Amphetamine maintenance therapy during intermittent cocaine self-administration in rats attenuates psychomotor and dopamine sensitization and reduces addiction-like behavior

Abstract

D-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine's effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine's potency at the DAT. Male rats self-administered cocaine intermittently (5 min ON, 25 min OFF x10; 5-h/session) for 14 sessions, with or without concomitant D-amphetamine maintenance therapy during these 14 sessions (5 mg/kg/day via s.c. osmotic minipump). We then assessed responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. We also assessed the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core using fast scan cyclic voltammetry ex vivo. IntA cocaine self-administration produced psychomotor (locomotor) sensitization, strong motivation to take and seek cocaine, and it increased cocaine's potency at the DAT. D-amphetamine co-administration suppressed the psychomotor sensitization produced by IntA cocaine experience. After cessation of D-amphetamine treatment, the motivation to take and seek cocaine was also reduced, and sensitization of cocaine's actions at the DAT was reversed. Thus, treatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

Fig. 1. D-amphetamine did not significantly influence cocaine intake, but it abolished both cocaine-induced psychomotor sensitization and spikes in locomotor activity during cocaine self-administration sessions.

a In Experiment 1, rats self-administered cocaine under intermittent-access (IntA) conditions (COC). Some rats received D-amphetamine maintenance (COC + A; 5 mg/kg/day, via s.c. osmotic minipump) during intermittent cocaine self-administration. During D-amphetamine treatment/IntA cocaine self-administration, we assessed changes in cocaine intake and locomotor activity. After cessation of D-amphetamine treatment/IntA, we assessed responding for cocaine under a progressive ratio (PR) schedule of reinforcement, and cocaine-induced reinstatement of extinguished cocaine-seeking behavior. b The two groups took a similar number of cocaine injections, and both escalated their intake over time. c Horizontal locomotor activity/min increased over IntA-sessions only in COC rats, suggesting that only COC rats developed psychomotor sensitization to self-administered cocaine. d–f Intermittent cocaine intake produced spikes in locomotor activity during the 5-h IntA-sessions, and D-amphetamine suppressed this effect. g–i Locomotor activity/min averaged over the ten, 5-min cocaine (shaded in gray) and the ten, 25-min no cocaine periods of the 1st, 7th, and the 14th IntA-sessions. In COC rats only, locomotion increased over sessions, and was highest during the 5-min cocaine periods. Locomotion was also greater in COC versus COC + A rats. Data are mean ± SEM. n = 22 for the COC group, and n = 11 for the COC + A group. *P’s < 0.05, versus IntA-sessions 2–7 in COC and versus IntA-sessions 4–6 in COC + A. ^%p = 0.005, COC versus COC + A. ^#P’s < 0.05, Group × Session or Group × Time interaction effect. ^&P’s < 0.05, main effect of Group. IntA, Intermittent Access. COC, Cocaine. A, D-amphetamine.

Fig. 2. D-amphetamine maintenance during intermittent cocaine self-administration decreased subsequent cocaine-taking and -seeking.

a During progressive ratio tests, responding for cocaine was dose-dependent, and COC + A rats responded less for cocaine compared with COC rats. b–d Cumulative number of self-administered cocaine injections (left y-axis) and corresponding ratio (right y-axis) during each 5-h progressive ratio test, as a function of cocaine dose. Correlations between the average number of cocaine injections taken per 5-h IntA-session and number of cocaine injections earned during progressive ratio tests at 0.063 mg/kg/infusion (e), 0.125 mg/kg/infusion (f) and 0.25 mg/kg/infusion (g) cocaine. Cocaine intake during IntA-sessions predicted responding for all doses of cocaine tested under a progressive ratio schedule in COC + A rats, but not in COC rats. h Under extinction conditions, COC + A rats showed less cocaine-seeking behavior than COC rats, and both groups extinguished responding over time. i During pre-reinstatement sessions (additional extinction sessions, but where cocaine cues were no longer presented) both groups decreased their active-lever pressing over sessions with no group differences. j COC + A rats were less vulnerable to cocaine-induced reinstatement of extinguished cocaine-seeking than COC rats were, in particular after a 15 mg/kg cocaine prime. *p < 0.01, main effect of Group. ^&p ≤ 0.01, non-zero slope. ^#p < 0.01, versus COC + A. Data are mean ± SEM. (a–g) n = 22 for the COC group, and n = 11 for the COC + A group. (h–j) n’s = 10–11/group. IntA, Intermittent Access. COC, Cocaine. A, D-amphetamine.

Fig. 3. D-amphetamine maintenance does not prevent the escalation of cocaine intake in already cocaine-experienced rats.

a In Experiment 1, a subset of COC rats was used to compare responding for cocaine under a PR schedule before and after D-amphetamine treatment, in a within-subjects design. Thus, after 14 initial IntA-sessions without D-amphetamine (IntA-sessions 1–14) and PR tests, these rats were given 14 more IntA-sessions now with concomitant D-amphetamine treatment (IntA-sessions 15–28). After the 28th IntA-session, D-amphetamine treatment was ceased, and rats received a second set of PR tests. b Before and with D-amphetamine treatment, rats escalated their cocaine intake over IntA-sessions. c Locomotor activity increased over intermittent cocaine self-administration sessions, and it stabilized with D-amphetamine (IntA-session 15 versus 28). Locomotor activity/min averaged over the 5-min cocaine periods (d) increased from the 1st to the 14th IntA-session (before D-amphetamine) and (e) decreased from the 15th to the 28th IntA-session, when rats now received concomitant D-amphetamine treatment. f–h Locomotor activity during intermittent cocaine self-administration sessions followed a spiking pattern before D-amphetamine, and (i–k) D-amphetamine attenuated this spiking effect. Data are mean ± SEM. n = 11. *P’s < 0.0001, main effect of Session. ^#P’s < 0.05, versus IntA-session 1. ^&p < 0.05, versus IntA-session 15. IntA, Intermittent Access. A, D-amphetamine.

Fig. 4. In cocaine-experienced rats, D-amphetamine maintenance during intermittent cocaine self-administration decreases later responding for cocaine under a progressive ratio schedule of reinforcement.

a Rats earned less cocaine injections after versus before D-amphetamine treatment. b–d Responding for cocaine under progressive ratio in individual rats before (b) and after (a) D-amphetamine treatment. e–g Cumulative number of self-administered cocaine injections (left y-axis) and corresponding ratio (right y-axis) during each 5-h progressive ratio test, as a function of cocaine dose. Data are mean ± SEM. n = 11. *p = 0.002, main effect of Treatment. A, D-amphetamine.

Fig. 5. D-amphetamine maintenance during intermittent cocaine intake prevents sensitization to cocaine’s effects at the dopamine transporter.

a In Experiment 2, rats self-administered cocaine (COC) or saline (SAL), with or without concomitant D-amphetamine treatment (COC + A and SAL + A). After cessation of D-amphetamine treatment/IntA experience, we used fast-scan cyclic voltammetry (FSCV) to assess cocaine-induced dopamine reuptake inhibition at the dopamine transporter in the nucleus accumbens core. b As in Experiment 1, intermittent cocaine intake produced spikes in locomotor activity, and spike amplitude increased with more extensive cocaine-taking experience. D-amphetamine attenuated both the locomotion spikes and the increase in spike amplitude over time. c D-amphetamine initially increased locomotion in rats self-administering saline, but this effect abated by the last (14th) session. d Representative traces from a SAL rat showing relative extracellular dopamine levels over time evoked by bath-application of different cocaine concentrations in the nucleus accumbens core. Fast-scan cyclic voltammetry heat maps from the same SAL rat illustrate the current (color in the z-axis) as a function of the potential applied to the electrode (y-axis) and time (x-axis). Pseudo-color plots were magnified to highlight dopamine spikes. The position of oxidative and reduction currents in the pseudo-color plots identify the oxidized substance as dopamine. e, f Electrically-evoked dopamine overflow (analysed as dopamine peak height) increased as a function of cocaine concentration, with no group differences. g, h % of apparent Km as a function of cocaine dose preferentially increased in COC rats and this increase is prevented in COC + A rats. The dose of 30 μM cocaine more effectively inhibited dopamine uptake in COC rats than in the other groups. In rats previously naive to cocaine (SAL), D-amphetamine did not change cocaine-induced dopamine uptake inhibition. Because in e and g, SAL and SAL + A rats were similar in all measures, they were pooled together in f and h. Data are mean ± SEM. n = 4–7/group. *p < 0.05, COC versus all other groups. IntA intermittent access, DA dopamine, COC cocaine, SAL Saline. A, D-amphetamine.