Modulation of neuropeptide Y levels is impaired in crack withdrawal patients.

Introduction The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has a key role in drug addiction susceptibility. In addition to the well-known relationship between cortisol and the HPA axis, other molecules are involved with stress response and could modify the HPA activation, such as the neuropeptide Y (NPY), which has anxiolytic proprieties. There are few studies evaluating the effect of NPY levels on addiction, especially in crack cocaine dependence. Objective To evaluate NPY in crack users during early withdrawal to determine its relationship with drug use and cortisol levels. Methods We analyzed 25 male inpatient crack users. Serum NPY levels were measured at admission and discharge (mean of 24 days). Morning salivary cortisol was measured at admission. Results Serum NPY levels at admission and discharge were very similar. Lower NPY levels at discharge were associated with higher lifetime crack use. Also, a negative correlation was found between morning cortisol and delta NPY (NPY discharge - NPY admission). Conclusion These preliminary findings indicate that crack use influences the modulation of NPY levels and modifies stress response. The NPY pathway may play an important role in the pathophysiology of crack addiction, and the anxiolytic effect of NPY may be impaired in crack users. Future studies should consider NPY as a measurable indicator of the biological state in addiction.


Introduction
Drug addiction is associated with several biological dysfunctions. Chronic exposure to drugs of abuse affects the reward system, but evidence also showed that other brain systems are deeply involved with addictive behaviors. 1 Dysregulation of the hypothalamic-pituitaryadrenal (HPA) axis plays a key role in drug susceptibility, addiction severity and craving, 2,3 and is also involved in stress response. In animal studies, it has been shown that the HPA axis is activated after administration of cocaine, which promotes the release of corticotropinreleasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol. 4 Nevertheless, chronic exposure to drugs is also associated with attenuated HPA response. 5 Animal models have demonstrated the essential influence of stress on addiction-related outcomes, being associated with increased self-administration of drugs and the reestablishment of drug seeking behavior. 6 Moreover, the inability to tolerate stress is an important factor that affects drug consumption, relapse and treatment dropout. 7,8 Several studies have shown that neuropeptide Y (NPY) administration can modify the activation of the HPA axis. 9,10 In fact, NPY is associated with anxiolytic effects and with modulation of stress response by inhibiting ACTH and cortisol release in humans and animals. 9,10 NPY is a 36-amino acid peptide widely expressed in the brain and could affect the rewardseeking behavior related to drug addiction. 11 Animal studies showed that acute and chronic alcohol intake decrease NPY expression in brain areas related to reward behavior, such as the parietal cortex, amygdala and hypothalamus. 12,13 Interestingly, NPY administration in the brain reduces alcohol intake in ethanol-abstinent rats 14 and anxiety behavior in alcohol-preferring rats. 15 Conversely, NPY administration in the brain has also been involved with increased cocaine self-administration and hyperactivity. 16 Only

Results
The clinical characteristics of the sample are shown in  (Figure 1).

Discussion
The present study shows, for the first time, the influence of crack addiction on NPY levels during early withdrawal. These findings were strengthened by the two collection time points, which demonstrated that crack users, even without current drug consumption, could exhibit a disruptive stress response.
Our results indicate that lifetime crack use (years of frequent use) has a negative impact on NPY levels during early withdrawal. These findings suggest that crack use is associated with a putative down-regulation of peripheral NPY levels. This occurs specifically during discharge, when stress and craving could be elevated due to abstinence symptoms. 20 This could explain the increase in anxiety symptoms that may lead to early relapse. 21 The variation in NPY levels may be affected primarily by drug use, since NPY levels were not associated with psychiatric comorbidities or childhood maltreatment in our sample (Table S1, available as online-only supplementary material).
Corroborating our findings, animal studies have shown a reduction of NPY levels in the brain during early withdrawal of alcohol and cocaine abuse. Interestingly, this reduction of NPY levels was observed in specific brain areas related to the HPA axis, such as the arcuate nucleus and paraventricular regions of the hypothalamus and the central and medial nucleus of the amygdale. 12,22 It is also known that these brain areas play a key role in addiction severity and craving. 3 Moreover, NPY infusion was associated with decreased activity of pyramidal output neurons in the basolateral amygdala, which was associated with stress resilience. 23,24