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Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence - PubMed

Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence

Aliou B Gueye et al. Neuropsychopharmacology. 2019 May.

Abstract

Cocaine is thought to be more addictive when it reaches the brain rapidly. We predicted that variation in the speed of cocaine delivery influences the likelihood of addiction in part by determining the risk of relapse after abstinence. Under an intermittent-access schedule, rats pressed a lever for rapid (injected over 5 s) or slower (90 s) intravenous cocaine injections (0.5 mg/kg/injection). Control rats self-administered food pellets. A tone-light cue accompanied each self-administered reward. The 5s- and 90s-rats took a similar average amount of cocaine. One or 45 days after withdrawal from cocaine/forced abstinence, lever-pressing behaviour was extinguished during a 6-h session. Immediately thereafter, cue- or cocaine (10 mg/kg, i.p.)-induced reinstatement was assessed for 1 h. One or 45 days after withdrawal, only 5s-rats showed significant cocaine-induced reinstatement of reward-seeking behaviour. In both cocaine groups, cue-induced reinstatement behaviour was more pronounced after 45 days than after 1 day of withdrawal from cocaine, indicating incubation of conditioned drug craving. However, cue-induced reinstatement after extended abstinence was greatest in the 5s-rats. Brain-derived neurotrophic factor (BDNF) activity in the brain regulates reinstatement behaviour. Thus, 24 h after reinstatement tests, we measured BDNF protein concentrations in mesocorticolimbic regions. Only 5s-rats showed time-dependent increases in BDNF concentrations in the prelimbic cortex, nucleus accumbens core and ventral tegmental area after withdrawal from cocaine (day 45 > day 1). Thus, rapidly rising brain cocaine levels might facilitate addiction by evoking changes in the brain that intensify drug craving after abstinence, and these changes persist long after the last bout of cocaine use.

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Figures

Fig. 1
Fig. 1

Timeline of experimental events, estimated brain cocaine concentrations and cocaine self-administration behaviour. a Rats were implanted with intravenous catheters and trained to press a lever for 45-mg, banana-flavoured food pellets. A subset of the rats was then trained to self-administer intravenous cocaine (0.5 mg/kg/injection, delivered over 5 s). The cocaine rats were then divided into two groups. For three 1-h sessions, they were given access to cocaine under a fixed ratio 3 schedule of reinforcement. Each injection was delivered over 5 s to one group (5s-rats), and over 90 s (90s-rats) to the other group. The subset of cocaine-naïve rats continued to self-administered food pellets. Next, self-administration sessions were extended to 6 h, during which cocaine (or food) was available intermittently (intermittent-access or IntA; 6-min periods of reward access, separated by 26-min periods of no reward). Following 10 IntA sessions, rats were kept in their home cages for 1 or 45 days. At each time point, rats received a single extinction session (6 h), immediately followed by a 1-h cue-induced reinstatement test (all rats) or cocaine-induced reinstatement test (cocaine rats only). 24 h after the reinstatement tests, the rats were sacrificed and their brain were removed for BDNF protein quantification. b Cocaine intake patterns and (c) modelled brain cocaine concentrations in a representative 5s-rat (black) and a representative 90s-rat (grey). The 5s-rats were limited to a maximum of 3 injections/6-min cocaine period [indicated by the horizontal line in (e). c Under these conditions, the IntA procedure produces similar spikes and troughs in estimated brain cocaine concentrations in 5 s- and 90s-rats. In (d–f), WD1 and WD45 indicate rats that will be given reinstatement tests 1 or 45 days after withdrawal from drug self-administration, respectively. d During IntA sessions, both 5s-rats and 90s-rats groups pressed more on the active versus inactive lever, with no group differences in this behaviour. In (e), the left Y-axis shows the number of injections taken during each 6-min cocaine period. The right Y-axis shows the number of injections self-administered during each 6-h IntA session. Both e cocaine intake over the sessions and f cumulative drug intake were similar in 5s- and 90s-rats. All data are mean ± SEM. 5s-rats, n = 15 for WD1 and n = 22 for WD45; 90 s-rats, n = 14 for WD1 and n = 19 for WD45

Fig. 2
Fig. 2

Taking rapid (5 s), but not slower (90 s) intravenous cocaine injections promotes incubation of extinction responding during abstinence. After 1 or 45 days of forced abstinence/withdrawal (WD) from cocaine, all rats were placed in the cocaine-associated context and given a 6-h extinction session. Lever presses produced no cocaine and no discrete cocaine cues. a When replaced into the cocaine-taking context under extinction conditions, drug-seeking behaviour (pressing on the previously cocaine-associated lever) was greatest in the 5s-rats withdrawn for 45 days. b The total number of active lever presses during the extinction session was also greatest in this group. c, d During the extinction sessions, there were no group differences in pressing on the inactive lever. Rats that had previously self-administered food pellets were also replaced in the food-taking context and tested under extinction conditions, 1 and 45 days after the last self-administration session. e, f In food control rats, extinction responding did not vary with withdrawal time. g, h In food control rats, pressing on the inactive lever decreased from WD1 to WD45. All data are mean ± SEM. *5 s-rats on WD45 versus all other groups, p < 0.05; #versus WD1, p < 0.05. 5s-rats, n = 15 on WD1 and n = 22 on WD45; 90s-rats, n = 14 on WD1 and n = 19 on WD45; Food rats, n = 5 on WD1 and n = 6 on WD45

Fig. 3
Fig. 3

Taking rapid (5 s), but not slower (90 s) intravenous cocaine injections promotes cue-induced reinstatement after forced abstinence/withdrawal (WD) from cocaine. Immediately after the 6-h extinction session given on WD1 or WD45, rats were given a 1-h cue-induced reinstatement test. During cue-induced reinstatement, pressing on the active lever did not produce cocaine, but it was reinforced by presentations of the tone-light drug cue. Responding during reinstatement tests (black bars) was compared to responding in the last hour of the extinction sessions (white bars). a On WD1 and WD45, only the 5s-rats showed cue-induced reinstatement of extinguished cocaine-seeking behaviour. This was indicated by greater pressing on the active lever during the cue-induced reinstatement test versus extinction. Cue-induced reinstatement intensified during abstinence in both the 5s- and 90s-rats (WD45 > WD1). b During cue-induced reinstatement tests, there were no group differences in pressing on the inactive lever. c, d In food control rats, there was no effect of food cue presentation on either active or inactive lever-pressing behaviour. All data are mean ± SEM. *versus extinction session in 5s-rats at the same withdrawal time, p < 0.05; &versus 5s-rats during cue-induced reinstatement on WD1, p < 0.05; #versus 90 s-rats during the reinstatement test on WD45, p < 0.05, $versus 90s-rats during the reinstatement test on WD1. 5s-rats, n = 8 on WD1 and n = 15 on WD45; 90 s-rats, n = 7 on WD1 and n = 13 on WD45; Food rats, n = 5 on WD1 and n = 6 on WD45

Fig. 4
Fig. 4

Taking rapid (5 s), but not slower (90 s) intravenous cocaine injections promotes cocaine-primed reinstatement after forced abstinence/withdrawal (WD). Immediately after a 6-h extinction session given on WD1 or WD45, rats were given a 1-h cocaine (10 mg/kg, i.p.)-induced reinstatement test. During cocaine-induced reinstatement, lever pressing produced no cocaine and no cues. Responding during reinstatement tests (black bars) was compared to responding in the last hour of the extinction sessions (white bars). a After 1 or 45 days of forced abstinence/withdrawal from cocaine, only 5s-rats showed significant cocaine-induced reinstatement of extinguished drug-seeking behaviour. b During cocaine-induced reinstatement tests, there were no group differences in pressing on the inactive lever. All data are mean ± SEM. *versus extinction session in 5s-rats at the same withdrawal time, p < 0.05; #versus 90s-rats during the reinstatement test on WD45, p < 0.05. 5s-rats, n = 7 on each of WD1 and WD45; 90s-rats, n = 7 on WD1 and n = 6 on WD45

Fig. 5
Fig. 5

Forced abstinence/withdrawal (WD) from rapid (5 s), but not slower (90 s) intravenous cocaine injections evokes time-dependent increases in brain BDNF protein concentrations. 24 h after the reinstatement tests given on WD1 or WD45, brains were extracted and BDNF protein expression was quantified in a prelimbic cortex (PrL), b nucleus accumbens core (Nac) and c ventral tegmental area (VTA). Data are presented as the percentage of mean values of food control rats (± SEM). In the subset of rats tested for cue-induced reinstatement on WD45 (top three panels), 5s-rats had greater BDNF protein concentrations relative to both 90s-rats and food control rats in d the PrL, e Nac and f VTA. In the subset of rats used for cocaine-induced reinstatement on WD1 or WD45 (bottom three panels), 5s- and 90s-rats had unchanged BDNF protein concentrations in g the PrL and h Nac. i Both groups had increased BDNF protein expression in the VTA, and 5s-rats had the highest expression levels. All data are mean ± SEM. *versus 5s-rats tested on WD1, p < 0.05; #versus 90s- or food control rats tested on WD45, p < 0.05; $versus 90s-rats and food control rats, across withdrawal times, p < 0.05; &versus food control rats, across withdrawal times, p < 0.05. Cue-induced reinstatement rats: 5s-rats, n = 5 on WD1 and n = 6 on WD45; 90 s-rats, n = 5 on WD1 and n = 6 on WD45; Food rats, n = 5 on WD1 and n = 6 on WD45. Cocaine-induced reinstatement rats: 5s-rats, n = 6 on each of WD1 and WD45; 90s-rats, n = 6 on WD1 and n = 5 on WD45

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