Cocaine but Not Natural Reward Self-Administration nor Passive Cocaine Infusion Produces Persistent LTP in the VTA

Abstract

Summary 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.

Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior

“…Lack of NMDARs in DA neurons not only impairs burst firing, but also precludes LTP of synaptic AMPARs (21,22). AMPAR currents are transiently potentiated in DA neurons after exposure to cocaine, stress, or during learning paradigms (21,22,(45)(46)(47). However, the role of AMPAR LTP in DA neurons is unclear.…”

“…Mice were given 5 trials per day for 4 days to learn the location of a hidden platform using cues located within the maze. KO mice (n ϭ 8) were significantly slower to learn the task, as measured by latency to find the hidden platform, compared with controls (n ϭ 9) (2-way repeated measures ANOVA, genotype ϫ day, F (3,45) ϭ 2.88; P Ͻ 0.05; see Fig. 3E); however, they demonstrated equivalent recall (time spent in zone where hidden platform was located) once the task was learned (Fig.…”

Prenatal Stress Exposure Increases the Excitation of Dopamine Neurons in the Ventral Tegmental Area and Alters Their Reponses to Psychostimulants

“…For example, enhancing the expression in GluR2-lacking AMPARs in the VTA DA neurons leads to increased sensitivity to drug reward (Carlezon et al, 2000), whereas blocking glutamate receptors in the VTA during psychostimulant pre-exposure prevents enhanced psychostimulant self-administration (Suto et al, 2003). Exposure to psycho-stimulants, ethanol, or stress leads to augmented AMPA receptor function and greater glutamate synaptic strength in VTA DA neurons (Argilli et al, 2008;Bellone and Luscher, 2006;Borgland et al, 2004;Chen et al, 2008;Churchill et al, 1999;Fitzgerald et al, 1996;Ortiz et al, 1995;Saal et al, 2003;Stuber et al, 2008;Ungless et al, 2001;Zhang et al, 1997). Therefore, increased glutamate neurotransmission might contribute to PSE-induced overexcitation/depolarization block in VTA DA neurons and mediate the increased responding to psychostimulants and addiction risk.…”

Dopamine in the Dorsal Hippocampus Impairs the Late Consolidation of Cocaine-Associated Memory

“…Neuroadaptations that are caused by repeated passive exposure to the drug itself have been widely studied (Nestler, 1992;Lüscher and Malenka, 2011), but there are further changes in brain function that reflect the memory of drug experience. These further brain changes are seen in animals that self-administer the drug, but are absent in animals that have passively received 'yoked' injections of the same drug at the same dose and temporal pattern (Wang et al, 2005;You et al, 2007You et al, , 2008Chen et al, 2008;Caillé et al, 2009). Here, we were concerned with brain changes involved in the consolidation of the memory for drug-environment association established by Pavlovian conditioning.…”