Control of the serotonergic system by the medial prefrontal cortex: potential role in the etiology of PTSD and depressive disorders

The prefrontal cortex is involved in an array of higher brain functions that are altered in psychiatric disorders. Serotonergic neurons of the midbrain rapbe nuclei innervate the prefrontal cortex and are the cellular target for drugs used to treat mood disorders such as the selective serotonin (5-HT) reuptake inhibitors. Anatomical evidence supports the existence of projections from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DR). We report on a functional control of the activity of DR 5-HT neurons by projection neurons in the mPFC. The stimulation of the mPFC elicits two types of responses in DR 5-HT neurons, orthodromic excitations and inhibitions. Excitations are mediated by AMPA/KA and NMDA receptors whereas inhibitions are mediated by GABA(A) and 5-HT(1A) receptors. The activation of a subgroup of 5-HT neurons increases 5-HT release which subsequently activates 5-HT(1A) autoreceptors on other 5-HT neurons. GABA(A)-mediated inhibitions involve GABAergic elements in the DR or adjacent areas. Pyramidal neurons of the mPFC co-express postsynaptic 5-HT(1A) (inhibitory) and 5-HT(2A) (excitatory) receptors. Consistent with the above observations, the selective activation of both receptors in mPFC reduced and increased, respectively, the firing activity of DR 5-HT neurons and the 5-HT release in mPFC. Overall, these data indicate that the activity of the 5-HT system is strongly controlled by the mPFC. Thus, the abnormal prefrontal function in post-traumatic stress disorder and depressive patients may induce a disregulation of 5-HT neurons projecting to other brain areas that can underlie the existing symptomatology in these psychiatric disorders.     

Parkinson's disease: imaging update

PURPOSE OF REVIEW: We aim to review recent neuroimaging contributions to our understanding of the cause and pathogenesis of Parkinson's disease, as well as treatment-related complications of disease, with a focus on functional anatomy and neurochemistry. RECENT FINDINGS: Recent reports describe altered dopaminergic activity in extrastriatal regions, as well as changes in other monoaminergic systems, such as serotonin. Attempts to correlate altered dopaminergic function with personality traits have also been described in the last year. The role of different markers of presynaptic dopaminergic integrity in the assessment of disease progression is discussed, as is the role of biomarkers in detection of preclinical disease. Cerebral activation studies not only confirm altered function of cortico-striatal-thalamo-cortical loops in Parkinson's, but also emphasize the importance of networks involving the cerebellum. The ability to detect changes in synaptic availability of dopamine using positron emission tomography with [(11)C]raclopride is reviewed, including the application to detect altered levels of dopamine in response to pharmacological, mechanical and behavioral stimuli. Such studies have been used to identify altered patterns associated with the development of motor fluctuations, as well as a biochemical substrate underlying the placebo effect in Parkinson's. SUMMARY: Functional imaging studies can provide novel insights into the etiopathogenesis of Parkinson's disease, as well as the mechanisms that contribute to complications of long-term therapy. They also shed light on the mechanisms that may underly behavioral changes and benefit derived from surgical interventions.     

Evidence for environmental causation of Parkinson's disease

To address the question of whether Parkinson's disease (PD) is a genetic or an environmental disorder; (i) we modeled the hazard of PD using two-parameter hazard functions; and (ii) we investigated whether the hazard rate of index cases depended on the age of symptom onset in the affected parent (genetic model) or depended on the age of the index case at the time the affected parent developed PD (environmental model). We found that the hazard of PD increased monotonically with age according to a Weibull function. The risk associated with the presence of maternal PD did not depend on the age of onset of the affected mother but on the child's age at the time, the affected mother developed symptoms. The younger the child when the mother began to have symptoms, the higher the risk for the child. When the affected parent was the father, both models provided similar results. Whichever parent had PD, the age at onset of index cases correlated with their age at the time the affected parent developed PD, but not with the age of onset in the affected parent. Since the degree of environmental exposure shared by parents and children decreases as the child's age increases, these results indicate that PD is usually caused by an accumulation of transient environmental events. We provide evidence that this is not only true for sporadic cases but also for the majority of familial ones.     

Learned fear, emotional reactivity and fear of heights: a factor analytic map from a large F(2) intercross of Roman rat strains

Anxiety-related behaviours were evaluated across various tests in a 800 F(2)-intercross of the Roman high- and low-avoidance inbred rats. These tests either evoke unlearned (open field [OF]; plus-maze [PM]; hole-board [HB]; spontaneous activity [A]; and acoustic startle reflex [ASR]) or learned (classical fear conditioning [CFC]; and shuttlebox avoidance conditioning [SAC]), anxious/fearful responses. Using factor analysis (oblique rotation), we obtained a six-fold solution with 14 variables derived from all tests. These six factors represented SAC, CFC, PM anxiety, PM and OF activity, ASR anxiety, plus a mixed whole of anxious and activity variables (from OF and A), respectively. In searching for a smaller number of meaningful factors, we applied a three-factor solution that coherently corresponded with differentiated facets of fearfulness, rather than with the tests. Results showed that (1) measures of SAC and CFC strongly loaded onto Factor 1, labelled as "Learned Fear"; (2) a blend of almost all variables loaded onto Factor 2, called "Emotional Reactivity"; and (3) open arm behaviour in the PM loaded onto Factor 3, called "Fear of Heights." After discussing limitations of this apparently consistent behavioural map of anxiety, we advance some connections between those factors with quantitative trait loci candidates (genetic markers) as detected in the same sample.     

Comorbid conditions in obsessive-compulsive disorder

The objective of this study was to investigate axis I comorbidity in obsessive-compulsive disorder (OCD). A total of 147 patients diagnosed as OCD for DSM-III-R criteria were included in the study. At least one comorbid axis I disorder was present in 68.7% of the patients. Major depression was the most common comorbid disorder (39.5%). Uncomplicated (n = 46) and comorbid (n = 101) OCD groups were compared with respect to the demographic variables and the scores obtained from the Hamilton Rating Scale for Anxiety (HRSA), the Hamilton Rating Scale for Depression (HRSD) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). No significant difference in terms of age, sex, marital status, age at onset, or duration of illness was found between the groups. The scores on the HRSA, HRSD, and Y-BOCS were significantly higher in the comorbidity group. Our results demonstrate that at least one psychiatric disorder is present in approximately two thirds of OCD patients, the majority being depressive disorders and anxiety disorders. The fact that comorbid conditions raise not only anxiety and depression levels, but also the severity of obsessions and compulsions, is noteworthy.     

Mitochondrial DNA A4336G mutation in Alzheimer's and Parkinson's diseases

OBJECTIVES: To determine whether the mitochondrial DNA (mtDNA) A4336G mutation represents a risk factor for Spanish patients with both Alzheimer's disease (AD) and Parkinson's disease (PD). MATERIAL AND METHODS: One hundred and sixty-one AD and 106 PD unrelated patients were included in the study. Seventy-eight age-matched and 144 randomly chosen healthy subjects served as controls. The frequency of the A4336G mutation in these groups was compared using the chi(2) and Fisher's exact tests. p < 0.05 was established as a statistically significant differential value. RESULTS: The mtDNA A4336G mutation was present in 1/161 of AD patients (0.6%), in 3/106 of PD patients (2.8%), in 1/78 of age-matched controls (1.3%) and in 2/144 of the randomly chosen controls (1.4%). These differences were not statistically significant. CONCLUSION: Our results do not support the hypothesis that this mutation represents a risk factor for either AD or PD patients, at least in the case of this Spanish sample.     

Sex differences and right-left asymmetries in rat hippocampal components

Previous reports have indicated morphologic hippocampal asymmetry in thickness in male and female rats. In the present study, the possible sex differences and right-left asymmetries in rat hippocampal components were investigated. Pyramidal cells in four hippocampal sectors on thionin-stained sections were counted and the thickness of the hippocampal components was measured on microslide-projected images. The present study showed significant sexual dimorphism in two hippocampi as well as asymmetry in male. These findings agree with those found in humans.     

Current role of surgery for the treatment of portal hypertension

Portal hypertension surgery has evolved widely in the last decades. Since the first surgical shunt was done in 1945 for the treatment of recurrent hemorrhage, many surgical options have been developed including selective shunts, low diameter shunts and extensive devascularization procedures. Many of them have been studied and compared showing their advantages and disadvantages, evolving also their role in the therapeutic armamentarium. Surgery is nowadays a second line treatment option (after b blockers and endoscopic therapy), and it's main indication is for patients whose main and only problem is history of bleeding, with good liver function (Child-Pugh A). For emergency situations it has a very limited role and for primary prophylaxis virtually has also no role. Patients with good liver function, electively operated with portal blood flow preserving procedures are the patients that benefit from surgical treatment. Patients with a bad liver function are better candidates for a liver transplant.     

Dopamine release in human ventral striatum and expectation of reward

Using the ability of [11C]raclopride to compete with dopamine for D(2)/D(3) receptors, we investigated by positron emission tomography the effect of placebo (saline) injection on dopamine release in the ventral striatum of patients with Parkinson's disease. We found evidence for placebo-induced dopamine release of similar magnitude to that reported in healthy volunteers after amphetamine administration. However, in contrast to the dorsal striatum, there were no differences in [11C]raclopride binding potential changes between patients who experienced the reward (those who reported placebo-induced clinical benefit) and those who did not. We conclude that the release of dopamine in the ventral striatum (nucleus accumbens) is related to the expectation of reward and not to the reward itself. These observations have potential implications for the treatment of drug addiction.