The Alteration Of Nucleus Accumbens Neuronal Excitability During Morphine Withdrawal In Rats

Nucleus accumbens is an important component of brain reward pathway. It receives glutamatergic inputs from cognition and decision-making related prefrontal cortex, learning and memory related hippocampus and emotion and affection related amygdala. Similarly, it is innervated by dopaminergic terminals originated from ventral tegmental area, which takes charge of encoding the incentive value of external stimuli. After information integration, the medium spiny neurons project to the output nuclei of the basal ganglia to influence voluntary behavior. Medium spiny neurons are the main cell type in nucleus accumbens, which takes up about 90% - 95% of the total cell amount.Nucleus accumbens plays a critical role in opioid rewarding effect and relapse. Treatments, such as lesion, inactivation or intracranial injection of glutamate receptor antagonist could effectively prevent reinstatement of opioid seeking behavior. Neuroadaptations in nucleus accumbens during withdrawal from repeated opioid treatment is considered to be one of the main neurobiological substrates underlying relapse. Neuroadaptations induced by opioid withdrawal includes alterations in the efficiency of synaptic transmission, gene transcription and protein expression and neuronal morphology et al. During short-term withdrawal from opioids, nucleus accumbens shows diminished excititory synaptic transmission efficiency, bluntness of responsiveness of GABAergic inhibitory inputs to modulatory factors, general repression of gene transcription and reduced dendritic branching and spine number. All these adaptations indicate a possible downregulation of nulceus accumbens activity during short-term opioid withdrawal. However, the activity of nucleus accumbens neurons is determinated not only by the strength of excitatory and inhibitory synaptic inputs it receives, but also by the intrinsic excitability of the neuron itself, which means the responsive capability of neuronal membrane to external stimuli. Up to now, it is still not clear about the critical question of the alteration of nucleus accumbens neuronal excitability during opioid withdrawal.In the present study, we investigated the change of nucleus accumbens neuronal excitability during short-term morphine withdrawal, using whole-cell patch-clamp recordings. During the 3 - 4 day withdrawal from 7 day intermittent morphine treatment, we found that the excitability of nucleus accumbens medium spiny neuron reduced significantly in the morphine withdrawal group of rats, comparing to that of saline control. The reduction of excitability is presented as increased rheobase current to generate the first spike and reduced spike number evoked by the same intensity of depolarizing current. The change of excitability is accompanie by the alterations of other membrane properties, such as the hyperpolarization of resting membrane potential, decrease of membrane input resistance and time constant, increase of inward rectification ability et al. Besides of those changes mentioned above, the time couse of action potential is also shortened during morphine withdrawal.The alterations of neuronal excitability, membrane properties and action potential kinetics during short-term withdrawal from repeated morphine exposure could influence the information processing and integration of nucleus accumbens by taking effect on the neuronal active status, neurotransmitter release and synaptic plasticity. Moreover, these changes could also affect the behavioral response of the subject to drug-related stimuli in a similar way. The neuroadaptations observed during morphine withdrawal in this study could be important neuronal substrates mediating reinstatement of drug seeking behavior, which could also be one of the causes underlying the reduction of rewarding effect of natural rewards during drug withdrawal.