Post-traumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and anti-stress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an anti-stress neuropeptide in the brain that promotes resilience in animal models of PTSD. METHODS: [ 11 C]NOP-1A PET was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [ 11 C]NOP-1A data from 18 healthy controls was also included to provide a contrast with the sexual violence group. [ 11 C]NOP-1A total distribution volume (V T) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional V T and Clinician-Administered PTSD Scale total symptom and subscale severity were examined using correlational analyses. RESULTS: No differences in [ 11 C]NOP-1A V T were noted between the sexual violence and control groups. V T in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month prior to PET. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their V T with that in controls showed no group differences. CONCLUSION: Decreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.
Phosphodiesterase-10a (PDE10a) is located exclusively in medium spiny neurons (MSN). Rodent studies show an increase in striatal MSN spine density following exposure to cocaine. These increases in MSN spine density are suggested to underlie neurobiological changes which contribute to cocaine self-administration. No postmortem or imaging studies have confirmed this finding in humans. Here, we hypothesized an increase in the MSN marker PDE10a in subjects with cocaine use disorder (“cocaine users”) compared to controls. PDE10a availability was measured with [11C]IMA107 and PET in 15 cocaine users and 15 controls matched for age, gender, and nicotine status. Cocaine users with no comorbid psychiatric, medical, or drug abuse disorders were scanned following two weeks of outpatient-monitored abstinence. [11C]IMA107 binding potential relative to nondisplaceable uptake (BPND) in the regions of interest were derived with the simplified reference tissue method. No significant effect of diagnosis on BPND was demonstrated using linear mixed modeling with [11C]IMA107 BPND as the dependent variable and regions of interest as a repeated measure. There were no significant relationships between BPND and clinical rating scales. To the extent that PDE10a is a valid proxy for MSN spine density, these results do not support its increase in recently abstinent cocaine users.
Addiction is composed of three phases: intoxication, withdrawal, and craving. Negative reinforcement, strengthening a behaviour by removing an aversive stimulus, has been associated with the withdrawal phase. An imbalance of neurotransmitters within the brain's stress (nociceptin, neuropeptide Y) and anti-stress (CRF, norepinephrine, etc.) system is attributed to negatively reinforced compulsive behaviours associated with relapse. Similarly, post-traumatic stress disorder is characterized by an overactive stress system. In a PTSD mouse model, rodents exhibited impaired cued-fear memory consolidation when nociceptin transmission was blocked. Furthermore, a single-nucleotide polymorphism has been identified between women diagnosed with PTSD and the severity of PTSD symptoms, suggesting a genetic basis. Therefore, it is critical to understand the functions and interactions between the brain's stress and anti-stress neurotransmitters, specifically nociceptin. This paper will examine the hypothalamic-pituitary-adrenocortical axis, evaluate the functions of corticotropin-releasing-factor and nociceptin, discuss nociceptin's role as an anxiolytic or anxiogenic, and discuss PET-imaging studies-all of which targeted nociceptin receptors (NOP-R). Finally, the discussion of pharmacological interventions will be proposed as preventative or therapeutic treatments for those suffering from PTSD and substance-use disorders.
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