Farouk Karoum

Bio: Farouk Karoum is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Dopamine & Homovanillic acid. The author has an hindex of 39, co-authored 133 publications receiving 5255 citations. Previous affiliations of Farouk Karoum include University of Colorado Denver & St. Elizabeths Hospital.

Restoration of dopaminergic function by grafting of fetal rat substantia nigra to the caudate nucleus: long-term behavioral, biochemical, and histochemical studies.

Abstract: Motor deficits produced in rats by unilateral substantia nigra lesions have been found to be reduced by grafts of fetal rat substantia nigra to the dopamine denervated caudate nucleus. In the present study these grafts were examined behaviorally, histochemically, and biochemically over six to 10-month periods. The grafts were found to survive in a healthy condition and contain catecholaminergic cells and fibers after eight to ten months. Concentrations of dopamine in adjoining parts of the caudate nucleus were increased when examined six months after grafting. Apomorphine induced rotation was reduced by the grafts, and these reductions persisted for at least six months. Although signs of aging were observed in the brains of the host animals when sacrificed eight to ten months after grafting, the grafts remained healthy and showed no signs of aging or deterioration. It is concluded that substantia nigra grafts can become permanent, functional constituents of the brains of host animals with prior substantia nigra lesions.

3-Methoxytyramine Is the Major Metabolite of Released Dopamine in the Rat Frontal Cortex: Reassessment of the Effects of Antipsychotics on the Dynamics of Dopamine Release and Metabolism in the Frontal Cortex, Nucleus Accumbens, and Striatum by a Simple Two Pool Model

Abstract: 3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used, respectively, to assess the dynamics of dopamine (DA) release and turnover in the rat frontal cortex, nucleus accumbens, and striatum. Assuming total (re)uptake and metabolism of released DA are relatively uniform among the three brain regions, a simplified two pool model was used to assess the metabolic fate of released DA. Under basal conditions, 3-MT formation was found to comprise >60% of total DA turnover (sum of 3-MT plus DOPAC rates of formation) in the frontal cortex, and not more than 15% in the nucleus accumbens and striatum. Haloperidol increased the 3-MT rate of formation to a greater extent in the frontal cortex than in the two other regions. Clozapine increased the 3-MT rate of formation in the frontal cortex and decreased it in the striatum. Both drugs increased DOPAC rate of formation in the frontal cortex and nucleus accumbens. It was elevated by haloperidol but not clozapine in the striatum. It is concluded that (1) O-methylation is a prominent step in the catabolism of DA in the frontal cortex under both physiological conditions and after acute treatment with antipsychotics, (2) 3-MT is the major metabolite of released DA in the frontal cortex and possibly also in the nucleus accumbens and striatum, (3) in contrast to the frontal cortex, most of the DOPAC in the nucleus accumbens and striatum appear to originate from intraneuronal deamination of DA that has not been released, (4) because presynaptic uptake and metabolism of DA give rise to DOPAC, whereas postsynaptic uptake and metabolism produced both DOPAC and 3-MT, the ratio of 3-MT to DOPAC rates of formation can be a useful index of reuptake inhibition.

Increased stress response and β–phenylethylamine in MAOB –deficient mice

Abstract: MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines1–5. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and nore-pinephrine (NE), whereas MAOB preferentially oxidizes β-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control6,7. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease8,9, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-ll alcoholism and in cigarette smokers10,11. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect12,13. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

Norepinephrine and Its Metabolites in Cerebrospinal Fluid, Plasma, and Urine: Relationship to Hypothalamic-Pituitary-Adrenal Axis Function in Depression

Abstract: Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients.

Phenylethylamine in paranoid chronic schizophrenia.

Abstract: Phenylethylamine (PEA) is an endogenous amine that is structurally and pharmacologically related to amphetamine. Urinary PEA excretion is significantly higher in paranoid chronic schizophrenics than in nonparanoid chronic schizophrenics and normal controls. Diet, hospitalization, and medication do not account for differences in PEA concentrations. These findings offer some indication that PEA may be an endogenous amphetamine.

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

Abstract: Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

A neuropsychological theory of positive affect and its influence on cognition.

Abstract: Positive affect systematically influences performance on many cognitive tasks. A new neuropsychological theory is proposed that accounts for many of these effects by assuming that positive affect is associated with increased brain dopamine levels. The theory predicts or accounts for influences of positive affect on olfaction, the consolidation of long-term (i.e., episodic) memories, working memory, and creative problem solving. For example, the theory assumes that creative problem solving is improved, in part, because increased dopamine release in the anterior cingulate improves cognitive flexibility and facilitates the selection of cognitive perspective.

Dopamine in Schizophrenia: A Review and Reconceptualization

Abstract: Objective: The initial hypothesis that schizophrenia is a manifestation of hyperdopaminergia has recently been faulted. However, several new findings suggest that abnormal, although not necessarily excessive, dopamine activity is an important factor in schizophrenia. The authors discuss these findings and their implications. Method: All published studies regarding dopamine and schizophrenia and all studies on the role of dopamine in cognition were reviewed. Attention has focused on post-mortem studies, positron emission tomography, neuroleptic drug actions, plasma levels of the dopamine metabolite homovanillic acid (HVA), and cerebral blood flow. Results: Evidence, particularly from intracellular recording studies in animals and plasma HVA measurements, suggests that neuroleptics act by reducing dopamine activity in mesolimbic dopamine neurons. Post-mortem studies have shown high dopamine and HVA concentrations in various subcortical brain regions and greater than normal dopamine receptor densities in the brains of schizophrenic patients. On the other hand, the negative/deficit symptom complex of schizophrenia may be associated with low dopamine activity in the prefrontal cortex. Recent animal and human studies suggest that prefrontal dopamine neurons inhibit subcortical dopamine activity. The authors hypothesize that schizophrenia is characterized by abnormally low prefrontal dopamine activity (causing deficit symptoms) leading to excessive dopamine activity in mesolimbic dopamine neurons (causing positive symptoms). Conclusions: The possible co-occurrence of high and low dopamine activity in schizophrenia has implications for the conceptualization of dopamine ‘s role in schizophrenia. It would explain the concurrent presence of negative and positive symptoms. This hypothesis is testable and has important implications for treatment of schizophrenia and schizophrenia spectrum disorders.

The Neuropsychiatric Inventory: Assessing psychopathology in dementia patients

Abstract: The Neuropsychiatric Inventory (NPI) was developed to assess psychopathology in dementia patients. It evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The severity and frequency of each neuropsychiatric symptom are rated on the basis of scripted questions administered to the patient's caregiver. The NPI also assesses the amount of caregiver distress engendered by each of the neuropsychiatric disorders. A total NPI score and a total caregiver distress score are calculated, in addition to the scores for the individual symptom domains. Content validity, concurrent validity, inter-rater reliability, and test-retest reliability of the NPI are established. Different neurologic disorders have characteristic neuropsychiatric manifestations and distinctive NPI profiles. The NPI is sensitive to treatment effects and has demonstrated the amelioration of behavioral symptoms in Alzheimer's disease by cholinergic agents. The NPI is a useful instrument for characterizing the psychopathology of dementia syndromes, investigating the neurobiology of brain disorders with neuropsychiatric manifestations, distinguishing among different dementia syndromes, and assessing the efficacy of treatment.