Dopamine Levels In Prefrontal Cortex Research Articles

Long Mu Qing Xin mixture improves behavioral performance in spontaneously hypertensive rats (SHR/NCrl) by upregulating catecholamine neurotransmitters in prefrontal cortex and striatum via DRD1/cAMP/PKA-CREB signaling pathway.

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder in children, can be effectively alleviated by the herbal preparation Long Mu Qing Xin Mixture (LMQXM), but its mechanism has not been fully elucidated. To scrutinize the potential pharmacological mechanisms by which LMQXM improves behavior in spontaneously hypertensive rats (SHR/NCrl). The SHR/NCrl rats were randomly stratified into the model (SHR) group, the methylphenidate hydrochloride (MPH) group, and groups subjected to varying dosages of LMQXM into the medium dose (MD) group with a clinically effective dose, the low dose (LD) group with 0.5 times the clinically effective dose, and high dose (HD) group with 2 times the clinically effective dose. Furthermore, the WKY/NCrl rats constituted the control group. The evaluation of behavior involved the open field test and the Morris water maze test. HPLC, LC-MS, ELISA, immunohistochemistry, Western blot, and RT-qPCR were utilized to scrutinize the catecholamine neurotransmitter content and the expression of proteins and genes associated with the dopamine receptor D1 (DRD1)/cAMP/protein kinase A (PKA)-cAMP response element-binding (CREB) pathway in prefrontal cortex (PFC) and striatum. MPH and LMQXM ameliorated hyperactivity and learning and memory deficits of SHR/NCrl rats. Among them, LMQXM-MD and MPH also upregulated dopamine (DA), norepinephrine (NE), adenylate cyclase (AC) and cAMP levels, and the expression of proteins and genes associated with the DRD1/cAMP/PKA-CREB pathway in PFC and striatum of SHR/NCrl rats. PFC and striatum DA levels were also upregulated in the LMQXM-LD group as well as the striatum DA levels in the LMQXM-HD group, but there were no statistically significant differences in their NE levels compared to the SHR group. LMQXM-LD and LMQXM-HD also upregulated some DRD1/cAMP/PKA-CREB pathway-related proteins and gene expression, but the effects were discernibly disparate in PFC and striatum. Upon comprehensive analysis, LMQXM-MD appeared to be the most effective dose. Our study tentatively suggests that LMQXM may rectify hyperactivity and learning and memory deficits of SHR/NCrl rats by elevating catecholamine neurotransmitters in the PFC and striatum. This effect may be attributed to the potential activation of the DRD1/cAMP/PKA-CREB signaling pathway, which appears to achieve an optimal response at moderate doses.

Disruption of Astrocyte-Dependent Dopamine Control in the Developing Medial Prefrontal Cortex Leads to Excessive Grooming in Mice

BackgroundAstrocytes control synaptic activity by modulating perisynaptic concentrations of ions and neurotransmitters including dopamine (DA) and, as such, could be involved in the modulating aspects of mammalian behavior. MethodsWe produced a conditional deletion of the vesicular monoamine transporter 2 (VMAT2) specifically in astrocytes (aVMTA2cKO mice) and studied the effects of the lack of VMAT2 in prefrontal cortex (PFC) astrocytes on the regulation of DA levels, PFC circuit functions, and behavioral processes. ResultsWe found a significant reduction of medial PFC (mPFC) DA levels and excessive grooming and compulsive repetitive behaviors in aVMAT2cKO mice. The mice also developed a synaptic pathology, expressed through increased relative AMPA versus NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioral and synaptic phenotypes were rescued by re-expression of mPFC VMAT2 and L-DOPA treatment, showing that the deficits were driven by mPFC astrocytes that are critically involved in developmental DA homeostasis. By analyzing human tissue samples, we found that VMAT2 is expressed in human PFC astrocytes, corroborating the potential translational relevance of our observations in mice. ConclusionsOur study shows that impairment of the astrocytic control of DA in the mPFC leads to symptoms resembling obsessive-compulsive spectrum disorders such as trichotillomania and has a profound impact on circuit function and behaviors.

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

Exposure to unfamiliar odorants induces an array of repetitive defensive and non-defensive behaviors in rodents which likely reflect adaptive stress responses to the uncertain valence of novel stimuli. Mice genetically deficient for dopamine β-hydroxylase (Dbh−/−) lack the enzyme required to convert dopamine (DA) into norepinephrine (NE), resulting in globally undetectable NE and supranormal DA levels. Because catecholamines modulate novelty detection and reactivity, we investigated the effects of novel plant-derived odorants on repetitive behaviors in Dbh−/− mice and Dbh+/− littermate controls, which have catecholamine levels comparable to wild-type mice. Unlike Dbh+/− controls, which exhibited vigorous digging in response to novel odorants, Dbh−/− mice displayed excessive grooming. Drugs that block NE synthesis or neurotransmission suppressed odorant-induced digging in Dbh+/− mice, while a DA receptor antagonist attenuated grooming in Dbh−/− mice. The testing paradigm elicited high circulating levels of corticosterone regardless of Dbh genotype, indicating that NE is dispensable for this systemic stress response. Odorant exposure increased NE and DA abundance in the prefrontal cortex (PFC) of Dbh+/− mice, while Dbh−/− animals lacked NE and had elevated PFC DA levels that were unaffected by novel smells. Together, these findings suggest that novel odorant-induced increases in central NE tone contribute to repetitive digging and reflect psychological stress, while central DA signaling contributes to repetitive grooming. Further, we have established a simple method for repeated assessment of stress-induced repetitive behaviors in mice, which may be relevant for modeling neuropsychiatric disorders like Tourette syndrome or obsessive-compulsive disorder that are characterized by stress-induced exacerbation of compulsive symptoms.

First Demonstration of Double Dissociation between COMT-Met158 and COMT-Val158 Cognitive Performance When Stressed and When Calmer.

We present here the first evidence of the much-predicted double dissociation between the effect of stress on cognitive skills [executive functions (EFs)] dependent on prefrontal cortex (PFC) by catechol-O-methyltransferase (COMT) genotype. The COMT gene polymorphism with methionine (Met) at codon 158 results in more dopamine (DA) in PFC and generally better EFs, while with valine (Val) at codon 158 the result is less PFC DA and generally poorer EFs. Many have predicted that mild stress, by raising PFC DA levels should aid EFs of COMT-Vals (bringing their PFC DA levels up, closer to optimal) and impair EFs of COMT-Mets (raising their PFC DA levels past optimal). We tested 140 men and women in a within-subject crossover design using extremely mild social evaluative stress. On trials requiring EFs (incongruent trials) of the Flanker/Reverse Flanker task, COMT-Val158 homozygotes performed better when mildly stressed than when calmer, while COMT-Met158 carriers performed worse when mildly stressed. Two other teams previously tried to obtain this, but only found stress impairing EFs of COMT-Mets, not improving EFs of COMT-Vals. Perhaps we found both because we used a much milder stressor. Evidently, the bandwidth for stress having a facilitative effect on EFs is exceedingly narrow.

Dopamine effects on memory load and distraction during visuospatial working memory in cognitively normal Parkinson’s disease

ABSTRACT Visuospatial working memory (WM) impairments in Parkinson’s disease (PD) are more prominent and evolve earlier than verbal WM deficits, suggesting some differences in underlying pathology. WM is regulated by dopaminergic neurotransmission in the prefrontal cortex, but the effect of dopamine on specific processes supporting visuospatial WM are not well understood. Dopamine therapeutic effects on different WM processes may also differ given the heterogeneity of cognitive changes in PD. The present study examined the effect of dopamine therapy on memory load and distraction during visuospatial WM. Exploratory analyses evaluated whether individual differences in medication effects were associated with a gene, catechol-O-methyltransferase (COMT), which regulates prefrontal cortex dopamine levels. Cognitively normal PD participants (n = 28) and controls (n = 25) performed a visuospatial WM task, which manipulated memory load and the presence/absence of distractors. PD participants performed the task on and off medication. PD COMT groups were comprised of Met homozygote (lower COMT activity) and heterozygote and Val homozygote carriers (higher COMT activity, Het/Val). The results showed that handling higher memory loads and suppressing distraction were impaired in PD off, but not on medication. Medication improved distraction resistance in Met, but not Het/Val group. COMT did not modulate medication effects on memory load. These findings demonstrate that dopaminergic therapy restores visuospatial WM processes in patients without cognitive impairment and suggest that COMT variants may partly explain the mixed effects of medication on specific processes governed by distinct brain systems. Future investigations into gene-modulated effects of medication could lead to individualized strategies for treating cognitive decline.

Treadmill exercise modifies dopamine receptor expression in the prefrontal cortex of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder for which there is no cure. PD is a dopamine (DA)-deficit disorder marked by progressive motor and nonmotor disturbances, including cognitive impairment. Executive function (EF) is the most common subtype of cognitive impairment in PD and consists of deficits in number of processes including behavioral flexibility. The prefrontal cortex (PFC) is an important brain region subserving EF. Furthermore, DA plays a key neuromodulatory role in the PFC and altered DA neurotransmission is believed to contribute toward EF deficits in PD. The mechanisms underlying PFC dysfunction are not fully understood and there are no effective treatments for EF deficits in PD. Exercise is a promising therapeutic strategy that may exert beneficial effects on PFC function in PD. Our previous work suggests that exercise improves motor function and restores striatal DA-D2 receptor (DA-D2R) expression after DA depletion. This study builds upon our previous work by exploring whether exercise modulates PFC function, specifically DA levels and DA receptor expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mouse model of DA depletion. We found that exercise restores PFC DA levels, reverses the MPTP-induced increase in DA-D1R and decrease in DA-D4R, and exerts differential effects on D2Rs. The modest effect of exercise in PFC function may suggest that other types of exercise, such as those that are more skill based, would be required to target these cognitive behavioral circuits.

Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice.

The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG -/- , PTPRZ -/- , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ -/- mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia. Both knockouts showed elevated dopamine levels in prefrontal cortex, hippocampus, and most particularly amygdala, but not striatum, accompanied by reduced dopamine beta hydroxylase activity only in amygdala. In addition, PTPRG KO elicited a distinct increase in hippocampal serotonin level not observed in PTPRZ KO. PTPRG and PTPRZ gene loss therefore induces distinct patterns of behavioral change and region-specific alterations in neurotransmitters, highlighting their usefulness as models for neuropsychiatric disorder mechanisms and making these receptors attractive targets for therapy.

A frontal dopamine system for reflective exploratory behavior

The COMT gene modulates dopamine levels in prefrontal cortex with Met allele carriers having lower COMT enzyme activity and, therefore, higher dopamine levels compared to Val/Val homozygotes. Concordantly, Val/Val homozygotes tend to perform worse and display increased (interpreted as inefficient) frontal activation in certain cognitive tasks. In a sample of 209 participants, we test the hypothesis that Met carriers will be advantaged in a decision-making task that demands sequencing exploratory and exploitive choices to minimize uncertainty about the reward structure in the environment. Previous work suggests that optimal performance depends on limited cognitive resources supported by prefrontal systems. If so, Met carriers should outperform Val/Val homozygotes, particularly under dual-task conditions that tax limited cognitive resources. In accord with these a priori predictions, Met carriers were more resilient in the face of cognitive load, continuing to explore in a sophisticated manner. We fit computational models that embody sophisticated reflective and simple reflexive strategies to further evaluate participants’ exploration behavior. The Ideal Actor model reflectively updates beliefs and plans ahead, taking into account the information gained by each choice and making choices that maximize long-term payoffs. In contrast, the Naïve Reinforcement Learning (RL) model instantiates the reflexive account of choice, in which the values of actions are based only on the rewards experienced so far. Its beliefs are updated reflexively in response to observed changes in rewards. Converging with standard analyses, Met carriers were best characterized by the Ideal Actor model, whereas Val/Val homozygotes were best characterized by the Naive RL model, particularly under dual-task conditions.

Sex Differences Distinguish Intracortical Glutamate Receptor-Mediated Regulation of Extracellular Dopamine Levels in the Prefrontal Cortex of Adult Rats.

Executive functions of the prefrontal cortex (PFC) are sensitive to local dopamine (DA) levels. Although sex differences distinguish these functions and their dysfunction in disease, the basis for this is unknown. We asked whether sex differences might result from dimorphisms in the glutamatergic mechanisms that regulate PFC DA levels. Using antagonists selective for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, we compared drug effects on in vivo microdialysis DA measurements in the PFC of adult male and female rats. We found that baseline DA levels were similar across sex, AMPA antagonism decreased PFC DA in both sexes, and NMDA antagonism increased DA in males but decreased DA in females. We also found that, at subseizure-producing drug levels, γ-aminobutyric acid (GABA)-A antagonism did not affect DA in either sex but that GABA-B antagonism transiently increased PFC DA in both sexes, albeit more so in females. Finally, when NMDA antagonism was coincident with GABA-B antagonism, PFC DA levels in males responded as if to GABA-B antagonism alone, whereas in females, DA effects mirrored those induced by NMDA antagonism. Taken together, these data suggest commonalities and fundamental differences in the intracortical amino acid transmitter mechanisms that regulate DA homeostasis in the male and female rat PFCs.

Chapter Eight - Effects of the Adenosine A2A Receptor Antagonist on Cognitive Dysfunction in Parkinson's Disease

Parkinson's disease (PD) is primarily characterized by motor abnormalities, but cognitive changes also occur in the early and late stages of the disease process. In PD patients, cognitive dysfunction is associated with reduced quality of life, as well as increased morbidity and mortality, resulting in increases in caregiver burden, and health-related costs. Therefore, safe and effective approaches are needed to treat cognitive dysfunction in PD patients. The underlying pathophysiology of cognitive dysfunction is complex and not fully understood, however. α-Synuclein, amyloid-related proteins, and cholinergic deficits have been reported to partially contribute to cognitive dysfunction. Changes in cortical dopamine (DA) content may also be responsible for early cognitive changes in patients with PD. Certainly, dopaminergic afferents to the frontal cortex degenerate in PD, and there is a reduction of DA content in the prefrontal cortex (PFC). It has also been reported that PFC dopaminergic input plays an important role in working memory performance. Moreover, PFC DA levels and working memory performance are significantly reduced by a 6-hydroxydopamine lesion in the PFC of a rat. Recent findings in the areas of pharmacological manipulation and genetic ablation suggest that the adenosine A2A receptor is also related to cognitive functions, especially working memory. In addition, the blockade of adenosine A2A receptors reverses cognitive dysfunction in PFC-lesioned rats, and this blocking effect may be due to an increase in PFC DA content. Therefore, adenosine A2A receptor antagonists not only improve motor performance, but they may also lead to improved cognitive function in those with PD.

Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat

Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, but whether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0mg/kg/day for 14days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis. While acute administration of tesofensine (2.0mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. In conclusion, tesofensine produces weight loss together with reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity.

Pharmacological Characterisation of a Structurally Novel α2C ‐Adrenoceptor Antagonist ORM‐10921 and its Effects in Neuropsychiatric Models

The α2-adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three α2-AR subtypes (α2A , α2B and α2C ) have been available, the pharmacological profile of a new α2C-selective AR antagonist ORM-10921 is reported. Standard in vitro receptor assays and antagonism of α2, and α1-AR agonist-evoked responses in vivo were used to demonstrate the α2C-AR selectivity for ORM-10921 which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK-801. The Kb values of in vitro α2C-AR antagonism for ORM-10921 varied between 0.078-1.2 nM depending on the applied method. The selectivity ratios compared to α2A-AR subtype and other relevant receptors were 10-100 times in vitro. The in vivo experiments supported its potent α2C-antagonism combined with only a weak α2A-antagonism. In the pharmacodynamic microdialysis study, ORM-10921 was found to increase extracellular dopamine levels in prefrontal cortex in the baseline conditions. In the behavioural tests, ORM-10921 displayed potent antidepressant and antipsychotic-like effects in the forced swimming test and prepulse-inhibition models analogously with the previously reported results with structurally different α2C-selective AR antagonist JP-1302. Our new results also indicate that ORM-10921 alleviated the NMDA-antagonist-induced impairments in social behaviour and watermaze navigation. This study extends and further validates the concept that α2C -AR is a potential therapeutic target in CNS disorders such as schizophrenia or Alzheimer's disease and suggests the potential of α2C-antagonism to treat such disorders.

Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex

Altered cognitive function is a common feature of both the early and later stages of Parkinson's disease (PD) that involves alterations in cortical dopamine content. Adenosine A2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined. The present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A2A antagonist administration modulates dopamine levels in the PFC. Bilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied. PFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC-lesioned rats. PFC dopaminergic input plays an important role in working memory performance. Blockade of A2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition.

Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val158 Met polymorphism in adults with 22q11 deletion syndrome

22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22, which includes the gene coding for catechol-O-methyl-transferase (COMT). High dopamine (DA) levels due to COMT haplo-insufficiency may be associated with the increased risk of developing schizophrenia in adults with 22q11DS. Reduced prepulse inhibition (PPI) of the acoustic startle response has been associated with schizophrenia and with disrupted DAergic transmission in the prefrontal cortex (PFC). COMT Val(158)Met polymorphism has been shown to influence PPI. We report the first study in adults with 22q11DS to examine PPI of the acoustic startle response and its modulation by COMT Val(158)Met polymorphism. Startle reactivity (SR) and PPI of the acoustic startle response were measured in 23 adults with 22q11DS and 21 healthy controls. 22q11DS subjects were genotyped for the functional COMT Val(158)Met polymorphism. 22q11DS Met hemizygotes showed reduced SR and PPI compared with 22q11DS Val hemizygotes. The effect of COMT Val(158)Met polymorphism on PPI was no longer significant when controlling for baseline SR. Met hemizygosity in 22q11DS is associated with reduced SR and influences PPI indirectly. Decreased PFC functioning following excessive PFC DA levels may be one of the mechanisms by which the Met genotype in 22q11DS disrupts SR.

Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Rat Prefrontal Cortical Dopamine Response to Dual Acting Norepinephrine Reuptake Inhibitor and 5-HT1A Partial Agonist

Evidence suggests that compounds possessing both norepinephrine reuptake inhibition and 5-HT(1A) partial agonism (NRI/5-HT(1A)) activities may have a greater efficacy in treating neuropsychiatric disorders than compounds possessing either activity alone. The objectives of the present study were first to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the plasma concentrations of atomoxetine (NRI) and buspirone (5-HT(1A) partial agonist), administered alone and in combination, on the prefrontal cortex dopamine levels in rats, and second to use the model developed to characterize the PK/PD relationship of novel NRI/5-HT(1A) compounds, PF-04269339 and PF-03529936, in a NRI/5-HT(1A) drug discovery program. Maximal dopamine elevation was twofold higher after administration of atomoxetine and buspirone in combination, PF-04269339, or PF-03529936 than after administration of atomoxetine or buspirone alone. A mechanism-based extended indirect response model characterized the time profiles of the prefrontal cortex dopamine response to atomoxetine and buspirone, administered alone or in combination. After fixing three mechanism-specific pharmacodynamic parameters (I (max) and γ2 for NRI and γ1 for 5-HT(1A)) based on the model for atomoxetine and/or buspirone, the model fitted the exposure-response profiles of PF-04269339 and PF-03529936 well. Good in vitro-to-in vivo correlation was demonstrated with the compound-specific pharmacodynamic parameters (IC(50) for NRI and SC(50) and S (max) for 5-HT(1A)) across the compounds. In summary, a piecewise modeling approach was used successfully for the characterization of the PK/PD relationship of novel NRI/5-HT(1A) compounds on prefrontal cortex dopamine levels in rats. The application and value of the mechanism-based modeling in the dual pharmacology drug discovery program are also discussed.

Prefrontal Dopamine Levels Determine the Balance between Cognitive Stability and Flexibility

A key mechanism by which the prefrontal cortex (PFC) supports goal-oriented behaviors is attentional set formation: the formation and maintenance of an attentional bias toward relevant features. It has previously been proposed that a common single nucleotide polymorphism (val158met) in the gene that codes for the catechol O-methyltransferase (COMT) enzyme may affect an individual's ability to form and maintain an attentional set by modulating PFC dopamine (DA) levels. Here, we present data from a functional magnetic resonance imaging study that investigated the effect of this polymorphism on the tendency for older adults to display set-like behavior, and we compare these results to preexisting data from Parkinson's Disease (PD) patients. Our results demonstrate that putatively different levels of PFC DA predict both attentional set formation and right dorsolateral PFC (DLPFC) activation. More specifically, while for PD patients, val homozygotes showed heightened DLPFC activation and increased set-like behavior, for healthy older adults, the opposite pattern of results was observed. This interaction between COMT genotype and PD accords well with previous studies that have shown an excess of DA in the PFC in early PD patients and, furthermore, supports the hypothesis that there is an inverted-U shaped functional relationship between PFC DA levels and attentional set formation.

COMT Val158Met, BDNF Val66Met, and OPRM1 Asn40Asp and Methamphetamine Dependence Treatment Response

COMT Val158Met, BDNF Val66Met, and OPRM1 Asn40Asp and Methamphetamine Dependence Treatment Response

Dopamine Effects on Human Error Processing Depend on Catechol-O-Methyltransferase VAL158MET Genotype

Brain dopamine (DA) has been linked to error processing. Because high and low (vs medium) prefrontal cortex (PFC) DA levels may facilitate D2-receptor-related modulations of PFC neural activation patterns, we hypothesized that high and low DA predicts increased error-specific transitions of PFC activity. Male human participants (n = 169) were genotyped for the catechol-O-methyltransferase (COMT) Val158Met polymorphism, associated with low (Val) and medium (Met) PFC DA levels. In addition, DRD2TaqIa and 5-HTTLPR, associated with striatal D(2) receptor density and serotonin uptake, respectively, were assessed. Participants received placebo or a selective DA-D(2) receptor blocker (sulpiride, 200 mg) and performed a Flanker task. EEG was recorded and decomposed into independent brain components (ICs) using independent component analysis. After errors, participants displayed (1) a negative deflection in ICs source-localized to the proximity of the anterior midcingulate cortex [IC-error-related negativity (IC-ERN)], (2) increased midcingulate cortex IC power in the delta/theta frequency range, and (3) slowing in the subsequent trial [posterror slowing (PES)]. Importantly, all, IC-ERN, delta/theta power, and PES were modulated by COMT × Substance interactions such that the Val allele predicted elevated IC-ERN, delta/theta power, and PES after placebo; this association was reversed under sulpiride. Because low doses of sulpiride presumably increase PFC DA levels, the COMT × Substance interaction supports the hypothesis that low (Val, placebo) and high (Met, sulpiride) versus medium (Val, sulpiride; Met, placebo) DA levels elevate reactivity to errors. Consistent with an influence of serotonin on PFC DA, the COMT × Substance interaction was modulated by 5-HTTLPR.

Androgen Influence on Prefrontal Dopamine Systems in Adult Male Rats: Localization of Cognate Intracellular Receptors in Medial Prefrontal Projections to the Ventral Tegmental Area and Effects of Gonadectomy and Hormone Replacement on Glutamate-Stimulated Extracellular Dopamine Level

Although androgens are known to modulate dopamine (DA) systems and DA-dependent behaviors of the male prefrontal cortex (PFC), how this occurs remains unclear. Because relatively few ventral tegmental area (VTA) mesoprefrontal DA neurons contain intracellular androgen receptors (ARs), studies presented here combined retrograde tracing and immunolabeling for AR in male rats to determine whether projections afferent to the VTA might be more AR enriched. Results revealed PFC-to-VTA projections to be substantially AR enriched. Because these projections modulate VTA DA cell firing and PFC DA levels, influence over this pathway could be means whereby androgens modulate PFC DA. To assess the hormone sensitivity of glutamate stimulation of PFC DA tone, additional studies utilized microdialysis/reverse dialysis application of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor subtype-selective antagonists which act locally within the PFC and tegmentally via inhibition or disinhibition of PFC-to-VTA afferents to modulate intracortical DA levels. Here, we compared the effects of these drug challenges in control, gonadectomized, and gonadectomized rats given testosterone or estradiol. This revealed complex effects of gonadectomy on antagonist-stimulated PFC DA levels that together with the anatomical data above suggest that androgen stimulation of PFC DA systems does engage glutamatergic circuitry and perhaps that of the AR-enriched glutamatergic projections from PFC-to-VTA specifically.

The potential and limitations of DOV 216,303 as a triple reuptake inhibitor for the treatment of major depression: A microdialyis study in olfactory bulbectomized rats

DOV 216,303 belongs to a new class of antidepressants, the triple reuptake inhibitors (TRIs), that blocks serotonin, norepinephrine and dopamine transporters and thereby increases extracellular brain monoamine concentrations.The aim of the present study was to measure extracellular monoamine concentrations both in the prefrontal cortex (PFC) and dorsal hippocampus (DH) after chronic administration of DOV 216,303 in the OBX animal model of depression and to compare the effects with acute drug treatment.OBX animals showed lower dopamine levels in PFC upon acute administration of DOV 216,303 than sham animals for up to five weeks after surgery. No such changes were observed in the DH. Unexpectedly, a DOV 216,303 challenge in chronic DOV 216,303 treated sham animals resulted in a blunted dopamine response in the PFC compared to the same challenge in vehicle treated animals. This blunted response probably reflects pharmacokinetic adaptations and/or pharmacodynamic changes, since brain and plasma concentrations of DOV 216,303 were significantly lower after chronic administration compared to acute administration.Surprisingly, and in contrast what we have reported earlier, chronic DOV 216,303 treatment was unable to normalize the hyperactivity of the OBX animals. Interestingly, by measuring the drug plasma and brain levels, it was demonstrated that at the time of behavioral testing (24h after last drug treatment) DOV 216,303 was not present anymore in either plasma or brain. This seems to indicate that this putative antidepressant drug has no lasting antidepressant-like behavioral effects in the absence of the drug in the brain.