Serotonergic Transporter Research Articles

Maternal separation alters serotonergic transporter densities and serotonergic 1A receptors in rat brain

Rationale The basic mechanisms underlying the association between early life maternal separation and adulthood psychiatric disorders are largely unknown. One possible candidate is the central serotonergic system, which is also abnormal in psychiatric illnesses. Neuroadaptational changes in serotonergic transporter and serotonergic 1A receptors may underlie links between early life stress and adulthood psychiatric disorders. Objective The aim of this study was to investigate the consequences of a rat model of maternal separation on serotonergic transporter and serotonergic 1A receptor densities and function in adult rat forebrain. Methods Rat pups were separated from dams from postnatal day 2 to postnatal day 14, each day, for zero time, 15 min and 180 min to determine the time-course of effects. A non-handled group was added to control for the effects of handling by an experimenter compared with the animal facility-reared group. Quantitative [ 125I]3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester and [ 125I]-mPPI autoradiography was used to determine serotonergic transporter and serotonergic 1A densities, respectively. Adult rats were challenged with saline or serotonergic 1A agonist (+) 8-hydroxy-2-(di- n-propylamino)tetralin, 0.4 mg/kg, s.c.) and plasma adrenocorticotropic hormone and corticosterone were determined. Results serotonergic transporter and serotonergic 1A densities were significantly lower in the non-handled group in the paraventricular, arcuate, dorsomedial and ventromedial nuclei of the hypothalamus. The non-handled group also displayed lower serotonergic transporter and serotonergic 1A densities in the basolateral anterior, basolateral ventral and basomedial amygdaloid nuclei. Serotonergic transporter densities were also decreased in the CA3 area of the hippocampus in the non-handled group. In contrast, the maternal separation 15 min group displayed the highest serotonergic transporter and serotonergic 1A densities in the basomedial nucleus of amygdala, basolateral anterior nucleus of amygdala, basolateral ventral nucleus of amygdala and basomedial nucleus of amygdala amygdaloid nuclei. Conclusions Early life maternal separation and the extent of handling can alter adult brain serotonergic transporter and serotonergic 1A levels and function in the forebrain. Alterations in these serotonergic systems by early rearing conditions might increase vulnerability for behavioral disorders in adulthood.

Human brain imaging and substance abuse

Over the past decade, functional neuroimaging has contributed greatly to our knowledge about the neuropharmacology of substance misuse in man. Techniques such as functional magnetic resonance imaging, positron emission tomography (PET) or single photon emission tomography (SPET) can measure changes in regional cerebral activity, whereas changes in neuropharmacological parameters (e.g. receptor number and neurotransmitter levels) can be directly measured only with PET and SPET. Recently, a series of studies have shown common effects of substances of misuse on the brain, such as an acute increase in dopamine release (followed by hypofunction after chronic use) and cue exposure-induced activation of the frontal cortex, as well as specific effects, such as ecstasy-induced decreases in serotonergic transporters and occupancy of opiate receptors by substitute drugs (e.g. methadone and buprenorphine) in opiate addicts.

Gene-environment interplay in alcoholism and other substance abuse disorders: expressions of heritability and factors influencing vulnerability.

Factors that confer predisposition and vulnerability for alcoholism and other substance abuse disorders may be described usefully within the gene-environment interplay framework. Thus, it is postulated that heritability provides a major contribution not only to alcohol but also to other substances of abuse. Studies of evoked potential amplitude reduction have provided a highly suitable and testable method for the assessment of both environmentally-determined and heritable characteristics pertaining to substance use and dependence. The different personal attributes that may co-exist with parental influence or exist in a shared, monozygotic relationship contribute to the final expression of addiction. In this connection, it appears that personality disorders are highly prevalent co-morbid conditions among addicted individuals, and, this co-morbidity is likely to be accounted for by multiple complex etiological relationships, not least in adolescent individuals. Co-morbidity associated with deficient executive functioning may be observed too in alcohol-related aggressiveness and crimes of violence. The successful intervention into alcohol dependence and craving brought about by baclofen in both human and animal studies elucidates glutamatergic mechanisms in alcoholism whereas the role of the dopamine transporter, in conjunction with both the noradrenergic and serotonergic transporters, are implicated in cocaine dependence and craving. The role of the cannabinoids in ontogeny through an influence upon the expression of key genes for the development of neurotransmitter systems must be considered. Finally, the particular form of behaviour/characteristic outcome due to childhood circumstance may lie with biological, gene-based determinants, for example individual characteristics of monoamine oxidase (MAO) activity levels, thereby rendering simple predictive measures both redundant and misguiding.

Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function

High-dose administrations of amphetamine, methamphetamine, cathinone, methcathinone or methylenedioxymethamphetamine rapidly decrease dopamine and serotonin transporter function in vivo, as assessed in striatal synaptosomes obtained from drug-treated rats. In contrast, high-dose injections of fenfluramine, cocaine or methylphenidate had little or no effect on the activity of these transporters. Interestingly, the capacity of these agents to directly alter dopamine and serotonin uptake, as assessed in vitro by direct application to rat striatal synaptosomes, did not predict their potential to modulate transporter activity following in vivo administration. These findings demonstrate heretofore-unreported differences in the effects of these agents on monoamine transporter function, and a distinction between drug effects after direct application in vitro vs. administration in vivo.

Impulsive Aggression in Personality Disorder Correlates With Tritiated Paroxetine Binding in the Platelet

To examine the relationship between binding parameters of the platelet central serotonergic (5-HT) transporter and measures of aggression and impulsivity in adult human subjects. Maximal number of platelet tritiated paroxetine binding sites (Bmax) and dissociation constant (Kd) values were measured in patients with personality disorder (n = 24) and healthy volunteers (n = 12). Measures of aggression and impulsivity included the total score and aggression subscale of the Life History of Aggression, the Motor Aggression factor and the assault subscale of the Buss-Durkee Hostility Inventory, and the total score and motor impulsivity subscale of the Barratt Impulsiveness Scale. The Bmax, but not Kd, values of platelet tritiated paroxetine binding was inversely correlated with the Life History of Aggression total score and aggression score and with the Buss-Durkee Hostility Inventory assault score in patients with personality disorder but not in healthy volunteer subjects. This relationship was independent of influences of factors related to depression, global function, or history of alcoholism or drug abuse. Reduced numbers of platelet 5-HT transporter sites may covary with life history of aggressive behavior in patients with personality disorder. This may represent another abnormality in 5-HT function in individuals with personality disorder and aggressive behavior.

Programming of brainstem serotonin transporter development by prenatal glucocorticoids

Prenatal stress or exposure to excess glucocorticoids are known to alter central nervous system function and to result in lasting changes in reactions to stress. The potential involvement of specific elements of brainstem serotonergic neurons was examined in the current study. Pregnant rats were given 0.05, 0.2 or 0.8 mg/kg of dexamethasone on gestational days 17, 18 and 19, and the effects on development of the serotonin presynaptic transporter were assessed from birth to young adulthood by measurement of [ 3H]paroxetine binding to membrane preparations. Dexamethasone produced a dose-dependent retardation of body and brainstem growth but evoked a significant elevation of [ 3H]paroxetine binding that persisted into adulthood. Effects on [ 3H]paroxetine binding were robust even at the lowest dose, which did not suppress growth, indicating that the programming of this transporter is more sensitive to glucocorticoids than is general development. At the highest dose, promotional effects on serotonin transporter expression were offset by impaired growth, so that the peak effect was seen at the intermediate dose of dexamethasone. There were no comparable effects on serotonin transmitter levels, indicating selectivity toward promotion of transporter expression as distinct from simply increasing the number of serotonergic persistent than those on other monoamine transporters, and is not shared by postnatal treatment or by treatment in adulthood, it likely represents specific programming by glucocorticoids during the prenatal period. Aberrant serotonergic transporter expression may contribute to alterations of synaptic function that ultimately produce the physiological abnormalities seen after prenatal stress or glucocorticoid treatment.

The nature of d,l-fenfluramine-induced 5-HT reuptake transporter loss in rats.

The administration of the anorexigenic drug d,l-fenfluramine (Ponderax) to laboratory animals results in a dose-dependent reduction in presynaptically located serotonergic reuptake transporter protein. This long-term effect may represent an altered mechanism of synthesis of the transporter (downregulation). Alternatively, fenfluramine may destroy the serotonergic terminals on which 5-HT transporters are located. To distinguish between these two alternatives, we applied an assay of neurotransmitter-specific nerve endings (alpha) to brain tissue from two animal models of reduced 5-HT transporter density. In Model 1, serotonergic nerve terminals were destroyed (rats received 5,7-dihydroxytryptamine [5,7-DHT] intracisternally); in Model 2, there was a loss of 5-HT transporter per se on otherwise intact serotonergic nerve terminals. The manner in which alpha declined as transporter density was decreased (reducing Vmax values) in animal Models 1 and 2 was found to be significantly different. In rats treated with fenfluramine, the association between 5-HT transporter density and alpha was the same as in the neurotoxic model.

Platelet 3H-imipramine binding, serotonin uptake, and plasma α1 acid glycoprotein in disruptive behavior disorders

Tritiated imipramine labels with high affinity a recognition site associated with the serotonergic transporter in blood piatelets (Langer and Galzin 1988). Concomitant measurement of platelet 3Himipramine binding (IB) and 3H-5-hydroxytryptamine (5-HT) uptake in various diseases does not usually reveal parallel changes in these parameters. De~ eased platelet 5-HT uptake without accompanying changes in platelet IB has been observed in depression or schizophrenia (Wood et al 1983), panic disorder (Pecknold and Suranyi-Cadotte 1986), alcoholic cirrhosis (Ahtee et al 198 ! ), hypertension (Kamal et al 1984), Alzheimcr's dis~a~ (Suranyi-Cadotte et al 1985), and Parkinson's disease (Suranyi-Cadotte et al 1985). Decreased platelet IB but no corresponding changes in platelet 5-HT uptake has been found in depressed women (Roy et al 1987) and adolescents with obsessive--compulsive disorder (Weizman et al 1986a), anore,da nervosa

Differences in the temperature dependence of drug interaction with the noradrenaline and serotonin transporters

High affinity, sodium-dependent binding of [ 3H]mazindol is associated with the noradrenergic transporter while the binding of [ 3H]imipramine and [ 3H]paroxetine are associated with the serotonin transporter, e.g. in human platelets. In general radioligand binding studies to the monoamine transporters are performed at a temperature different from the physiological temperature (37°C) at which uptake occurs. Previously reported data show a temperature dependence for tricyclic but not for nontricyclic inhibitors of the uptake of serotonin in their interaction with radioligand binding to the serotonin transporter. In the present study, both tricyclic and nontricyclic inhibitors of the uptake of noradrenaline were shown to have equal affinity for the binding of [ 3H]mazindol to the noradrenergic transporter at 0° and 25°C. Moreover, whereas serotonin transporter substrates inhibit the binding of [ 3H]imipramine/ paroxetine in human platelets in an essentially temperature-independent manner (0–37°C), noradrenaline transporter substrates are of higher affinity in inhibiting the binding of [ 3H]mazindol at 0°C than at 25°C. At 0°C, substrate affinity for inhibition of the binding of [ 3H]mazindol to the noradrenaline transporter in the salivary gland of the rat approximates to the substrate affinity for transport by the noradrenaline carrier. The present data point to significant differences in the interaction of both substrates and inhibitors with the noradrenergic and serotonergic transporters, as studied using the radioligand binding. Thus, the pharmacological profile of the serotonin transporter, in terms of substrate and inhibitor affinity, is best studied using radioligand binding at 37°C, whereas radioligand binding to the noradrenaline transporter is most representative at 0°C. Furthermore, these observations provide an experimental model to study substrate affinity for the [ 3H]mazindol recognition site of the noradrenaline transporter.

Studies on the serotonin transporter in platelets.

[3H]-Imipramine and [3H]-paroxetine label with high affinity a recognition site which is associated with the serotonergic transporter in blood platelets. The pharmacological profile of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of drugs to inhibit the uptake of serotonin. Dissociation kinetic experiments suggest that the substrate recognition site for serotonin may be different from the modulatory site which is labeled with [3H]-imipramine or [3H]-paroxetine. The existence of an endocoid acting on the imipramine receptor to modulate the serotonin transporter has been proposed by several laboratories. In clinical studies most laboratories have reported a decrease in Bmax of [3H]-imipramine binding in platelets from depressed untreated patients when compared with matched healthy volunteers. The Bmax of [3H]-imipramine binding in platelets appears to be a state-dependent biological marker in depression.

Association of [3H]-imipramine and [3H]-paroxetine binding with the 5HT transporter in brain and platelets: relevance to studies in depression.

[3H]-Imipramine and [3H]-paroxetine label with high affinity a site which is associated with the serotonergic transporter in brain and platelets. The pharmacological profile of inhibition by drugs of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of the drugs to inhibit the uptake of 5HT. Denervation of serotonergic neurons by electrolytic lesions or with 5,7-dihydroxytryptamine produces marked decreases in the density of [3H]-imipramine as well as [3H]-paroxetine binding. Dissociation kinetic experiments support the view that the substrate recognition site for 5HT is different from the modulatory site which is labelled by [3H]-imipramine or [3H]-paroxetine. The existence of an endogenous ligand acting on the [3H]-imipramine recognition site to modulate the 5HT transporter was proposed by several laboratories. [3H]-Imipramine binding in platelets appears to be a biological marker in depression. Studies carried out in several laboratories report a significant decrease in the Bmax of platelet [3H]-imipramine binding without changes in Kd, when severely depressed untreated patients are compared with healthy volunteers matched for age and sex. The Bmax of platelet [3H]-imipramine binding appears to be a state-dependent biological marker in depression. It is tempting to speculate that the endocoid of the [3H]-imipramine recognition site may play a role in the pathogenesis of depression.