prior to the test session that commenced under a VR5 schedule of reinforcement. Conditions were identical on the second test day for all rats except that the pretreatment given 30 minutes before session start was reversed such that rats that had received vehicle previously were given SB 224,289 and rats that had received SB 224,289 previously were given vehicle. Data are expressed as the mean (+ SEM). Asterisk (*) represents a difference from all other groups (Tukey’s posthoc test, P<.05).

Figure 4.

Effects of 5-HT_1B receptor drugs on spontaneous locomotion. Rats were placed on abstinence from methamphetamine for a total of 29 days following acquisition and stabilization on a progressive ratio schedule of reinforcement. Habituation to the locomotor testing chambers occurred on abstinence day 24. On the first test day, rats (group 1: n=7, group 2: n=7) received a pretreatment of either vehicle (Veh, white bar) or SB 224,289 (SB; 10 mg/kg, i.p., gray bar) 30 minutes before commencement of the session. They then received a treatment of either vehicle (Veh) or CP 94,253 (CP; 10 mg/kg, s.c., black bar) 15 minutes prior to the same session. Conditions were identical on the second test day for all rats except that the pretreatment given 30 minutes before session start was reversed such that rats who had received vehicle previously were given SB 224,289 and vice versa. All rats underwent 3 days off between tests 1 and 2 while remaining in abstinence. Data are expressed as the mean (+SEM) distance traveled in meters across the 2-hour session. Pretreatment with 5-HT_1B receptor drugs produced no significant differences in spontaneous locomotion.

Figure 5.

Effects of zolmitriptan, a 5-HT_1B/1D receptor agonist, on infusions (A,C), and active lever (B,C) responses on a VR5 schedule of methamphetamine (0.1 mg/kg, i.v.) reinforcement during pre- and postabstinence tests (left and right panels, respectively). Data are expressed as the mean (±SEM). Rats were pretreated 15 minutes prior to the start of the 2-hour sessions with either vehicle (white bar/open circles; n = 6) or zolmitriptan (10 mg/kg, s.c.; black bar/filled squares; n = 9). Asterisks (*) represent a difference from vehicle condition (t test or ANOVA main effect, P<.05).