Cocaine‐ and morphine‐induced synaptic plasticity in the nucleus accumbens

Abstract

The critical brain areas and molecular mechanisms involved in drug abuse and dependence have been extensively studied. Drug-induced persistent behaviors such as sensitization, tolerance or relapse, however, far outlast any previously reported mechanisms. A challenge in the field of addiction, therefore, has been to identify drug-induced changes in brain circuitry that may subserve long-lasting changes in behavior. The present study examined behavioral changes and electron microscopic evidence of altered synaptic connectivity within the nucleus accumbens (NAc) following repeated administration of cocaine or morphine. The unbiased quantitative stereological physical disector method was used to estimate the number of synapses per neuron. Increases in synapse to neuron ratio were found in the NAc shell of cocaine-treated (49.1%) and morphine-treated (55.1%) rats and in the NAc core of cocaine-treated animals (49.1%). This study provides direct ultrastructural evidence of drug-induced synaptic plasticity and identifies synaptic remodeling as a potential neural substrate underlying drug-induced behavioral sensitization.

Ultrastructural analysis of sex differences in nucleus accumbens synaptic connectivity

“…Additionally, these studies were performed in males only. Alcantara et al (2011) recently reported a stereological EM analysis of NAc core and shell synapses in female rats in response to chronic cocaine or morphine; their core spine synapse density data in controls match well with our averaged data for females. However, this study was focused on a more limited rostro-caudal level of the NAc (Bregma 1.2, which falls into our caudal category).…”

Biological substrates of addiction

“…Importantly, this effect is dependent upon the state of cocaine exposure ( in vivo drug experience), since excitatory signaling in the NAc is potentiated following extended withdrawal but depressed following drug re-exposure 111 . Similar differences in synaptic transmission have been obtained following morphine treatment 112 , and gross changes in synapse morphology that mirror the electrophysiology have also been observed 113 . Prior to, and perhaps facilitating these biphasic synaptic changes that occur following extended withdrawal and re-exposure is the generation of silent synapses that occurs acutely following repeated cocaine exposure 114 .…”

Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

“…Drug-induced neuronal modifications suggestive of alterations in patterns of synaptic connectivity have been identified in the VTA, nucleus accumbens and mPFC. [124][125][126][127] The changes in dendritic structure in VTA neurons are particularly intriguing because the VTA is a critical site for the initiation of sensitization; administration of amphetamine directly into the VTA is sufficient to produce sensitized DA release in the nucleus accumbens and behavioural response to a subsequent systemic injection of this drug. 122 Blockade of glutamate receptors directly in the VTA during stimulant drug pretreatment prevents the development of sensitization.…”