Affect Dopamine Transmission Research Articles

Estrogen receptors observed at extranuclear neuronal sites and in glia in the nucleus accumbens core and shell of the female rat: Evidence for localization to catecholaminergic and GABAergic neurons.

Estrogens affect dopamine-dependent diseases/behavior and have rapid effects on dopamine release and receptor availability in the nucleus accumbens (NAc). Low levels of nuclear estrogen receptor (ER) α and ERβ are seen in the NAc, which cannot account for the rapid effects of estrogens in this region. G-protein coupled ER 1 (GPER1) is observed at low levels in the NAc shell, which also likely does not account for the array of estrogens' effects in this region. Prior studies demonstrated membrane-associated ERs in the dorsal striatum; these experiments extend those findings to the NAc core and shell. Single- and dual-immunolabeling electron microscopy determined whether ERα, ERβ, and GPER1 are at extranuclear sites in the NAc core and shell and whether ERα and GPER1 were localized to catecholaminergic or γ-aminobutyric acid-ergic (GABAergic) neurons. All three ERs are observed, almost exclusively, at extranuclear sites in the NAc, and similarly distributed in the core and shell. ERα, ERβ, and GPER1 are primarily in axons and axon terminals suggesting that estrogens affect transmission in the NAc via presynaptic mechanisms. About 10% of these receptors are found on glia. A small proportion of ERα and GPER1 are localized to catecholaminergic terminals, suggesting that binding at these ERs alters release of catecholamines, including dopamine. A larger proportion of ERα and GPER1 are localized to GABAergic dendrites and terminals, suggesting that estrogens alter GABAergic transmission to indirectly affect dopamine transmission in the NAc. Thus, the localization of ERs could account for the rapid effects of estrogen in the NAc.

“The path is smooth that leadeth on to danger”: caffeine and psychosis

AimsTo review literature on the importance of caffeine intake with regard to psychosis. The need for intervention with regard to caffeine intake hinges on effectively recognizing potential risks.BackgroundCaffeine is the most widely consumed psychoactive substance worldwide and as such is generally considered acceptable but as a competitive adenosine antagonist, it affects dopamine transmission. Patients with serious mental illness are known to have higher caffeine intakes than the general population. The hierarchy of needs for this patient population is complex, frequently leaving the intake of caffeine under the radar of clinical priorities.MethodPubMed and Google Scholar search for caffeine/coffee and psychosis/schizophreniaResultOf the 43 articles that were considered relevant for clinical practice, caffeine consumption was associated with 1) appearance of psychotic symptoms and episodes (caffeine-induced psychosis) and chronic psychosis in high intake 2) exacerbation of psychosis in schizophrenic patients even in lower intakes, 3) treatment resistance possibly due to interference with antipsychotics (ex. clozapine), 4) abuse and addiction, 5) comorbidity with tobacco smoking and other addictions. Caffeine in low doses was associated with ameliorating cognitive and extrapyramidal side-effects of medication and as a potential treatment strategy for treatment-resistant schizophrenia.ConclusionCaffeine consumption may have a greater impact on psychotic symptoms and episodes than is recognized with negative effects outweighing any potential benefits. Greater awareness of the necessity to quantify caffeine intake and implementation of interventions to curb intake may contribute to better quality of care of serious mental illness. Further research is warranted.

Trace Amine-Associated Receptor 1 Modulates the Locomotor and Sensitization Effects of Nicotine.

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for addiction treatments because it affects dopamine transmission in the mesolimbic pathway. TAAR1 is involved in the effects of addictive drugs, such as amphetamines, cocaine and ethanol, but the impact of TAAR1 on the effects of nicotine, the psychoactive drug responsible for the development and maintenance of tobacco smoking, has not yet been studied. This study was performed to investigate the possible modulatory action of TAAR1 on the effects of nicotine on locomotor behaviors in rats and mice. Pretreatment with the TAAR1 agonist RO5263397 dose-dependently decreased nicotine-induced hyperlocomotion in rats habituated to locomotor boxes, prevented the development of nicotine sensitization and blocked hypermotility in nicotine-sensitized rats at the highest tested dose (10 mg/kg). The lack of TAAR1 failed to affect the effects of nicotine on the locomotion of mutant mice. Based on the results of the present study, TAAR1 activation attenuates the locomotion-stimulating effects of nicotine on rats. These results further support the previously proposed hypothesis that TAAR1 is a promising target for the prevention and treatment of drug addiction. Further studies aimed at analyzing the effects of TAAR1 agonists on animal models of nicotine addiction are warranted.

High Oestradiol Replacement Reverses Response Memory Bias in Ovariectomised Female Rats Regardless of Dopamine Levels in the DorsalStriatum.

Oestrogens influence memory system bias in female rats such that high levels of oestrogen are associated with place (or spatial) memory use, and low oestrogen levels with response (or habitual) memory use. Moreover, striatal-dependent response memory is sensitive to dopamine transmission in the dorsal striatum, and oestrogens have been shown to affect dopamine release in that brain area. In the present study, the effects of oestrogens and dopamine transmission on multiple memory system bias were explored in ovariectomised rats receiving low or high 17β-oestradiol replacement under saline, autoreceptor-activating doses of the dopamine D2 receptor agonist, apomorphine (50 and 80μg/kg), or amphetamine (0.5mg/kg) administration. Furthermore, dorsal striatal dopamine release was measured after administration of the same drug conditions using invivo microdialysis. As expected, high oestradiol rats predominantly used place memory, whereas the opposite pattern was observed in low oestradiol rats. However, the high apomorphine dose statistically significantly altered memory bias in high oestradiol rats from predominant place to predominant response memory, with a similar trend in the low apomorphine dose and the amphetamine group. There was no effect of drugs on memory bias in low oestradiol rats. Rats with high oestradiol replacement receiving amphetamine exhibited greater dorsal striatal dopamine release than low oestradiol replacement rats, and this difference was amplified in the right hemisphere. Furthermore, a logistic regression analysis revealed that oestradiol, but not dorsal striatal dopamine levels, significantly predicted response memory bias. These findings provide further evidence that oestradiol modulates memory system bias, and also that memory bias is changed by systemic apomorphine administration. However, although oestradiol affects dopamine transmission in the dorsal striatum in a lateralised manner, this does not predict memory system bias.

Estrogen receptor α and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum

Estrogens affect dopamine transmission in the striatum, increasing dopamine availability, maintaining D2 receptor density, and reducing the availability of the dopamine transporter. Some of these effects of estrogens are rapid, suggesting that they are mediated by membrane associated receptors. Recently our group demonstrated that there is extra-nuclear labeling for ERα, ERβ, and GPER1 in the striatum, but that ERα and GPER1 are not localized to dopaminergic neurons in this region. GABAergic neurons are the most common type of neuron in the striatum, and changes in GABA transmission affect dopamine transmission. Thus, to determine whether ERα or GPER1 are localized to GABAergic neurons, we double labeled the striatum with antibodies for ERα or GPER1 and GABA and examined them using electron microscopy. Ultrastructural analysis revealed that ERα and GPER1 are localized exclusively to extranuclear sites in the striatum, and ∼35% of the dendrites and axon terminals labeled for these receptors contain GABA immunoreactivity. Binding at membrane-associated ERα and GPER1 could account for rapid estrogen-induced decreases in GABA transmission in the striatum, which, in turn, could affect dopamine transmission in this region.

Estrogen Receptors Are Found in Glia and at Extranuclear Neuronal Sites in the Dorsal Striatum of Female Rats: Evidence for Cholinergic But Not Dopaminergic Colocalization

Estrogens rapidly affect dopamine (DA) neurotransmission in the dorsal striatum (dSTR) and DA-related diseases, such as Parkinson's disease and schizophrenia. How estrogens influence DA function remains unclear, in part, because the ultrastructural localization of estrogen receptors (ER) in the dSTR is not known. Light microscopic studies of the dSTR have suggested the presence of ER. This experiment used electron microscopy to determine whether these ER are at extranuclear sites in the dSTR, providing evidence for a mechanism through which estrogen could rapidly affect DA transmission. The dSTR was labeled with antibodies for ERα, ERβ, and G protein-coupled ER 1 (GPER-1) to confirm whether these ER were present in this brain area. After this, the dSTR was dual labeled with antibodies for ERα or GPER-1 and tyrosine hydroxylase or vesicular acetylcholine transporter to determine whether ER are localized to dopaminergic and/or cholinergic processes, respectively. Ultrastructural analysis revealed immunoreactivity (IR) for ERα, ERβ, and GPER-1 exclusively at extranuclear sites throughout the dSTR. ERα-, ERβ-, and GPER-1-IR are mostly frequently observed in axons and glial profiles but are also localized to other neuronal profiles. Dual labeling revealed that ERα- and GPER-1-IR is not associated with DA axons and terminals but is sometimes associated with cholinergic neurons. Because these receptors are exclusively extranuclear in the dSTR, binding at these receptors likely affects neurotransmission via nongenomic mechanisms.

Nicotine differentially affects dopamine transmission in the nucleus accumbens shell and core of Lewis and Fischer 344 rats

Genetic factors are known to affect the reinforcing properties of nicotine. Thus, inbred Lewis rats have been reported to be more sensitive to nicotine compared to Fischer 344 rats in self-administration, conditioned place preference and drug discrimination paradigms. In order to clarify the mechanisms of these differences we investigated, by means of dual probe microdialysis, the effect of different doses of nicotine (0.05, 0.1, 0.2, 0.4 mg/kg s.c.) on dopamine transmission in the shell and in the core of nucleus accumbens. Behavior was monitored during microdialysis. While no differences were observed between strains in dopamine basal values, Lewis rats, compared to Fischer 344 ones, showed in general a larger increase of DA transmission following nicotine both in the shell and in the core of the nucleus accumbens. In regard to behavioral stimulation no differences were observed between strains at higher doses while at the lowest doses Lewis rats appeared more sensitive than Fischer 344 rats to the locomotor stimulating effects of nicotine. These results suggest that strain-related differences in the sensitivity of mesolimbic dopamine transmission to nicotine might be involved in the reported differences in the reinforcing effect of nicotine in Lewis and Fischer 344 rats.

Caffeine-Induced Psychosis

As a competitive adenosine antagonist, caffeine affects dopamine transmission and has been reported to worsen psychosis in people with schizophrenia and to cause psychosis in otherwise healthy people. We report of case of apparent chronic caffeine-induced psychosis characterized by delusions and paranoia in a 47-year-old man with high caffeine intake. The psychosis resolved within 7 weeks after lowering caffeine intake without use of antipsychotic medication. Clinicians might consider the possibility of caffeinism when evaluating chronic psychosis.

Activation of nociceptin/orphanin FQ‐NOP receptor system inhibits tyrosine hydroxylase phosphorylation, dopamine synthesis, and dopamine D1 receptor signaling in rat nucleus accumbens and dorsal striatum

Nociceptin/orphanin FQ (N/OFQ) has been reported to inhibit dopamine (DA) release in basal ganglia mainly by acting on NOP receptors in substantia nigra and ventral tegmental area. We investigated whether N/OFQ could affect DA transmission by acting at either DA nerve endings or DA-targeted post-synaptic neurons. In synaptosomes of rat nucleus accumbens and striatum N/OFQ inhibited DA synthesis and tyrosine hydroxylase (TH) phosphorylation at Ser40 via NOP receptors coupled to inhibition of the cAMP/protein kinase A pathway. Immunofluorescence studies showed that N/OFQ preferentially inhibited phospho-Ser40-TH in nucleus accumbens shell and that in this subregion NOP receptors partly colocalized with either TH or DA D(1) receptor positive structures. In accumbens and striatum N/OFQ inhibited DA D(1) receptor-stimulated cAMP formation, but failed to affect either adenosine A(2A) or DA D(2) receptor regulation of cAMP. In accumbens slices, N/OFQ inhibited DA D(1)-induced phosphorylation of NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, whereas in primary cultures of accumbal cells, which were found to coexpress NOP and DA D(1) receptors, N/OFQ curtailed DA D(1) receptor-induced cAMP-response element-binding protein phosphorylation. Thus, in accumbens and striatum N/OFQ exerts an inhibitory constraint on DA transmission by acting on either pre-synaptic NOP receptors inhibiting TH phosphorylation and DA synthesis or post-synaptic NOP receptors selectively down-regulating DA D(1) receptor signaling.

DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability

The C957T polymorphism in the dopamine D2 receptor (DRD2) gene and the Val158Met polymorphism in the Catechol- O-Methyl-Transferase (COMT) gene affect dopamine transmission and have been found to be associated with schizophrenia. Since DRD2 in mice and the COMT gene in humans modulate working memory, we examined the relationship and possible interaction of both polymorphisms to working memory performance in 188 healthy adults. Subjects having the DRD2 C/C allele showed the poorest performance in a word serial position test. Moreover, the effect of the C957T genotype was strengthened when interaction with the COMT Val158Met polymorphism was included in the analysis. We propose that an interaction of the DRD2 C957T and COMT Val158Met may be involved in the generation of some working memory deficits in schizophrenia.

The substance P (SP) heptapeptide fragment SP 1–7 alters the density of dopamine receptors in rat brain mesocorticolimbic structures during morphine withdrawal

The aminoterminal fragment of substance P (SP), SP 1–7, has been suggested to modulate the expression of opiate tolerance and withdrawal behaviors in rodents. However, the mechanism of this effect is not yet clarified. Using a rat model we have previously demonstrated that SP 1–7 affects dopamine transmission and the expression of the dopamine D2-receptor gene transcript in the nucleus accumbens during naloxone precipitated morphine withdrawal. In the present study, we have applied autoradiography to investigate the effect of the heptapeptide on the binding of dopamine D1- and D2-receptors in mesocorticolimbic brain areas of male rats during morphine withdrawal. Morphine dependent animals were treated with an injection of SP 1–7 into the ventral tegmental area prior to naloxone challenge. The result indicated that the SP fragment elicited a significant decrease in specific binding to D1-like receptors in the caudate putamen, nucleus accumbens shell, nucleus accumbens core, substantia nigra and medial globus pallidus. Radioligand binding to dopamine D2-like receptors was also altered by SP 1–7. The heptapeptide induced a decreased density of these sites in the ventral tegmental area but an increased binding in the substantia nigra and the frontal cortex. The observed alterations in the D1- and D2-like receptor density could reflect activations in dopamine pathways associated with the above-mentioned brain regions. The result provides further evidence for the modulatory effect of SP 1–7 on dopamine systems during opioid withdrawal, suggesting the possible role for the heptapeptide to regulate morphine withdrawal reactions.

It's all in the timing

Timing is crucial to many aspects of human performance – from catching a cricket ball to delivering a punch line. A recent study sheds new light on the identity of the brain's timekeeper [Rao, S.M. et al. (2001) Nature Neurosci. 4, 317–323]. Subjects were asked to compare the time intervals between two pairs of sounds. Using event-related fMRI, the researchers were able to separate out activation occurring at different stages of the task. Activation after the first pair of sounds reflected encoding of timing information, whereas later activation associated with comparison of the time intervals reflected more general processes of decision making and response preparation. Early activation was detected in the basal ganglia and right parietal cortex. This concurs with the observation that people with Parkinson's disease, which affects dopamine transmission in the basal ganglia, are impaired with regard to time perception. By contrast, activation of the cerebellum, which is often hypothesized to be the brain's timekeeper, was detected only later in the task. HJB

Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain

The present study was performed to determine the effects of neonatal excitotoxic lesions of the left entorhinal cortex on dopamine (DA) metabolism and release in limbic regions of the rat brain. Quinolinic acid or phosphate buffered saline was infused into the left entorhinal cortex of rat pups on postnatal day 7 (PD7). Concentrations of DA,3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the lateral amygdala, nucleus accumbens, caudate-putamen, and medial prefrontal cortex were determined in the postmortem brains of lesioned and sham-operated rats on PD35 and PD56. On PD35, concentrations of DA in the bilateral lateral amygdala and HVA in the left lateral amygdala were significantly increased in lesioned rats compared with sham-operated animals, while no significant change was observed in the other three brain areas. On PD56, in addition to the increased concentration of DA in the left lateral amygdala, those of DA, DOPAC and HVA in the caudate-putamen, and DA in the nucleus accumbens were found to be increased, but DA concentrations in the right medial prefrontal cortex were decreased. The DOPAC/DA concentration ratio was, however, decreased in the amygdala and nucleus accumbens of the lesioned rats. In an in vivo microdialysis study, methamphetamine (MAP: 2 mg/kg, i.p.)-induced DA release in the amygdala of lesioned rats was significantly enhanced compared with sham-operated rats on both PD35 and PD56. There were no significant differences in MAP-induced DA release in the caudate-putamen between the sham-operated and lesioned rats at any time point. These findings provide evidence that neonatally induced structural abnormalities in the entorhinal cortex affect DA transmission in the limbic regions at the adolescent stage.

Sodium depletion and aldosterone decrease dopamine transporter activity in nucleus accumbens but not striatum

Motivated behaviors, including sodium (Na) appetite, are correlated with increased dopamine (DA) transmission in the nucleus accumbens (NAc). DA transporter (DAT) modulation affects DA transmission and may play a role in motivated behaviors. In vivo Na depletion, which reliably induces Na appetite, was correlated with robust decreases in DA uptake via the DAT in the rat NAc with rotating disk electrode voltammetry [1,277 +/- 162 vs. 575 +/- 89 pmol. s-1. g-1; Vmax of transport for control vs. Na-depleted tissue]. Plasma aldosterone (Aldo) levels increase after in vivo Na depletion and contribute to Na appetite. Decreased DAT activity in the NAc was observed after in vitro Aldo treatment (428 +/- 28 vs. 300 +/- 25 pmol. s-1. g-1). Neither treatment affected DAT activity in the striatum. These results suggest that a direct action of Aldo is one possible mechanism by which Na depletion induces a reduction in DAT activity in the NAc. Reduced DAT activity may play a role in generating increased NAc DA transmission during Na appetite, which may underlie the motivating properties of Na for the Na-depleted rat.

Dopamine and the mechanisms of cognition: Part II. D-amphetamine effects in human subjects performing a selective attention task

A neural network computer model described in a companion paper predicted the effects of increased dopamine transmission on selective attention under two different hypotheses. To evaluate these predictions we conducted an empirical study in human subjects of D-amphetamine effects on performance of the Eriksen response competition task. Ten healthy volunteers were tested before and after placebo or D-amphetamine in a double-blind cross-over design. D-amphetamine induced a speeding of reaction time overall and an improvement of accuracy at fast reaction times but only in the task condition requiring selective attention. This pattern of results conforms to the prediction of the model under the hypothesis that D-amphetamine primarily affects dopamine transmission in cognitive rather than motor networks. This suggests that the principles embodied in parallel distributed processing models of task performance may be sufficient to predict and explain specific behavioral effects of some drug actions in the central nervous system.

The Effect of Amoxapine and Imipramine on Serum Prolactin Levels

The effect of traditional tricyclic antidepressants on serum prolactin levels is controversial. In a five-week double-blind study of depressed outpatients, imipramine hydrochloride therapy did not lead to any significant change in serum prolactin levels. In contrast, amoxapine, a new antidepressant, produced significant elevations in serum prolactin levels in female and in male patients. Amoxapine may block dopamine receptors in central tuberoinfundibular pathways, which would account for its prolactin-elevating activity. On the other hand, imipramine and other traditional tricyclic antidepressants do not affect dopamine transmission, do not raise serum prolactin levels, and are not effective antipsychotic drugs.

The effect of amoxapine and imipramine on serum prolactin levels

• The effect of traditional tricyclic antidepressants on serum prolactin levels is controversial. In a five-week double-blind study of depressed outpatients, imipramine hydrochloride therapy did not lead to any significant change in serum prolactin levels. In contrast, amoxapine, a new antidepressant, produced significant elevations in serum prolactin levels in female and in male patients. Amoxapine may block dopamine receptors in central tuberoinfundibular pathways, which would account for its prolactin-elevating activity. On the other hand, imipramine and other traditional tricyclic antidepressants do not affect dopamine transmission, do not raise serum prolactin levels, and are not effective antipsychotic drugs. (<i>Arch Intern Med</i>1981;141:1023-1025)