Brain Monoamine Function Research Articles

Vapor Cannabis Exposure Promotes Genetic Plasticity in the Rat Hypothalamus

It is well established that cannabis use promotes appetite. However, how cannabis interacts with the brain’s appetite center, the hypothalamus, to stimulate feeding behavior is unknown. A growing body of evidence indicates that the hypothalamic transcriptome programs energy balance. Here, we tested the hypothesis that cannabis targets alternative polyadenylation (APA) sites within hypothalamic transcripts to regulate transcriptomic function. To do this, we used a novel cannabis vapor exposure model to characterize feeding in adult male Long Evans rats and aligned this behavioral response with APA events using a Whole Transcriptome Termini Sequencing (WTTS-Seq) approach as well as functional RNA abundance measurements with real-time quantitative polymerase chain reactions. We found that vapor cannabis exposure promoted food intake in free-feeding and behaviorally sated rats, validating the appetite stimulating properties of cannabis. Our WTTS-Seq analysis mapped 59 unique cannabis-induced hypothalamic APAs that occurred primarily within exons on transcripts that regulate synaptic function, excitatory synaptic transmission, and dopamine signaling. Importantly, APA insertions regulated RNA abundance of Slc6a3, the dopamine transporter, suggesting a novel genetic link for cannabis regulation of brain monoamine function. Collectively, these novel data indicate that a single cannabis exposure rapidly targets a key RNA processing mechanism linked to brain transcriptome function.

Differential change in cortical and hippocampal monoamines, and behavioral patterns in streptozotocin-induced type 1 diabetic rats.

Objective(s):Diabetes mellitus (DM) is a widespread metabolic disorder worldwide. Clinical physicians have found diabetic patients have mild to middle cognitive dysfunction and an alteration of brain monoaminergic function. This study explored the change in various patterns of behavioral models and brain monoamine function under streptozotocin (STZ)-induced type 1 diabetes.Materials and Methods:We established a type 1 DM model via intravenous injection with STZ (65 mg/kg) in rats. Three weeks after the STZ injection, various behavioral measurements including the inhibitory avoidance test, active avoidance test and Morris water maze were conducted. Finally, all rats were dissected and the concentrations of monoamines and their metabolites in cortex and hippocampus were measured by high performance liquid chromatography with electrochemical detection.Results:We found that STZ induced type 1 diabetes (hyperglycemia and lack of insulin) in rats. STZ-induced diabetic rats had cognitive impairment in acquisition sessions and long-term retention of the active avoidance test. STZ-induced diabetic rats also had cognitive impairment in spatial learning, reference and working memory of the Morris water maze. STZ significantly reduced concentrations of norepinephrine (NE) in the cortex and dopamine (DA) in the hippocampus, but increased concentrations of DA and serotonin (5-HT) in the cortex 35 days after injection. The concentration of 5-HT in the hippocampus was also significantly increased.Conclusion:The data suggested that this cognitive impairment after a short-term period of STZ injection might be related to cortical NE dysfunction, differential alteration of cortical and hippocampal DA function, and brain 5-HT hyperfunction.

Acute Serotonin and Dopamine Depletion Improves Attentional Control: Findings from the Stroop Task

Schizophrenia is associated with impairments of attentional control on classic experimental paradigms such as the Stroop task. However, at a basic level the neurochemical mechanisms that may be responsible for such impairments are poorly understood. In this study, we sought to investigate the influence of brain monoamine function on Stroop task performance in healthy participants using the established methods of acute dietary serotonin, dopamine, and combined monoamine depletion. The study was a double-blind placebo controlled design in which 12 healthy male participants completed the Stroop task under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Decreased Stroop interference indicating improved attentional control was observed after both tryptophan depletion and tyrosine/phenylalanine depletion, while there was no significant change in interference after combined monoamine depletion. Findings suggest that reduced tonic dopamine or serotonin activity within specific neural circuits (such as the striatum, anterior cingulate, or prefrontal cortex) may play a critical role in attentional control, possibly by improving gating of information via reducing noise in monoaminergic systems. These findings enhance our understanding of the neurochemical basis of attentional control and the possible cause of attentional control deficits in schizophrenia.

Effects of treatment with chromium picolinate on peripheral amino acid availability and brain monoamine function in the rat.

Elemental chromium (Cr) is an essential micronutrient. It is required for optimal insulin activity and normal carbohydrate and lipid metabolism. Tri-valent chromium (Cr3+) is recommended for the treatment of diabetes and obesity. There is evidence that Cr3+ may have antidepressant properties, possibly by enhancement of monoamine function through its ability to increase amino acid transport to the brain. The aim of the present study was to investigate further the possible effects of Cr3+ treatment on peripheral amino acid availability and brain monoamine function in the rat. We undertook three studies in rats. The first was a time-course study in which animals were administered single doses of 50 mg/kg of Cr3+ picolinate and the second a dose-response study in which animals were given either 20 or 50 mg/kg Cr3+ picolinate versus vehicle alone via the intra-peritoneal route. In the third, animals were fed a diet containing Cr3+ picolinate (100 mg/kg) or a similar control diet for two weeks and were then sacrificed. Blood was sampled and brains were removed for later analysis. Results from the Cr3+ time-course study defined an optimal time for sampling of two hours after dosing. Results from the second study showed dose-related responses to Cr3+ treatment for a number of measured biochemical parameters including serum corticosterone. In the sub-chronic treatment study Cr3+ significantly increased serum free tryptophan (TRP), non-esterified free fatty acids (NEFFAs), corticosterone, together with brain TRP, serotonin (5-hydroxytryptamine, 5-HT), noradrenaline (NA) and pineal melatonin. From other studies in our laboratory we have shown that Cr3+ treatment can modify brain 5-HT function, perhaps by altering the sensitivity of central 5-HT2A receptors. The peripheral effect of Cr3+ picolinate treatments and their consequential central effect on increased serotonergic and noradrenergic function may suggest that Cr3+ could have some antidepressant-like actions. Future studies to confirm this are to be done.

Central GABAergic systems and depressive illness.

Clinical depression and other mood disorders are relatively common mental illnesses but therapy for a substantial number of patients is unsatisfactory. For many years clinicians and neuroscientists believed that the evidence pointed toward alterations in brain monoamine function as the underlying cause of depression. This point of view is still valid. Indeed, much of current drug therapy appears to be targeted at central monoamine function. Other results, though, indicate that GABAergic mechanisms also might play a role in depression. Such indications stem from both direct and indirect evidence. Direct evidence has been gathered in the clinic from brain scans or postmortem brain samples, and cerebrospinal fluid (CSF) and serum analysis in depressed patients. Indirect evidence comes from interaction of antidepressant drugs with GABAergic system as assessed by in vivo and in vitro studies in animals. Most of the data from direct and indirect studies are consistent with GABA involvement in depression.

Pharmacological studies of alcohol susceptibility and brain monoamine function in stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHRSR).

Differences of alcohol drinking behavior, brain dopamine (DA) and serotonin (5-HT) levels and releases in the striatum were investigated in stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched stroke-resistant spontaneously hypertensive rats (SHRSR). Voluntary alcohol (EtOH) consumption in SHRSP rats increased at 1 and 2 hours in the 4 hour time access. In the DA level, SHRSP showed decreases in the caudate-putamen (C/P) and dorsal raphe nucleus (DRN) compared with in SHRSR. 5-HT levels in the C/P, ventral tegmental area-subtantia nigra (V/S) and DRN of the SHRSP were decreased compared with that in SHRSR. The basal extracellular levels of 5-HT release in the C/P were increased in SHRSP as compared with those in SHRSR. K(+)- or EtOH-induced DA and 5-HT releases in the C/P of the SHRSP were a lower magnitude than those in SHRSR. Increased basal extracellular 5-HT releases showing low levels of 5-HT in the C/P of SHRSP mean an abnormality of serotonergic neuronal functions in a normal physiological condition. Higher voluntary alcohol drinking behavior, so called lower susceptibility to EtOH, in the SHRSP may be associated with the degenerated rewarding system including the DRN. These results suggest that the hypertensive state causes the dysfunction in the striatum of the brain rewarding system and induces the risk for increasing alcohol consumption to compensate for the alteration of serotonergic neurons.

Maternal obesity alters adiposity and monoamine function in genetically predisposed offspring.

The impact of maternal obesity on brain monoamine function in adult offspring of dams selectively bred to express diet-induced obesity (DIO) or diet resistance (DR) was assessed by making dams obese or lean during gestation and lactation. After 12 wk on chow and 4 wk on a 31% fat diet, offspring hypothalamic nucleus size and [(3)H]nisoxetine binding to norepinephrine transporters (NET) and [(3)H]paroxetine binding to serotonin transporters (SET) were measured. Offspring of obese DIO dams became more obese than all other groups, but maternal obesity did not alter weight gain in DR offspring (25). Maternal obesity was associated with 10-17% enlargement of ventromedial nuclei (VMN) and dorsomedial nuclei in both DIO and DR offspring. Offspring of obese DIO dams had 25-88% lower NET binding in the paraventricular nuclei (PVN), arcuate nuclei, VMN, and the central amygdalar nuclei, while offspring of obese DR dams had 43-67% higher PVN and 90% lower VMN NET binding and a generalized increase in SET binding across all hypothalamic areas compared with other groups. Thus maternal obesity was associated with alterations in offspring brain monoamine metabolism, which varied as a function of genotype and the development of offspring obesity.

Amino acid metabolism, branched-chain amino acid feeding and brain monoamine function.

Although fatigue during prolonged exercise has traditionally been associated with peripheral factors relating to muscle metabolism, such as the depletion of muscle glycogen, more recent research has generated a renewed interest in amino acid metabolism per se and in the role of amino acids as precursors of brain neurotransmitter function. The concept of a 'central fatigue hypothesis' has done much to stimulate scientists to explore the functional role of the brain and CNS in the aetiology of the fatigue process. The concept has also generated a number of testable hypotheses by which it is possible to examine how the 'central' component of fatigue may act. The present review has attempted to bring together the current research in this area. There is good reason to believe that nutritional intervention may play an important role in relation to fatigue residing within the brain and CNS. Although an exciting possibility exists that nutritional manipulation may affect brain neurochemistry and ultimately sports performance, the experimental evidence to support this claim is, as yet, equivocal. A greater understanding of amino acid metabolism and, in particular, amino acid transport, will greatly improve future experimental designs used to test the efficacy of nutritional manipulation of amino acids and their effect on the central component of the fatigue process.

Moclobemide effects on prolactin plasma levels in healthy individuals

Neuroendocrine challenge studies are frequently used to study the pathophysiology of psychiatric illnesses and the effects of psychotropic drug treatment on brain monoamine function. Moclobemide, a reversible inhibitor of monoamine oxidase, with predominant effects on the A-type of the enzyme, was administered to 15 healthy men. Seven out of the 15 also received single blind placebo a week before the moclobemide. The individuals received moclobemide as a single dose (150 mg), followed by doses of 150 mg three times a day, during a 4-week period. Plasma prolactin was measured in the morning over a 150-min period, following the single dose, and then at the end of weeks 1, 2 and 4 of moclobemide intake. The present data show an acute and transitory increase of plasma prolactin levels after the single dose, and also during the long-term moclobemide administration. It might indicate that steady-state moclobemide levels, during the long-term drug administration, were low and thus large fluctuations of drug levels occurred between doses. Thus, it is suggested that larger doses or administering smaller doses more frequently, or both, may induce hyperprolactinaemia with clinical consequences.

Effect of the placebo control condition in neuroendocrine challenge studies

Neuroendocrine challenge studies are frequently used to make inferences about the pathophysiology of psychiatric illness or about the effects of chronic psychotropic drug treatment on brain monoamine function. The outcome of these exploratory neuroendocrine tests, however, may be influenced by the effects of confounding variables, such as specific stress effects and variations in basal hormone levels. The inclusion of a placebo control condition minimizes the variability due to these variables. A number of recent neuroendocrine studies have omitted the placebo control condition. Based on experimental data, it can be shown that failure to include a placebo control condition may result in both Type I and Type II errors of inference. These results suggest a placebo control condition should be included in exploratory neuroendocrine challenge studies.

Are there neurochemical indicators of risk for schizophrenia?

The genetic predisposition for certain forms of schizophrenia may involve heritable abnormalities in the functioning of neurochemical systems that project to and modulate limbic brain structures. However, with regard to both dopaminergic and serotonergic systems, there is little evidence that either basal cerebrospinal markers or plasma markers predict increased risk for the development of schizophrenia. Either their validity as correlates of brain monoamine function is uncertain or they are highly dependent upon clinical state. Both (1) platelet and neuroendocrine markers of serotonergic function and (2) an individual's capacity to decrease plasma homovanillic acid concentrations following neuroleptic blockade appear to be less state dependent, and these are worthy of further study as markers of risk for the development of schizophrenia.

In utero methamphetamine effects: I. Behavior and monoamine uptake sites in adult offspring

Chronic in utero methamphetamine treatment, throughout gestation in rats, resulted in alterations in both behavior and brain monoamine function in the adult offspring. The higher dose of methamphetamine (10 mg/kg/b.i.d.) caused a significant decrease in square crossing and rearing in an open field, as well as a regional increase of serotonin and dopamine uptake sites. In contrast, the lower dose of in utero methamphetamine (2 mg/kg/b.i.d.) resulted in a significant decrease in regional densities of serotonin and dopamine uptake sites, and only decreased rearing behavior. Across treatment groups, there were significant correlations between open-field square crossing activity and the number of uptake sites in specific brain areas. Other measured behaviors, such as the neonate righting reflex and the adult Morris water maze performance, were unaffected by either in utero drug regimen. These results are discussed in terms of the known neurotoxicity of amphetamines and the ability of the immature nervous system to compensate for fetal exposure to methamphetamine.

Monoamine function in anxiety and depression: Information from neuroendocrine challenge tests

AbstractNeuroendocrine challenge tests are being increasingly employed to assess brain monoamine function in man. This review describes some recent studies which have used neuroendocrine tests to investigate brain noradrenaline (NA) and 5‐hydroxytrytptamine function (5‐HT) in patients suffering from anxiety and depression. A number of abnormalities, particularly in the noradrenergic system, have been identified, and some interesting similarities and contrasts have emerged between panic disorder and depression. Challenge tests can also be used to identify adaptive changes in monoamine pathways following administration of psychotropic drugs. Tolerance has been demonstrated to the ability of benzodiazepines to reduce brain 5‐HT function, a finding which could underlie some of the symptoms of the withdrawal syndrome. In addition, it seems likely that long‐term administration of tricyclic antidepressants stabilizes NA synaptic function.

Studies on the effect of chronic L-triiodothyronine (T 3) treatment on brain Na +,K +-ATPase activity in the mature rat

Mature rats were dosed with T 3 by different routes and dose-levels at either 0.1 mg/kg for 14 days s.c. (Group A), 1 mg/kg for 3 alternative days i.p. (Group B), 5 mg/kg for 14 days p.o. (Group C), or with propylthiouracil (PTU 50 mg/day for 14 days p.o. — Group D). Measurement of cerebellar and striatal NA +,K +-ATPase activities showed that whereas Groups A, B and D were unaffected when compared with controls, there were 35–70% increases respectively in the activities of both molecular forms of the enzyme, α(+), high ouabain affinity, and α, low ouabain affinity, in Group C rat brains at the highest dose of T 3 tested. Kidney Na +,K +-ATPase activity was also elevated (67% increase) in this group of animals showing significant changes in renal medullary tissue only. Acute elevation of brain dopamine levels by administration of an MAOI plus L-DOPA (50 mg/kg, 60 min) significantly elevated (20% increase) the activities of both molecular forms of Na +,K +-ATPase in corpus striatum. Treatment with L-tryptophan (50 mg/ kg, 60 min) failed to produce any changes in the striatal activities. The possible relationship of increases in enzyme activities with T 3 and increased brain monoamine function is discussed. Both plasma free T 4(FT 4) and total T 4(TT 4) were markedly depressed in all T 3-treated rats. Although hypothalamic thyrotropin releasing hormone (TRH) concentrations were unaltered by any of the T 3 treatments, pituitary thyroid stimulating hormone (TSH) concentrations were greatly diminished and it is thought that this may reflect a direct effect of T 3 on TSH synthesis.

Anomalous growth hormone responses to thyrotropin-releasing hormone and glucose in cirrhotic patients: the effect of metergoline.

The anomalous GH response to TRH or glucose loading was evaluated in patients with severe liver disease untreated or pretreated with metergoline (MCE), a potent antiserotoninergic drug. In 9 patients, injection of 400 micrograms TRH as a bolus induced a clear-cut GH rise (> 8 ng/ml), with peak levels 15-90 min post injection. Pretreatment with MCE did not modify baseline GH levels but potentiated the TRH-induced GH rise in 4 patients. In addition, 2 of 8 TRH nonresponder patients developed the anomalous GH response after MCE pretreatment. Like MCE, methysergide, another antiserotoninergic drug, potentiated the TRH-induced GH rise in 2 of 4 patients. Glucose administration (100 g, orally) induced a paradoxical rise of GH in 9 of 10 patients; after MCE, the paradoxical GH response to glucose was potentiated in 6 patients. These data provide the first experimental evidence that a derangement in brain monoamine (serotonin) function is actually involved in the occurrence of anomalous GH responses in subjects with severe liver disease.