Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration - PubMed (original) (raw)

Review

. 2004 Sep-Oct;11(5):648-57.

doi: 10.1101/lm.81404.

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Review

Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration

David W Self et al. Learn Mem. 2004 Sep-Oct.

Abstract

Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydroxylase levels in the nucleus accumbens (NAc) shell, an effect that could help ameliorate dysphoria and depression associated with withdrawal from chronic cocaine use. Extinction training also increases levels of GluR1 and GluR2/3 AMPA receptor subunits, while normalizing deficits in NR1 NMDA receptor subunits, in a manner consistent with long-term potentiation of excitatory synapses in the NAc shell. Our results suggest that extinction-induced increases in AMPA and NMDA receptors may restore deficits in cortico-accumbal neurotransmission in the NAc shell and facilitate inhibitory control over cocaine-seeking behavior. Other changes identified by gene expression profiling, including up-regulation in the AMPA receptor aggregating protein Narp, suggest that extinction training induces extensive synaptic reorganization. These studies highlight potential benefits for extinction training procedures in the treatment of drug addiction.

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Figures

Figure 1

Figure 1

Neuroadaptations to chronic drug exposure are thought to promote addictive behavior, but these changes can be modulated by experiential factors such as repeated exposure to extinction conditions. Our studies suggest that extinction training during withdrawal from chronic cocaine self-administration modifies these neuroadaptations in a manner that may reduce (dotted line) their contribution to drug-seeking behavior.

Figure 2

Figure 2

(A) Extinction training (EXT) for 4 h/d during withdrawal (WD) from chronic cocaine self-administration increases immunoreactivity for GluR1 (F(4,56) = 4.382, P = 0.004), and reverses withdrawal-induced deficits in NR1 (F(4,56) = 4.114, P = 0.005) in homogenates of NAc shell tissue. Both effects require access to the response levers allowing extinction of cocaine-seeking responses at the drug-paired lever. Extinction training also increases the GluR1/NR1 ratio in cocaine-trained animals compared to similar extinction training procedures in animals trained to self-administer sucrose. (B) In contrast, there was no significant regulation of GluR1 and NR1 in the NAc core. Data are expressed as the mean ± S.E.M. of percent change from age- and group-matched untreated control tissue. *P < 0.05; **P < 0.01 in cocaine-trained animals compared to NAc tissue from sucrose-trained animals subjected to identical extinction training procedures by Fisher's post-hoc tests (†P < 0.05 by Student's _t_-test corrected for multiple comparisons). Sample sizes (shell, core) are 1-wk EXT sucrose (9, 10); 1-d WD (9, 8); 1-wk WD (13, 11); 1-wk EXT (19, 18); levers retracted (11, 10). GluR1 data are from Sutton et al. 2003 (with permission).

Figure 3

Figure 3

Extinction training (EXT) during withdrawal (WD) from chronic cocaine self-administration increases expression of a novel neuronal pentraxin receptor (NPR) in the NAc shell and Narp (neuronal activity-regulated pentraxin) protein that interacts with NPR. (A) Extinction training induces expression of NPR mRNA (F(2,5) = 20.123, P = 0.004). (B) Extinction training reverses withdrawal-induced deficits in Narp protein (F(2,32) = 4.465 P = 0.019) in homogenates of NAc shell tissue. In contrast, there are no changes in NPR mRNA or Narp protein in adjacent punches of NAc core tissue. Changes in mRNA levels were identified by microarray profiling (Affymetrix rat chips) of mRNA from pooled NAc core and shell tissue samples (n = 5/pool) in untreated control (four pools), WD and EXT groups (two pools each) in two independent comparisons (see Materials and Methods). *P < 0.05; **P < 0.01 compared to untreated age- and batch-matched control tissue by Fisher's post-hoc tests. Sample sizes for Western blot analysis of Narp (shell, core) are 10-d WD (10, 8), EXT (9, shell only), and pooled untreated controls (16, 7). NT, not tested.

Figure 4

Figure 4

Hypothetical behavioral consequences of drug- and extinction-induced neuroplasticity in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Drug-induced changes include a deficit in the rate-limiting enzyme for dopamine (DA) synthesis, tyrosine hydroxylase (TH), in dopaminergic terminals of the NAc shell that could contribute to negative mood disturbances including dysphoria, anhedonia, and depression in early stages of cocaine withdrawal. Extinction-induced normalization of TH levels in the NAc shell, possibly the result of increased TH synthesis and transport from the VTA, would help to normalize affective disturbances by restoring extracellular dopamine levels. In addition, extinction-induced up-regulation in AMPA and NMDA glutamate (Glu) receptor subunits in the NAc shell resemble changes found in potentiated synapses. Extinction-induced increases in GluR1, and normalization of NR1, could revert LTD to LTP in excitatory synapses emanating from cortical and thalamic regions during drug withdrawal. Restoration of excitatory synaptic input to NAc shell neurons is hypothesized to restore inhibitory control over drug-seeking behavior.

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