Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA

Abstract

Persistent drug-seeking behavior is hypothesized to co-opt the brain's natural reward-motivational system. Although ventral tegmental area (VTA) dopamine (DA) neurons represent a crucial component of this system, the synaptic adaptations underlying natural rewards and drug-related motivation have not been fully elucidated. Here, we show that self-administration of cocaine, but not passive cocaine infusions, produced a persistent potentiation of VTA excitatory synapses, which was still present after 3 months abstinence. Further, enhanced synaptic function in VTA was evident even after 3 weeks of extinction training. Food or sucrose self-administration induced only a transient potentiation of VTA glutamatergic signaling. Our data show that synaptic function in VTA DA neurons is readily but reversibly enhanced by natural reward-seeking behavior, while voluntary cocaine self-administration induced a persistent synaptic enhancement that is resistant to behavioral extinction. Such persistent synaptic potentiation in VTA DA neurons may represent a fundamental cellular phenomenon driving pathological drug-seeking behavior.

Figure 1

Glutamatergic strength onto VTA DA neurons was enhanced one day after completion of cocaine, food, or sucrose self-administration. (A) Behavioral responses on the last day of training session in Cocaine, Food, and Sucrose groups. Active lever presses were 43 ± 3 presses for cocaine (n = 8 rats) 57 ± 2 presses for Food (n=11), and 53 ± 4 presses for Sucrose (n = 8). Cocaine rats earned 38 ± 3 infusions of cocaine (0.25 mg/kg/infusion), Food rats earned 44 ± 2 pellets of food, and Sucrose rats earned 44 ± 4 pellets of sucrose. Inactive lever responses averaged less than 3 presses for all groups. (B) Sample traces showing AMPAR- and NMDAR-mediated currents from Naïve rats and each of the self-administering groups. (C) Averaged AMPAR/NMDAR ratio from Naïve, Cocaine, Food, or Sucrose self-administrating rats. (D) Example traces of mEPSCs from Naïve, Cocaine, Food, and Sucrose groups. Scale bars, 20pA, 100 msec. Cumulative probability of frequency (E) and amplitude (F) of example cells from each of the four groups. Inset: averaged mEPSC frequencies were significantly increased in Cocaine, Food, and Sucrose rats compared with Naive rats, mEPSC amplitudes were not significantly different between the groups. *p < 0.05, **p < 0.01, ***p < 0.001 versus Naive.

Figure 2

Non-contingent cocaine delivery induced differential changes in glutamate function relative to voluntary cocaine self-administration. (A) Averaged AMPAR/NMDAR ratios from rats that received yoked cocaine (0.25 or 0.5 mg/kg/infusion, or a single i.v. bolus) were not significantly increased compared to Naïve rats. However, rats that received cocaine i.p. injections exhibited increased AMPAR/NMDAR ratios (B) Cumulative probability of frequency and amplitude (C) of example cells from each of the four groups. (Inset) Averaged mEPSC frequencies (B) and amplitudes (C) were not significantly different in rats that received cocaine noncontingently. Dotted lines represent averaged value from Naïve rats. **p < 0.01 versus Naïve, ^#p < 0.05 versus yoked groups.

Figure 3

Cocaine self-administration produced a significantly longer potentiation of glutamatergic transmission than food or sucrose self-administration. (A) AMPAR/NMDAR ratio in cocaine self-administering rats remained enhanced after 90 days of abstinence. However, in food and sucrose self-administering rats, increased AMPAR/NMDAR ratio is observed following 7d of abstinence but returned to Naïve levels by 21 days of abstinence. (B,C) Following 7d and 21d abstinence, mEPSC frequencies from Cocaine and Sucrose groups remained significantly enhanced relative to Naïve. In Food rats, (B), the mEPSC frequency was not significantly different than Naïve rats by 7 days of abstinence and remained unchanged at 21 days of abstinence (C). mEPSC frequencies from Cocaine continues to be significantly enhanced relative to Naïve at 3m abstinence. Dotted line represents averages from Naïve rats. * p < 0.05 versus Naive.

Figure 4

LTP was occluded exclusively in Cocaine rats after 21 days of abstinence. Example (top) and summary (bottom) of normalized EPSP amplitude before and after paired stimulation. (A) Naïve rats exhibited robust LTP while (B) LTP was not observed in Cocaine rats after 21 days of abstinence. (C) LTP was induced in Food rats after 21 days of abstinence. Arrows indicate time of LTP induction protocol.

Figure 5

Extinction training and reinstatement did not reduce synaptic potentiation in VTA DA synapses after cocaine self-administration. Behavioral responses in rats that underwent (A) 3 weeks of extinction training or (B) 3 wks extinction followed by 2 hr of cue-induced reinstatement. Error bars were removed for clarity. AMPAR/NMDAR ratios (C) and mEPSC frequency (D) remained elevated after 3 weeks of extinction and extinction/reinstatement. (E) mEPSC amplitude was not altered after extinction and extinction/reinstatement. Cumulative probability of frequency (F) and amplitude (G) of example cells from Ext and Reinst groups in comparison with Naive rats. Dotted line represents averages from Naive rats. *p < 0.05 versus Naïve rats.