It has been described that development and persistent expression of addictive behaviors occur through the usurpation of natural learning and memory mechanisms within the limbic system. The hippocampus (HP) and medial prefrontal cortex (mPFC) have been implicated in the neuropathological mechanisms of drug addiction and withdrawal. In cocaine-abstinent human addicts and rats in similar conditions, neuronal activity of the mPFC is increased in response to cocaine reexposure or drug-associated cues and HP synaptic plasticity was increased after both cocaine and diazepam (DZ) repeated exposure in rats. Nitric oxide (NO) is a diffusible neuromodulator synthesized in the brain primarily by glutamatergic receptors activation, and may play a role in initiating and maintaining behavioral effects of psychostimulants and also in modulation of neuronal excitability and synaptic plasticity in different brain structures including the HP and mPFC. In this chapter we discuss some of the molecular and functional changes within the HP and mPFC induced by repeated cocaine or DZ administration and the pharmacological and methodological strategies used to prevent or reverse DZ dependence and cocaine vulnerability, such as those that interfere with NO signaling, HP plasticity or alter environmental cues related to withdrawal symptoms experience. The mechanisms and strategies presented can be explored as possible targets for development of new therapeutic agents to treat dependence of and addiction to psychoactive drugs.