Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor

Abstract

The mesolimbic dopamine (DA) system has been implicated in drug reward, locomotor sensitization, and responding for reward-related stimuli [termed conditioned reinforcers (CR)]. Here, we investigated the effect of brain-derived neurotrophic factor (BDNF), which enhances the survival and function of dopaminergic neurons, on stimulant-induced locomotor sensitization and responding for CR. In experiment 1, BDNF was infused into the nucleus accumbens (NAc) or ventral tegmental area over 2 weeks via chronically implanted minipumps (1-2.5 microgram/d), and the psychomotor stimulant effects of cocaine (5-15 mg/kg, i.p.) were studied. We found that BDNF enhanced the initial stimulant effects of cocaine and seemed to facilitate the development of sensitization to repeated cocaine doses. In experiment 2, we studied the effects of intra-NAc BDNF infusions on responding for CR. BDNF-treated rats showed twice as many CR responses compared with controls when saline was first administered. BDNF enhanced responding on the CR lever more than four times that seen in control animals after a cocaine injection (10 mg/kg, i.p.). The enhanced response to cocaine in BDNF-treated animals persisted for more than a month after the BDNF infusions had stopped, indicating long-lasting changes in the mesolimbic DA system caused by BDNF administration. In experiment 3, we examined locomotor sensitization to cocaine in heterozygous BDNF knock-out mice and found that the development of sensitization was delayed compared with wild-type littermates. These results demonstrate the profound effects of BDNF on the enhancement of both cocaine-induced locomotion and facilitation of CR and suggest a possible role for BDNF in long-term adaptations of the brain to cocaine.

Fig. 1.

The locations of the cannula placements within the NAc and VTA are illustrated in diagrams of coronal sections reproduced from the atlas of Paxinos and Watson (1997). The region of the NAc (left) and VTA (right) where infusion tips were located are shown as hatched regions.

Fig. 2.

Effects of intra-NAc BDNF infusions on locomotor behavior in response to saline injections. Saline injections (0.3 ml, i.p.) significantly increased locomotor activity for 10 min after the injection (*p < 0.05) on days 5 and 6 (after surgery) in the BDNF-infused compared with the vehicle-infused group. In contrast, there were no differences before the injections on either day. Data are expressed as the mean ± SEM number of photocell disruptions over the 30 min test period.

Fig. 3.

Effects of intra-NAc BDNF infusions after cocaine challenge. Cocaine injection (15 mg/kg) given on day 7 (after surgery) resulted in locomotor activity rates that were markedly increased in the BDNF-infused compared with the vehicle-infused group; locomotor activity in the BDNF group was significantly higher at 10, 20, 30, 40, and 50 min after the cocaine injection (F_(1,10) = 13.04, 11.93, 11.43, 16.95, and 7.02, respectively; *p < 0.01). No differences before the injection were found. Data are expressed as the mean ± SEM number of photocell disruptions over the 30 min test period.

Fig. 4.

Effects of intra-NAc BDNF infusions on locomotor activation after a low dose of cocaine (5 mg/kg). At 5 mg/kg cocaine, a subthreshold sensitization dose, animals infused with BDNF developed sensitization, whereas vehicle-infused animals did not show sensitization. On day 8, there were no differences, whereas on days 9–12 there were significant differences between the groups at each of the time points shown (*p < 0.05). Differences were as follows: day 9 BDNF-infused animals had increased locomotor rates at 10 and 20 min after cocaine (F_(1,10) = 6.33 and 5.97, respectively;p < 0.05); day 10 increases were found at 10 min after cocaine (F_(1,10) = 5.21;p < 0.05); on day 11, a significant difference between vehicle-infused and BDNF-infused animals was observed at 10, 20, 30, and 40 min after the cocaine injection (F_(1,10) = 5.33, 12.03, 7.10, and 8.94, respectively; p < 0.05); on day 12, there continued to be differences between the BDNF-infused and vehicle-infused animals; significant differences between the groups were found at 10 min after the cocaine injection and a trend at 30 min (F_(1,10) = 7.71 and 3.76, respectively;p < 0.05 and 0.08, respectively). There were no differences between the groups before the cocaine injections. Data are expressed as the mean ± SEM number of photocell disruptions over the 30 min test period.

Fig. 5.

Effects of intra-NAc BDNF infusions on locomotor activation after 7.5 mg/kg cocaine. At 7.5 mg/kg cocaine, a near threshold sensitization dose, animals infused with BDNF showed a more rapid development of sensitization. Vehicle-infused animals also showed some evidence of sensitization. Cocaine injections (7.5 mg/kg) given on days 8 and 10 (after surgery) resulted in activity rates that were markedly increased in BDNF-infused compared with the vehicle-infused animals. Significant differences (*p < 0.05) at time points after cocaine injections were as follows: day 8 at 10, 20, and 30 min, F_(1,6) = 16.25, 12.01, and 10.67, respectively; day 10 at 10 and 20 min,F_(1,6) = 6.41 and 7.41, respectively. No differences between the groups were found before the cocaine injections. Data are expressed as the mean ± SEM number of photocell disruptions over the 30 min test period.

Fig. 6.

Effects of intra-NAc BDNF infusions on locomotor activation after 10 mg/kg cocaine. BDNF-infused animals showed higher activity rates than vehicle-infused animals after repeated cocaine injections (days 7–9). By day 10, the vehicle-infused animals were similar to BDNF-infused animals because they had become sensitized to this moderate dose of cocaine. No further differences between the groups were observed over subsequent days, except on day 13 when vehicle-infused animals showed lower activity rates (see Results). Significant differences (*p < 0.05) at time points after cocaine injections were as follows: day 7 at 10, 20, and 50 min, F_(1,6) = 15.35, 120.81, and 6.35, respectively; day 8 at 10, 20, 50, and 60 min,F_(1,6) = 6.03, 7.41, 6.11, and 6.47, respectively; day 9 at 10, 30, 40, and 50 min,F_(1,6) = 6.19, 6.67, 6.40, and 6.66, respectively; day 13 at 10, 20, and 50 minF_(1,6) = 11.35, 5.82, and 6.24, respectively. No differences between the groups were found before the cocaine injections. Data are expressed as the mean ± SEM number of photocell disruptions over the 30 min test period.

Fig. 7.

Effects of intra-VTA BDNF (left) or intra-VTA NGF (right) infusions on locomotor activation after 15 mg/kg cocaine. Intra-VTA BDNF-infused animals (n = 13) showed a greater amount of activity compared with vehicle-infused animals (n = 11) after the first 15 mg/kg cocaine injection (C1) and the final 15 mg/kg injection (C-TEST). Intra-VTA infusions of NGF (n = 5) did not result in activity counts that differed from vehicle-infused animals (n = 4) during habituation (H4), C1, or C-TEST. Both groups of vehicle-infused animals and NGF-infused animals showed sensitization to cocaine, whereas BDNF-infused animals did not show a progressive increase in locomotor activity over the C1 and C-TEST session (see Results). Significant differences are shown for BDNF-infused compared with vehicle-infused animals; *p < 0.05. Data are expressed as the mean ± SEM number of photocell disruptions over the 30 min test period.

Fig. 8.

Effects of intra-NAc BDNF infusions on responding for CR. Enhanced responding for CR was found after intra-NAc BDNF infusions. Intra-NAc BDNF infusions enhanced responding on the CR lever compared with animals given intra-NAc vehicle infusions after a saline (sal) challenge test (F_(1,6) = 9.10; *p < 0.02). After a cocaine (coc; 10 mg/kg, i.p.) challenge, animals given intra-NAc BDNF infusions showed an even greater potentiated responding on the CR lever (F_(1,6) = 19.81; **p < 0.01). Responding on the control lever (NCR) was lower than the CR lever under all conditions.

Fig. 9.

Long-term effects of intra-NAc BDNF infusions after saline or cocaine on responding for CR up to 5 weeks after cessation of BDNF administration. BDNF-infused animals showed enhanced responding for CR. After the first saline infusion (sal1), there were differences between the groups on the levers; CR lever responses were increased in the BDNF-infused compared with the vehicle-infused group (*p < 0.01). Similar effects were observed in sal2 in which there was a trend for a selective CR increase (F_(1,6) = 5.44;p = 0.06). After subsequent saline (sal3–sal4) injections, only preferences for CR over the NCR lever were found. Responding on the CR lever was markedly increased and persisted in the BDNF-infused compared with the vehicle-infused animals after these cocaine challenges on days coc1, coc2 (F_(1,6) = 19.81 and 13.01;p < 0.01), and coc4 (F_(1,6) = 6.87; p < 0.05), and there was a trend on coc3. Significant differences are shown as **. No differences in responding on the NCR lever were observed. Note that the data for sal1 and coc1 are the same as depicted in Figure 8.

Fig. 10.

Development of sensitization after 10 mg/kg cocaine in BDNF knock-out mice. Heterozygous BDNF knock-out animals showed a delay in the development of sensitization compared with wild-type littermate control animals. Data are expressed as the mean ± SEM number of photocell disruptions over the 30 min test period. BDNF knock-out animals (n = 5) showed a reduced amount of activity compared with littermate controls (n = 4) after the first 10 mg/kg cocaine injection (C1) but eventually became sensitized to cocaine. No differences between the groups were observed during baseline. Significant differences are shown for BDNF knock-out compared with wild-type littermate animals; F_(1,7) = 5.70; *p < 0.05.