Dopaminergic system activity in limbic structures (reward system) is related to motivational processes and adaptation to changing environmental conditions. Stress conditions can cause dopaminergic dysfunction, reduce motivational processes and induce compensatory drug use. The susceptibility to stress is characterized by individual variability. Psychostimulants such as cocaine, amphetamine and its derivatives act as positive reinforcers, affecting mood changes. Prolonged use of psychoactive substances can cause persistent plastic changes in the limbic system (disruption of neurogenesis, neurons atrophy), resulting in addictions or other forms of psychopathology like mood disorders. One of the reason is dysregulation of the dopaminergic system and dysfunction of local dopamine release in the nucleus accumbens. Stress factors also inhibit neuronal plasticity. In turn, antidepressants may increase brain-derived neurotrophic factor (BDNF) and TrkB receptors expression and improve neuronal proliferation, restoring proper functioning of the limbic regions. An important manifestation of the distinct functioning of the dopaminergic mesolimbic system is the difference between the sexes and the aging process. Epidemiological studies indicate that depression, anxiety disorders, and other emotional disorders often accompany drug abuse. The search for neurobiological basis of affective disorders and identification of factors, including epigenetic ones (interdependence of genetic and environmental factors), associated with different susceptibility to stress and predisposition to addiction to psychoactive substances is currently being carried out by many researches. Understanding the neurobiological factors of individual differences related to susceptibility to psychostimulants may aid in developing future therapies adapted to the patient’s needs and more effective treatment of addiction.