Chronic cocaine prevents depotentiation at corticostriatal synapses

Background. The advanced stages of addiction are characterized by compulsive drug-seeking and drug-taking behaviors despite the loss of the hedonic effect of drug consumption. A pathology of habit forming systems might underlie these features of addiction. Methods. We have compared use-dependent plasticity of corticostriatal synapses insaline- and cocaine-treated rats by means of single neuron electrophysiological recordings. Results: High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in treated and untreated animals. Saline- and acute- cocaine-treated rats, however, showed synaptic depotentiation in response to subsequent low-frequency stimulation of the same pathway, whereas chronic cocaine-treated animals were refractory to this process. Depotentiation was also absent in control slices bathed with cocaine, dopamine, or with the D1 receptor agonist SKF38393, The effect of cocaine on depotentiation was prevented by D1 but not D2 dopamine receptor antagonists and was mimicked by pharmacological inhibition of cyclin-dependent kinase 5, to enhance DI-receptor-associated intracellular signaling. Conclusions: These results provide the first evidence that cocaine blocks the reversal of LTP in brain circuits. This alteration might be important for the persistence of addictive behavior despite efforts to abstain.