Monoamine Activity Research Articles

Changes in behavior and monoamine levels in microdialysate from dorsal striatum after 6-OHDA infusions into ventral striatum

Long-Evans rats received bilateral 6-hydroxydopamine infusions into the nucleus accumbens and were tested immediately (1 and 2 days) or after a recovery period (14 and 15 days) for changes in extracellular levels of dorsal striatal monoamines using in vivo microdialysis. Compared to controls, the monoamine metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were generally enhanced when tested immediately after 6-hydroxydopamine treatment, including spontaneous levels and those following depolarizing infusions of potassium (60 mM, 20 min) through the microdialysis probes. Following 2 weeks recovery, dopamine metabolite levels were depressed and the serotonin metabolite levels remained enhanced. D-Amphetamine sulfate (1.5 mg/kg, SC) stimulated dopamine overflow was enhanced 2 days after 6-hydroxydopamine administration, but not after 2 weeks recovery. In contrast, potassium increased dopamine overflow to the same extent as control animals regardless of recovery period following 6-hydroxydopamine. The immediate changes in striatal monoamine activity were accompanied by a potentiation of amphetamine-induced stereotyped behaviors. We suggest that transient presynaptic changes within the dorsal Striatum following disruption of the ventral Striatum may mediate some general aspects of loss and recovery of behavior related to the time course of 6-hydroxydopamine neurotoxicity.

Monoamine modulation of the synaptic inhibition in the hippocampus.

Changes in the strength of synaptic inhibition have profound effects on the functions of cortical neurones. Accumulating evidence suggests that inhibitory synaptic transmission may be the target of actions of monoamines. In the hippocampal dentate gyrus, norepinephrine and serotonin (5-HT) have multiple direct and indirect actions on the presumed inhibitory hilar neurones. These effects are mediated through distinct mechanisms and signalled by different receptor subtypes. The predominant effects of norepinephrine are excitatory and are mediated by beta-adrenergic receptors. Accordingly, both the GABAA- and GABAB-receptor-mediated inhibition in granule cells is enhanced by activation of the beta-adrenergic receptor. 5-HT has more complex effects inhibiting a subpopulation of the hilar neurones and exciting other hilar cells. Study of the effects of 5-HT on inhibition in granule cells revealed that 5-HT enhanced Cl-IPSPs and blocked K-IPSPs. These results are in line with the suggestion that Cl- and K-IPSPs in granule cells are generated by two distinct populations of inhibitory neurones.

Morphine withdrawal alters anterior pituitary hormone secretion, brain endopeptidase activity and brain monoamine metabolism in the rat.

Rats were made tolerant to morphine by a 5-day regimen with increasing doses. The time course of changes in serum anterior pituitary hormone levels, brain endo- and exopeptidase activity, levels of brain biogenic amines and body weight were studied during abrupt morphine withdrawal. Cold stimulated secretion of thyrotropin and the secretion of growth hormone were both decreased whereas that of prolactin was increased. In the hypothalamus both prolyl endopeptidase and dipeptidyl peptidase IV activities were concomitantly increased. The hypothalamic 5 hydroxyindole acetic acid levels were also increased. Changes in hormone secretion, peptidase activity and monoamine turnover had returned to baseline levels by 92 hr. Our results indicate that morphine withdrawal and the associated stress produce alterations in anterior pituitary thyrotropin and growth hormone secretion. Concomitant increases in hypothalamic prolyl endopeptidase and dipeptidyl peptidase activities may contribute to these changes.

A test of conditioned blocking and its development in childhood and adolescence: Relationship to personality and monoamine metabolism

Conditioned blocking (CB) is the undermining of conditioning to a stimulus by conjoint exposure with one already associated with the unconditioned stimulus. CB is one of several tests of “learned inattention” in which performance has been found to depend on personality features of human participants and monoamine activity in animals. In Part 1, the performance of 25 healthy young adults on a new test form for demonstrating CB is described. From personality inventories and 24‐hr urine samples it was proposed that CB may be correlated with extroversion and increased catecholamine utilization. In Part 2, CB was shown to be present in 4 groups of 11 participants with mean ages of 10, 14, 17 and 22 years independent of IQ, but it was least marked in the prepubertal group. No relation of performance with personality features was found. As with the adult group, CB was positively correlated with dopamine activity, but unlike the adults it was negatively correlated with noradrenalin activity. The maturation of att...

Characteristics of BDNF-induced weight loss

There is evidence that central infusion of brain-derived neurotrophic factor (BDNF) induces weight loss in rats. We have begun to investigate the physiological basis for BDNF-induced weight loss by assessing its relationship to (a) appetite, (b) serum indices of metabolic and renal toxicity, and (c) brain monoamine activity in areas associated with feeding or motor function. BDNF (0–6 μg/day) was infused into the lateral ventricle (LV) of male Long-Evans rats for 14 days. Body weight and food intake were monitored throughout infusion and recovery periods. BNDF induced severe, dose-dependent appetite suppression and weight loss. Although appetite began to recover after the 10th infusion day, body weight had not returned to control values at the end of the recovery period. The weight loss observed in BDNF-infused rats was related to appetite suppression, since uninfused rats that were pair-fed to high dose BDNF-treated rats showed comparable weight loss. Despite severe weight loss, serum BUN, creatinine, thyroxine, glucose, and total protein were not affected by BDNF infusion. Striatal DO-PAC/DA was similarly unaffected by BDNF. In contrast, BDNF-infused rats showed a dose-dependent increase in hypothalamic 5-HIAA/5-HT that was not observed in pair-fed rats, suggesting that the observed increase in hypothalamic 5-HIAA/5-HT was a direct effect of BDNF infusion rather than a secondary effect of food restriction. These data suggest that BDNF may induce appetite suppression and weight loss through a central mechanism.

Sleep deprivation in the rat: XVIII. Regional brain levels of monoamines and their metabolites.

Several theories have linked sleep with change in monoamine activity. However, the use of sleep deprivation to show that changes in sleep generate changes in monoamines (directly or through feedback) has produced inconsistent results. To explore whether longer sleep deprivation, better documented sleep loss, more complete controls or regional brain analyses would produce clear sleep loss-induced change, eight rats were subjected to total sleep deprivation (TSD) by the disk-over-water method for 11-20 days and were guillotined along with yoked control (TSC) and home-cage control (HCC) rats. Brains were removed and dissected to obtain the caudate, frontal cortex, hippocampus, hypothalamus, midbrain and hindbrain (pons-medulla). Tissue sections were analyzed for concentrations of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and either norepinephrine or, in the caudate section, the DA metabolite homovanillic acid. The ratios DOPAC/DA and 5HIAA/5HT, which under some conditions are indicators of turnover, were also calculated. Because sleep deprivation time varied across sets of TSD, TSC and HCC rats and not all eight sets were analyzed simultaneously, a repeated-measures ANOVA was performed within sets with HCC, TSC and TSD considered as successive levels of sleep deprivation treatment. In no case did TSD rats have significantly higher or lower values of amines, metabolites or ratios than both HCC and TSC rats. The most common outlying values were for TSC rats. Thus, these results failed to demonstrate sleep loss-induced regional changes in levels of major brain monoamines or their metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell-type-specific expression of catecholamine transporters in the rat brain

The dopamine transporter (DAT) and norepinephrine transporter (NET) terminate catecholaminergic neurotransmission at synapses by high-affinity sodium-dependent reuptake into presynaptic terminals, and are the initial sites of action for drugs of abuse and antidepressants. In the present study, we used in situ hybridization combined with immunohistochemistry to study the distribution of DAT and NET mRNA in the adult rat brain. Cells were first immunolabeled with antisera directed against one of the catecholamine-synthetic enzymes, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), or phenylethanolamine-N-methyltransferase (PNMT), in order to identify dopaminergic, noradrenergic, or epinephrine-containing cells. The immunolabeled cells were subsequently assayed for their ability to express catecholamine transporter mRNAs by in situ hybridization using either a rat DAT or NET cRNA probe. All dopaminergic cell groups of the mesencephalon contained high levels of DAT mRNA but only the A12 and A13 dopaminergic cell groups of the diencephalon appear to express detectable levels of DAT. All norepinephrine-containing cell bodies in the brainstem (locus coeruleus and lateral tegmentum) appear to express NET mRNA. In contrast, epinephrine-containing cell bodies of the brainstem do not appear to express NET mRNA, which raises the possibility that epinephrine may utilize a transporter that is distinct from the other bioactive amines, or may act as an endocrine regulator that does not require rapid reuptake mechanisms. Moreover, the cell-type-specific expression of catecholamine transporters suggests that DAT and NET gene expression may be closely linked to cellular mechanisms that specify transmitter phenotype. The termination of neurotransmission is a critical component of neural signaling and depends on the rapid removal of neurotransmitters from the synaptic cleft. Pharmacological evidence indicates that the action of monoamines at the synapse is terminated predominantly by rapid reuptake into presynaptic nerve endings via neurotransmitter-specific, high-affinity, Na(+)-dependent membrane transporter proteins. The cDNAs encoding distinct transporter proteins for the monoamines dopamine, norepinephrine, and serotonin have been cloned, expressed, and characterized in a variety of heterologous systems (Blakely et al., 1991; Giros et al., 1991; Hoffman et al., 1991; Kilty et al., 1991; Pacholczyk et al., 1991; Shimada et al., 1991; Usdin et al., 1991). Although the monoamine transporters share a high degree of sequence homology, they are distinguished by their monoamine substrate specificities and by their differential sensitivities to a wide spectrum of transport antagonists. For example, pharmacological agents that potently inhibit norepinephrine and serotonin transport, such as desmethylimipramine and citalopram, have little effect on the activity of the dopamine transporter (Javitch et al., 1983).(ABSTRACT TRUNCATED AT 400 WORDS)

Monoamine activity reflected in urine of young patients with obsessive compulsive disorder, psychosis with and without reality distortion and healthy subjects: an explorative analysis.

Positive psychotic symptoms are reported to be associated with high, negative symptoms with low dopamine (DA) activity and serotonin (5HT) activity may be altered in obsessive-compulsive disorder (OCD). We analysed 24 h urine samples in these patient groups and in healthy controls for supportive evidence. Young unmedicated OCD subjects excreted more adrenaline (AD) and homovanillic acid (HVA) and showed a higher HVA/MHPG ratio and metabolic rate than healthy controls. Independent of general metabolic rate they showed higher HVA concentrations which suggests that the relative activity of catecholamine systems in OCD (HVA/MHPG) is due more to high DA than to low noradrenergic (NA) activity. Concentrations of 5HT were also high in OCD patients. In psychotic patients low levels of DA, HVA, NA and MHPG probably resulted from neuroleptic medication. Patients diagnosed with paranoid psychosis showed higher DA utilization than controls and those with few paranoid symptoms showed high 5HT utilization. These results support studies suggesting that paranoid psychosis is associated more with increased DA activity (discussed in the context of neuroleptic reactivity), that non-paranoid forms are associated more with increased 5HT activity and that OCD patients are unusually aroused with high levels of Ad, 5HT and HVA.

Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6

Cytokine-specific alterations of monoamine activity were evident in the hypothalamus, hippocampus and prefrontal cortex 2 h following peripheral administration of recombinant interleukin (IL)-1β, IL-2 and IL-6 (200 ng, i.p.) in male, BALB/c mice. IL-1 induced the broadest range of neurochemical changes, affecting central norepinephrine (NE), serotonin (5-HT) and dopamine (DA) activity. In particular, IL-1 enhanced NE turnover in the hypothalamus and hippocampus, 5-HT turnover in the hippocampus and prefrontal cortex (owing to increased utilization and reduced content of the transmitters in these brain regions), and enhanced DA utilization in the prefrontal cortex. IL-6 increased 5-HT and DA activity in the hippocampus and prefrontal cortex in a manner similar to IL-1, but failed to affect central NE activity. Moreover, IL-2 increased hypothalamic NE turnover (reflecting a profound increase in NE utilization) and enhanced DA turnover in the prefrontal cortex, but did not influence central 5-HT activity. Hence, these cytokines differentially altered neurochemical activity in brain regions that mediate neuroimmune interactions and that are influenced by physical and psychological stressors. In addition to the neurochemical changes, plasma corticosterone concentrations were profoundly enhanced in IL-1-treated animals, but not significantly altered by IL-2 or IL-6 treatment. The IL-1-induced corticosterone elevations did not significantly correlate with alterations of hypothalamic NE activity.

Monoamine activity in anterior hypothalamus of guinea pig pups separated from their mothers.

Monoamine activity in anterior hypothalamus of guinea pig pups separated from their mothers.

Monoamine activity in anterior hypothalamus of guinea pig pups separated from their mothers.

Brief isolation in a novel environment increased the ratios of 3-methoxy-4-hydroxyphenylethylene glycol to norepinephrine (MHPG:NE) and dihydroxyphenylacetic acid to dopamine (DOPAC:DA) in the anterior hypothalamus of guinea pig pups. Ratios were significantly elevated after 90 min of isolation and for MHPG:NE, after 30 min of isolation; changes were due to increases in MHPG and DOPAC. Home cage isolation produced no change in any measure of catecholamine activity. No changes in levels of serotonin or its metabolite were observed. In 1 experiment, resting levels of NE and DOPAC:DA were predictive of the rate of separation-induced vocalization. Maternal separation in the context of novelty increases hypothalamic NE and DA activity; however, both isolation and novelty are required because neither maternal separation in the home cage nor exposure to a novel cage together with the mother had any discernible effect.

Short Review on Monoamine Oxidase and Its Inhibitors

Since monoamine oxidase is an enzyme catalyzing bioactive monoamines, inhibitors of monoamines are expected to prolong the activity of monoamines in tissue. Monoamine oxidase type B is an active form in brain, and its preferential substrate is dopamine that is the most constantly reduced monoamine in Parkinson's disease brain. Therefore, it is natural to expect that monoamine oxidase inhibitors, deprenyl or lazabemide, could exhibit beneficial effects on parkinsonism, i.e. symptomatic effects. This short review summarizes characteristics of monoamine oxidase from biochemical and pharmacological points, and then briefly mentions the situation of clinical evaluation studies of deprenyl and lazabemide in terms of antiparkinsonian effects in Japan.

Effects of prenatal ethanol exposure on later sensitivity to the low-dose stimulant actions of ethanol in mouse offspring: possible role of catecholamines.

The purpose of this study was to examine whether prenatal ethanol (EtOH) exposure alters later sensitivity to the low-dose stimulant effects of EtOH. Because the locomotor stimulant effects of EtOH are thought to be mediated, at least in part, by activation of brain monoamine systems, and because prenatal EtOH exposure has been shown to alter brain monoamine activity, it was hypothesized that prenatal EtOH exposure may alter sensitivity to the stimulant actions of EtOH. To test this hypothesis, sensitivity to the locomotor stimulant effects of various challenge doses of EtOH was examined in male and female offspring from prenatal alcohol (A), pair-fed (PF), and lab chow (LC) groups at different ages. In addition, to address the hypothesis further, sensitivity to the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine (AMPT) was examined in these offspring, as well. Results indicated that male offspring prenatally exposed to EtOH exhibited reduced baseline activity and a blunted stimulant response to all challenge doses of EtOH (0.75-1.5 g/kg) in comparison with control offspring at 30 days of age, but these effects appeared to "normalize" at 70 days of age. Female EtOH-exposed offspring also exhibited a reduced baseline level of activity relative to control offspring, as well as a blunted stimulant response to the lowest challenge dose of EtOH (0.75 g/kg) at 30 days of age, and these effects persisted into adulthood. The stimulant response to higher doses of EtOH did not significantly differ among prenatal treatment groups in young or adult female offspring. However, because baseline activity was significantly lower in female EtOH-exposed offspring than control offspring, the stimulant response to these doses of EtOH (1.125 and 1.5 g/kg) was relatively greater than that for PF and LC offspring. Importantly, none of the differences in performance among the prenatal treatment groups could be attributed to an alteration in EtOH pharmacokinetics, because blood EtOH levels measured immediately following the 10-min test session were similar for all prenatal treatment groups across all of the EtOH test doses. Further, a similar response profile as that observed following EtOH challenge at 70 days of age was obtained following phenobarbital challenge (10-40 mg/kg). Finally, whereas AMPT (50-400 mg/kg) dose-dependently antagonized the stimulant effects of EtOH in all prenatal treatment groups, this effect of AMPT was significantly greater in mice prenatally exposed to EtOH in comparison with control offspring.(ABSTRACT TRUNCATED AT 400 WORDS)

Norepinephrine, dopamine, and 5-HT release from perfused hypothalamus of the rat during feeding induced by neuropeptide Y.

In the unrestrained rat, the hyperphagic-like ingestion of food evoked by the sustained elevation of neuropeptide-Y (NPY) in the hypothalamus was correlated with the release and turnover of monoaminergic transmitters in this structure. A single guide tube was implanted stereotaxically in the perifornical region of the hypothalamus for localized push-pull perfusion of an artificial CSF vehicle or NPY1-36 in a concentration of 10, 50, or 100 ng/1.0 microliters. After the rat was fully satiated, a site reactive to NPY was perfused repeatedly at a rate of 20 microliters/min for 6.0 min with an interval of 6.0-12 min elapsing between each perfusion. Samples of perfusate were analyzed by HPLC with coulometric detection for DA, HVA, DOPAC, NE, MHPG, 5-HT, and 5-HIAA. Although control perfusions were without effect on feeding or monoamine activity, NPY evoked mean cumulative intakes of food of 14 +/- 2.4, 25.6 +/- 3.0 and 26.5 +/- 3.2 g in response to 10, 50, or 100 ng/microliter concentrations of NPY, respectively, over the 4.0-5.0 hr test interval. HPLC analyses showed that during feeding the release of both NE and DA was enhanced significantly. The turnover of both catecholamines likewise increased significantly as reflected by the elevated levels of MHPG, DOPAC and HVA. However, neither the basal efflux of 5-HT nor its turnover, as reflected by the output of 5-HIAA, was affected during feeding induced by NPY perfused in the hypothalamus. These results suggest that a sustained elevation of NPY in the hypothalamus causes a perturbation in the basal activity of NE and DA which are both implicated in the neuronal mechanism regulating normal eating behavior. Thus, these catecholamine neurotransmitters are envisaged to comprise an intermediary step in the functional role played by NPY in the hypothalamus in integrating the control of energy metabolism and caloric intake.

Spontaneous feeding-related monoaminergic changes in the rostromedial hypothalamus revealed by microdialysis

The activity of hypothalamic monoamines in response spontaneous feeding was investigated using the in vivo technique of brain microdialysis together with the instrumental recording of feeding pattern. The simultaneous variations of dopamine (DA), serotonin (5-HT), and their respective metabolites, DOPAC and 5-HIAA, were measured in the rostromedian hypothalamus, where the probe was located between the PVN and VMH. Throughout the experiment, the changes in DOPAC followed a mirror image of those in DA: DA regularly increased, reaching its zenith within the 15-min sample collected during the meal before returning to the same level as just before the meal. Following a premeal plateau, both 5-HT and 5-HIAA increased as soon as the beginning of feeding; 5-HT reached its zenith during the meal while 5-HIAA showed a more delayed and prolonged increase. When a new meal was initiated, 60 to 70 min later, a similar monoaminergic pattern was observed again. These data suggest that building up hunger is announced by an ascending slope of DA and setting up of satiation is concomitant with a descending slope of DA. Concerning serotonergic changes, the sharp 5-HT release during the meal would be a signal of satiation (transient preabsorptive fullness) while the longer-lasting increase in 5-HIAA, reflecting 5-HT synthesis, would be associated with satiety (more persistent postabsorptive state substituting satiation). These data partially confirm and extend previous pharmacological studies as well as the findings on deprivation-induced, imposed meals. They suggest a possible causal relation between monoaminergic changes and behavioral initiatives.

D-Fenfluramine effects on hypothalamic monoamine activities and their hormonal correlates

In order to test the hypothesis that the anorectic effects of d-fenfluramine involve mediation by increased serotonin (5-HT) activity we examined the effects of acute and chronic d-fenfluramine on the hypothalamic activities of 5-HT as well as the other major monoamine neurotransmitters noradrenaline (NA) and dopamine (DA). Precise and specific gas chromatograph/mass spectrometer analyses of NA, 5-HT and DA and their primary metabolites dihydroxphenylethyleneglycol (DHPG), 5-hydroxyindolacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC), respectively, were made in combination with analysis of the hormonal correlates of the monoamines, glucose and adrenocorticotropin for NA, thyroid-stimulating hormone for 5-HT and prolactin for DA. Acute d-fenfluramine increased NA, while reducing 5-HT, functional activity. Chronic and acute after chronic, d-fenfluramine decreased both NA and 5-HT functional activity. The effect of acute d-fenfluramine on the DA system is consistent with a post-synaptic blockade which is compensated for by chronic treatment. Since chronic d-fenfluramine acted to depress noradrenergic tone, a further study was undertaken which showed that chronic d-fenfluramine does not impair the ability noradrenergic/sympathetic system to respond to stress. The results indicate that d-fenfluramine may not exert its anorectic and weight loss effects via serotonergic agonism and involvement of the NA and/or DA systems is likely.

Stimulation of the hypothalamo-pituitary-adrenocortical axis by the central serotonergic pathway: involvement of endogenous corticotropin-releasing hormone but not vasopressin.

Many reports indicate that serotonin plays a role in the regulation of the hypothalamo-pituitary-adrenocortical axis. The present study was designed to elucidate whether the activation of the central serotonergic pathway enhances adrenocorticotropin and corticosterone secretion, and if so, whether the CRH and vasopressin neuronal systems could be mediating this effect. Intraperitoneal administration of a low dose of L-5-hydroxytryptophan (an aromatic L-amino acid precursor of serotonin synthesis; 20 mg/kg bw, 30 minutes before the sacrifice) in rats pretreated with pargyline (a brain monoamine oxidase inhibitor, which enhances monoamine activity; 75 mg/Kg bw, 16 hours before the sacrifice) and carbidopa (a peripheral active inhibitor of the decarboxylation of aromatic L-amino acids, which would permit more monoamine precursor to be available to the brain; 50 mg/Kg bw, 90 minutes before the sacrifice) increased ACTH and corticosterone secretion in plasma. Such an effect was partially blocked by metergoline (a serotonin type-1 and-2 receptor blocker; 1 mg/Kg bw, 90 minutes before the sacrifice), but not by spiperone (a serotonin type-2 and dopamine receptor antagonist; 0.5 mg/Kg bw. 90 minutes before the sacrifice). The activation of the central serotonergic system enhanced the CRH content in the median eminence, whereas it decreased the content of this neuropeptide in the medial basal hypothalamus. These effects were fully abolished by metergoline, but not by spiperone pretreatment. The activation of the serotonergic pathway did not influence the vasopressinergic neuronal system. In vitro experiments using hypothalamic-median eminence fragments incubated with serotonin solutions indicate that this monoamine possesses a CRH releasing effect at concentrations of 1 microM or more.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of Effects of Various Types of NA and 5-HT Agonists on Transmission from Group II Muscle Afferents in the Cat.

A number of noradrenaline and serotonin agonists were tested to investigate which of them replicate the depressive actions of monoamines on transmission from group II muscle afferents in the cat spinal cord. The agonists were applied ionophoretically at the two sites at which maximal monosynaptic focal field potentials are evoked from group II afferents-in the intermediate zone and the dorsal horn of the 4th and 5th lumbar segments. Their effects were estimated from changes in the amplitude of the field potentials. The compounds tested fell into three categories according to the site at which they depressed transmission from group II afferents: one category with highly selective actions in the intermediate zone, a second category with similarly selective actions in the dorsal horn, and a third category with non-selective actions. Drugs in the first category included three noradrenaline agonists (tizanidine, B-HT 933 and clonidine), included in the second were five serotonin agonists (8-OH-DPAT, 5-methoxytryptamine, alpha-methyl serotonin, DOI and 2-methyl-serotonin), and in the third two noradrenaline agonists (phenylephrine and isoproterenol) and two serotonin agonists (RU 24969 and 5-carboxamidotryptamine). Field potentials evoked by group I afferents remained unaffected by all but one compound (8-OH-DPAT). Effects of one noradrenaline agonist and one serotonin agonist (tizanidine and 5-methoxytryptamine) were also tested on responses of single extracellularly recorded neurons. Tizanidine depressed responses induced by stimulation of group II afferents in intermediate zone interneurons, but not in dorsal horn neurons, while 5-methoxytryptamine depressed activation of the latter. Tizanidine had no effect on responses evoked by group I afferents, either in intermediate zone interneurons or in the dorsal spino-cerebellar tract neurons of Clarke's column. It is hypothesized that noradrenaline and serotonin released by descending monoaminergic neurons differ in the potency with which they depress transmission from group II afferents to different functional types of neuron. The results suggest that this depression may involve different membrane receptors at different locations, primarily alpha2 adrenoceptors in the intermediate zone/ventral horn and 5-HT1A serotonin receptors in the dorsal horn.

Medial basal hypothalamic monoamine activity associated with intracerebroventricular p-chlorophenylalanine-induced hyperphagia

There is evidence for reciprocal interactions between the brain monoamine neurotransmitters serotonin and noradrenaline which may play a critical role in homeostasis. The aim of the present study was to establish the effect of drug-induced damage to the serotoninergic system on noradrenergic activity in the hypothalamus. Bilateral intracerebroventricular injections of p-chlorophenylalanine (PCPA; 3 mg/kg in 2 × 6 μl) were made to induce destruction in the serotoninergic system. Relative to saline-injected controls, PCPA-injected rats began overeating by 3 days postinjection. On day 10, when the experimental rats were consuming approximately 120% that of controls, animals were 4-h food deprived, sacrificed and the medial basal hypothalamus was removed for later analysis (by gas chromatography/mass spectrometry) of noradrenaline (NA), serotonin (5-HT) and dopamine (DA) and their principal metabolites dihydroxyphenylethyleneglycol (DHPG), 5-hydroxyindoleacetic acid (5-IAAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), respectively. The ratio of metabolite to monoamine provided an index of functional activity. Trunk blood was collected for analysis of serum insulin and glucose. PCPA-injected animals had higher levels of DHPG ( P < 0.05), an increase in the DHPG/NA ratio ( P <0.02), lower serum insulin ( P < 0.05) and increased serum glucose ( P < 0.05). There were significant correlations between noradrenergic activity (DHPG/NA ratio) and: (1) food intake (day 9 and 10 average; r = 0.62, P < 0.05); and (2) serum glucose ( r = 0.59, P < 0.05). In contrast, PCPA treatment only marginally lowered levels of 5-HT and 5-HIAA with no change in the 5-HIAA/5-HT ratio and no changes in DA or DOPAC or the DOPAC/DA ratio. Neither serotoninergic nor dopaminergic activity was related to any of the intake, body weight, insulin or glucose measures. We conclude that intracerebroventricular PCPA chronically elevates hypothalamic noradrenergic activity and this, rather than decreased serotoninergic activity, may lead to the observed hyperphagia, hyperglycemia and hypoinsulinemia.

What's New in Personality Disorders?: An Update on Pharmacologic Treatment

Pharmacologic interventions in personality-disordered patients are directed at trait vulnerabilities in the areas of affect, cognition, anxiety, and impulse. These traits reflect heritable patterns of monoamine activity that define the biologic basis for symptom expression. Pharmacologic intervention will not cure character (which is greater than the sum of trait vulnerabilities) but may help regulate the neurochemistry of instability in affect, cognition, anxiety, and impulse.