Cortical Dopamine Metabolism Research Articles

COMT polymorphism modulates the resting-state EEG alpha oscillatory response to acute nicotine in male non-smokers.

Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists, and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting-state electroencephalographic (EEG) oscillations. In a sample of 62 healthy non-smoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double-blind, placebo-controlled design was shown to affect α oscillatory activity, increasing power of upper α oscillations in frontocentral regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak α frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower α frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain α oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT.

The val158met COMT polymorphism's effect on atrophy in healthy aging and Parkinson's disease

We investigated whether the val158met functional polymorphism of catechol-o-methyltransferase influenced age-related changes in grey matter density and volume, both in healthy individuals (n = 80, ages 18–79) and those with Parkinson's disease (n = 50). Global grey matter volumes and voxelwise estimates of grey matter volume and density were determined from structural magnetic resonance images at 3 T. Male and female ValVal homozygotes (low prefrontal cortical dopamine) had more grey matter in early adulthood, but this difference disappeared with increasing age. The insula and ventral prefrontal cortex had higher grey matter volume in younger, but not older, ValVal homozygotes. Conversely, the dominant premotor cortex revealed genotypic differences in grey matter density in later life. There were no global or local interactions between Parkinson's disease and COMT val158met genotype on morphometry. Since the val158met polymorphism is associated with differences in cortical dopamine metabolism, our data suggest a role for dopamine in cortical development followed by differential vulnerability to cortical atrophy across the adult life span.

In search of susceptibility genes for schizophrenia

After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone.

Stress-induced increase of cortical dopamine metabolism: attenuation by a tachykinin NK 1 receptor antagonist

The present study examined the potential role of tachykinin NK 1 receptors in modulating immobilisation stress-induced increase of dopamine metabolism in rat medial prefrontal cortex. In agreement with previous studies, 20 min immobilisation stress significantly increased medial prefrontal cortex dopamine metabolism as reflected by the concentration of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC). Pretreatment with the high affinity, selective, tachykinin NK 1 receptor antagonist (3( S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethyl amino)-2( S)-phenylpiperidine) (( S)-GR205171, 10 mg/kg, s.c.), a dose that in ex vivo binding studies extensively occupied rat brain tachykinin NK 1 receptors for approximately 60 min, significantly attenuated the stress-induced increase of mesocortical DOPAC concentration without affecting cortical DOPAC levels per se. In contrast, pretreatment of animals with the less active enantiomer ( R)-GR205171 (10 mg/kg, s.c.), which demonstrated negligible tachykinin NK 1 receptor occupancy ex vivo, failed to affect either basal or stress-induced DOPAC concentration in medial prefrontal cortex. Furthermore, pretreatment of animals with the benzodiazepine/GABA A receptor antagonist, flumazenil (15 mg/kg, i.p.), did not affect the ability of ( S)-GR205171 to attenuate the increase of medial prefrontal cortex DOPAC concentration by acute stress. Results demonstrate that the selective tachykinin NK 1 receptor antagonist, ( S)-GR205171, attenuated the stress-induced activation of mesocortical dopamine neurones by a mechanism independent of the benzodiazepine modulatory site of the GABA A receptor.

Persistent and anatomically selective reduction in prefrontal cortical dopamine metabolism after repeated, intermittent cannabinoid administration to rats.

Long-term abuse of delta-9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, produces behavioral and metabolic signs of frontal cortical dysfunction in humans; these effects persist even after short-term abstinence. Based on a preliminary finding that repeated administration of THC to rats reduces basal frontal cortical dopamine turnover (Jentsch et al. [1998] Neurosci Lett 246:169-172), we further investigated the effects of repeated administrations of THC or WIN 55,212-2 (WIN), a synthetic cannabinoid receptor agonist, on dopamine turnover in the prefrontal cortex, striatum, and nucleus accumbens. THC or WIN (twice daily for 7 or 14 days) caused a persistent and selective reduction in medial prefrontal cortical dopamine turnover; no significant alterations of dopamine metabolism were observed in the nucleus accumbens or striatum. Importantly, these dopaminergic deficits in the prefrontal cortex were observed after a drug-free period of up to 14 days. Thus, the cognitive dysfunction produced by heavy, long-term cannabis use may be subserved, in part, by drug-induced alterations in frontal cortical dopamine turnover.

Dopaminergic Parameters During Social Isolation in Low- and High-Active Mice

Alterations induced by social isolation (1 day to 18 weeks) in low- and high-active mice (LAM and HAM) were studied in respect to locomotor activity, [3H]-spiperone binding in the striatum, striatal, and cortical dopamine metabolism, and presynaptic dopaminergic sensitivity to apomorphine (0.75 mg/kg; IP). Isolated HAM and LAM showed increased locomotor activity compared to group-housed mice after long-term isolation (6–18 weeks). Considering the studied dopaminergic parameters, it has been found that social isolation did not affect striatal D2 receptors, striatal and cortical dopamine metabolism, and apomorphine-mediated reduction of dopaminergic metabolism. The change of housing conditions was generally associated with an increase of cortical dopamine metabolism after 1 week. Activity type specific differences in group-housed LAM and HAM were found in the basal striatal dopamine metabolism and in the sensitivity of the nigrostriatal system to autoreceptor activation. The reduced striatal dopamine metabolism and the higher presynaptic sensitivity of HAM may be related to their high active running wheel behavior.

Characterization of the phencyclidine-induced increase in prefrontal cortical dopamine metabolism in the rat.

1. We have investigated the effects of a schizophrenomimetic drug phencyclidine (PCP) and N-methyl-D-aspartate (NMDA)-related agents alone or in combination on dopamine metabolism in the medial prefrontal cortex and striatum of the rats by measuring the tissue concentrations of dopamine and its metabolite, 3,4-dihyroxyphenylacetic acid (DOPAC), and the rate of dopamine disappearance (dopamine utilization) after its synthesis inhibition. 2. Systemic injection of PCP and selective, non-competitive, NMDA antagonists caused an increase of both tissue concentrations of DOPAC and dopamine utilization in the prefrontal cortex but not in the striatum. The PCP-induced augmentation of cortical dopamine metabolism was not influenced by selective lesion of ascending noradrenergic neurones. 3. Intra-prefrontal cortical infusion of PCP or selective competitive or non-competitive antagonists of the NMDA receptor mimicked the ability of systemic PCP injection to enhance DOPAC levels and dopamine utilization in the prefrontal cortex. However, an NMDA antagonist injected into the cell body area of the mesocortical dopaminergic neurones failed to affect dopamine metabolism in the prefrontal cortex. 4. The increasing effects of PCP and selective NMDA antagonists on cortical dopamine utilization were not additive, although a dopamine receptor antagonist, haloperidol, still accelerated the disappearance of dopamine, even in the presence of PCP. 5. Intra-cortical or intra-ventricular infusion of NMDA or D-alanine but not L-alanine, attenuated the ability of systemic PCP administration to facilitate prefrontal dopamine utilization. 6. These data suggest that PCP might activate prefrontal cortical dopaminergic neurones, at least in part, by blocking the NMDA receptor in the prefrontal cortex which participates in a tonic inhibitory control of the mesoprefrontal dopaminergic projections.

Repeated exposure to Δ9-tetrahydrocannabinol reduces prefrontal cortical dopamine metabolism in the rat

Long-term abuse of marijuana by humans can induce profound behavioral deficits characterized by cognitive and memory impairments. In particular, deficits on tasks dependent on frontal lobe function have been reported in cannabis abusers. In the current study, we examined whether long-term exposure to Δ 9-tetrahydrocannabinol, the active ingredient in marijuana, altered the neurochemistry of the frontal cortex in rats. Two weeks administration of Δ 9-tetrahydrocannabinol reduced dopamine transmission in the medial prefrontal cortex, while dopamine metabolism in striatal regions was unaffected. These data are consistent with earlier findings of dopaminergic regulation of frontal cortical cognition. Thus, cognitive deficits in heavy abusers of cannabis may be subserved by drug-induced alterations in frontal cortical dopamine transmission.

L-701,324, a glycine/NMDA receptor antagonist, blocks the increase of cortical dopamine metabolism by stress and DMCM

Dopamine metabolism, as reflected by the concentration of dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex was significantly increased following 30 min immobilisation stress or systemic administration of the benzodiazepine/GABA A receptor inverse agonist methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). The response to stress was attenuated by pretreatment of rats with the benzodiazepine/GABA A receptor agonists diazepam and zolpidem. Furthermore, pretreatment with R-(+)-3-amino-1-hydroxypyrrolid-2-one ( R-(+)-HA-966), a low efficacy partial agonist, and 7-chloro-4-hydroxy-3(3-phenoxy) phenylquinolin-2-( H)-one (L-701,324) a novel, high affinity, full antagonist at the glycine/NMDA receptor attenuated the response to both stress and DMCM. These results demonstrate that antagonists at the glycine/NMDA receptor complex are comparable with benzodiazepine/GABA A receptor agonists in their ability to prevent activation of the mesocortical dopamine system by stress and GABA A receptor inverse agonists. Results are discussed in relation to the interaction between glycine/NMDA receptor antagonists, the mesocorticolimbic dopamine system and stress related disorders.

Contrasting Neurochemical Interactions of Tiletamine, a Potent Phencyclidine (PCP) Receptor Ligand, with the N‐Methyl‐D‐Aspartate‐Coupled and ‐Uncoupled PCP Recognition Sites

Neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate (NMDA)-coupled and -uncoupled PCP recognition sites were examined. Tiletamine potently displaced the binding of [3H]1-(2-thienyl)cyclohexylpiperidine with an IC50 of 79 nM without affecting sigma-, glycine, glutamate, kainate, quisqualate, or dopamine (DA) receptors. Like other PCP ligands acting via the NMDA-coupled PCP recognition sites, tiletamine decreased basal, harmaline-, and D-serine-mediated increases in cyclic cGMP levels and induced stereotypy and ataxia. Tiletamine was nearly five times more potent than PCP at inhibiting the binding of 3-hydroxy[3H]PCP to its high-affinity NMDA-uncoupled PCP recognition sites. However, following parenteral administration, dizocilpine maleate (MK-801), ketamine, PCP, dexoxadrol, and 1-(2-thienyl)cyclohexylpiperidine HCl, but not tiletamine, increased rat pyriform cortical DA metabolism and/or release, a response modulated by the NMDA-uncoupled PCP recognition sites. Pretreatment with tiletamine did not attenuate the MK-801-induced increases in rat pyriform cortical DA metabolism, a result suggesting that tiletamine is not a partial agonist of the NMDA-uncoupled PCP recognition sites in this region. However, following intracerebroventricular administration (100-500 micrograms/rat), tiletamine increased pyriform cortical DA metabolism with a bell-shaped dose-response curve. These data indicate a differential interaction of tiletamine with the NMDA-coupled and -uncoupled PCP recognition sites. The paradoxical effects of tiletamine suggest that tiletamine might activate receptor(s) or neuronal pathways of unknown pharmacology.

Mesocorticolimbic dopaminergic systems and emotional states

We have used the technique of in vivo voltammetry with carbon fibre electrodes to investigate further the involvement of ascending mesencephalic dopaminergic systems in emotional states in freely moving rats. In Sprague-Dawley rats, forced locomotion caused an increase in extracellular DOPAC levels in the striatum and nucleus accumbens but not in the prefrontal cortex. Immobilization (4 min) or systemic injection of the anxiogenic agent methyl-β-carboline carboxylate enhanced extracellular DOPAC in both prefrontal cortex and nucleus accumbens but not in striatum whereas tail-pinch provoked a selective increase in this parameter in the nucleus accumbens. These data suggest that mesolimbic and mesocortical dopaminergic systems can be specifically activated by certain kinds of anxiogenic stimuli. To evaluate the relationship between emotional status and the response of mesocortical dopaminergic neurons to stress, we investigated the effects of stressful conditions on dopamine metabolism in the prefrontal cortex of 2 genetically selected lines of rats which differ drastically in their level of emotionality. Introduction of the animals into an unfamiliar environment, application of a high-intensity loud noise or immobilization were associated with an increase in extracellular cortical DOPAC levels in the hypoemotional (RHA) but not in the hyperemotional (RLA) line. These results suggest that the increase in cortical dopamine metabolism induced by stress is not connected to the emotional reaction caused by the aversive nature of the stressor but may reflect activation of cognitive processes in an attempt to cope with the stressor.

Feeding or exposure to food odors increases extracellular DOPAC levels (as measured by in vivo voltammetry) in the prefrontal cortex of food-deprived rats

The effects of feeding or of exposure to food odors (without opportunity to feed) on dopamine metabolism in the prefrontal cortex have been investigated in rats food deprived for 24 h. Dopamine metabolism was assessed by measuring extracellular DOPAC levels by in vivo voltammetry with carbon fiber electrodes. Feeding in fasted rats was accompanied by an increase in extracellular cortical DOPAC levels which gradually returned to basal levels within 90 min after the onset of meal. A similar, though slightly less pronounced, increase in cortical dopamine metabolism was found in fasted rats exposed to food odors but not allowed to feed. These results indicate that feeding or the olfactory stimulation associated with food presentation causes an increase in mesocortical dopaminergic neuron activity.

Stressful environmental stimuli increase extracellular DOPAC levels in the prefrontal cortex of hypoemotional (Roman high-avoidance) but not hyperemotional (Roman low-avoidance) rats. An in vivo voltammetric study

The effects of a variety of stressful environmental situations on dopamine metabolism in the prefrontal cortex (as assessed by in vivo voltammetry with carbon fiber electrodes) have been compared in two genetically selected lines of rat (Roman high (RHA/Verh) and low (RLA/Verh) avoidance) which differ drastically in their level of emotionality. Heart rate was continuously monitored in these animals (via chronically implanted subcutaneous electrodes) so as to index the emotional reaction to the stressors. An electrochemical signal corresponding to the oxidation of dihydroxyphenylacetic acid (DOPAC) was recorded in the deeper laminae of the anteromedial prefrontal cortex in both lines of rats. Under normal condition, this signal was stable for at least 4 h and its amplitude was similar in both lines. Introduction of the animals into an unfamiliar environment (30 min), application of a mild tail pinch (10 min) or of a high-intensity loud noise (30 min) or immobilization (20 min) were all associated with an increase in extracellular cortical DOPAC levels in the hypoemotional RHA/Verh line but not in the hyperemotional RLA/Verh line. Similarly, forced locomotion on a rotarod (40 min) provoked a dramatic increase in the amplitude of the cortical DOPAC oxidation peak in RHA/Verh rats and only a mild increase in this parameter in RLA/Verh rats. In RHA/Verh rats, tolerance to this increase was observed when animals were subjected to forced locomotion every day for 5 days. All of the stressful situations investigated provoked an immediate augmentation of heart rate which resumed gradually after cessation of the stressful stimulus; the magnitude and duration of this increase were much greater in RLA/Verh than in RHA/Verh rats. Moreover, in all stress situations, RLA/Verh but not RHA/Verh rats showed behavioral signs of emotional response e.g. defecation, freezing and self-grooming. It is concluded that the increase in cortical dopamine metabolism induced by stress is not connected to the emotional reaction caused by the aversive nature of the stressor but may rather reflect a heightened attention of the animal or activation of cognitive processes in an attempt to cope with the stressor.

The effect of long-term concurrent administration of chlorpromazine and lithium on the striatal and frontal cortical dopamine metabolism in rats.

The effects of lithium and chlorpromazine chronically administered alone and together on the dopamine metabolism in the rat striatum and frontal cortex were investigated by measurement of the levels of dopamine (DA) and its main metabolite, homovanillic acid (HVA). Long-term chlorpromazine administration caused a significant increase in the striatal DA level and a decrease in that of HVA and HVA/DA ratio without any changes in those of the frontal cortex. The prolonged administration of lithium elevated the striatal levels of both HVA and DA, but no change in the frontal cortex was observed. The concurrent administration of chlorpromazine and lithium caused a significant increase in the frontal cortical DA level and a decrease in that of HVA and HVA/DA ratio. The striatal DA and HVA levels increased under the effect of the combined treatment, while the HVA/DA ratio remained unchanged.

Antipsychotic drug action in schizophrenic patients: effect on cortical dopamine metabolism after long-term treatment.

In the brains of deceased schizophrenics who underwent long-term treatment with antipsychotic drugs, the concentration of homovanillic acid (a dopamine metabolite) was significantly increased in the orbital frontal, cingulate, and temporal tip areas of the cortex, but not in the putamen or the nucleus accumbens. The concentration of homovanillic acid was normal in the brains of schizophrenics who were not treated with drugs.