Biomedical subjects

E V Gurevich

Publications and source records attributed to E V Gurevich.

At least 19 recordsLinked to original sources

PubMed2006

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia.

Arrestins and G proteins-coupled receptor kinases (GRKs) regulate signaling and trafficking of G protein-coupled receptors. We investigated changes in the expression of arrestins and GRKs in the striatum of patients with Parkinson's disease without (PD) or with dementia (PDD) at postmortem using Western blotting and ribonuclease protection assay. Both PD and PDD groups had similar degree of dopamine depletion in all striatal regions. Arrestin proteins and mRNAs were increased in the PDD group throughout striatum. Protein and mRNA of GRK5, the major subtype in the human striatum, and GRK3 were also upregulated, whereas GRK2 and 6 were mostly unchanged. The PD group had lower concentration of arrestins and GRKs than the PDD group. There was no statistical link between the load of Alzheimer's pathology and the expression of these signaling proteins. Upregulation of arrestins and GRK in PDD may confer resistance to the therapeutic effects of levodopa often observed in these patients. In addition, increased arrestin and GRK concentrations may lead to dementia via perturbation of multiple signaling mechanisms.

Aged↗

PubMed2005

L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain.

Dysregulation of dopamine receptors (DARs) is believed to contribute to Parkinson disease (PD) pathology. G protein-coupled receptors (GPCR) undergo desensitization via activation-dependent phosphorylation by G protein-coupled receptor kinases (GRKs) followed by arrestin binding. Using quantitative Western blotting, we detected profound differences in the expression of arrestin2 and GRKs among four experimental groups of nonhuman primates: (1) normal, (2) parkinsonian, (3) parkinsonian treated with levodopa without or (4) with dyskinesia. Arrestin2 and GRK6 expression was significantly elevated in the MPTP-lesioned group in most brain regions; GRK2 was increased in caudal caudate and internal globus pallidus. Neither levodopa-treated group differed significantly from control. The only dyskinesia-specific change was an elevation of GRK3 in the ventral striatum of the dyskinetic group. Changes in arrestin and GRK expression in the MPTP group were accompanied by enhanced ERK activation and elevated total ERK expression, which were also reversed by L-DOPA. The data suggest the involvement of arrestins and GRKs in Parkinson disease pathology and the effects of levodopa treatment.

Animals↗

PubMed2005

Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Taking advantage of a monkey brain bank constituted to study the pathophysiology of levodopa-induced dyskinesia, we here report the changes affecting D1, D2 and D3 dopamine receptors within the striatum of four experimental groups of non-human primates: normal, parkinsonian, parkinsonian treated with levodopa without or with dyskinesia. We also report the possible role of arrestin and G protein-coupled receptor kinases.

Antiparkinson Agents↗

PubMed2002

Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors.

Previous data suggest a relationship between the loss of response to levodopa in Parkinson's disease (PD) patients with the co-occurrence of dementia, but the role of alterations in the dopamine system has not been explored. We measured the extent of striatal DA loss and changes in striatal DA D(2) and D(3) receptors in postmortem striatum of PD patients who historically had or had not lost their clinical response to dopaminergic drugs and/or had an additional diagnosis of dementia. Clinical evaluation and retrospective chart reviews for PD and dementia, and neuropathological diagnoses were obtained. All PD cases (+/-dementia), regardless of response to dopaminergic drugs, exhibited a significant and similar degree and pattern of loss of tyrosine hydroxylase immunocytochemistry and DA transporter binding in striatum, and loss of tyrosine hydroxylase-immunoreactive neurons and brain-derived neurotrophic-immunoreactive neurons from the ventral midbrain. D(2) receptor concentrations were modestly elevated in the rostral striatum of all the PD cases (+/-dementia), whether or not they continued to respond to dopaminergic drugs. In contrast, loss of D(3) receptor concentration correlated with loss of response to dopaminergic drugs, independent of the presence or absence of dementia. A maintained response to dopaminergic drugs correlated with an elevation of D(3) receptors. Dementia with PD was highly correlated with a loss of response to dopaminergic drugs, and was also correlated with reduced D(3) receptors. The alterations in D(3) receptor concentrations were greatest in the nucleus accumbens, caudal striatum, and globus pallidus. Thus, loss of dopamine D(3) receptors may be a more important contributing factor to a loss of response to dopaminergic drugs than changes in the D(2) receptor.

Aged↗

PubMed2002

Arrestin2 and arrestin3 are differentially expressed in the rat brain during postnatal development.

Arrestins are adaptor proteins involved in homologous desensitization and trafficking of G protein-coupled receptors. Arrestins bind to activated phosphorylated receptors thus precluding further signal transduction. Two subtypes of non-visual arrestins, arrestin2 and arrestin3, have been cloned. Recently, specificity of various receptors to arrestins and differences in kinetics of receptor desensitization mediated by arrestins have been demonstrated. Both arrestins are expressed in the rat brain. However, quantitative assessment of their expression and detailed distribution are lacking. Here, we used quantitative ribonuclease protection assay and western blot to measure arrestin2 and arrestin3 mRNA and protein in the rat brain during postnatal development. In situ hybridization histochemistry was employed to study the detailed distribution of arrestin mRNAs in the adult and developing brain. Both arrestins were expressed from birth in all regions studied. Arrestin2 mRNA levels increased with development until the 14th postnatal day and then decreased, whereas arrestin2 protein levels continued to rise. Arrestin3 mRNA was maximal in neonates and then decreased, while arrestin3 protein changed little. In newborns and adults, the concentration of arrestin2 mRNA was two- to three-fold higher than that of arrestin3. In neonates, the excess of the arrestin2 protein over arrestin3 was commensurate with the excess of the arrestin2 mRNA (three-fold) but in the adult, the ratio was much higher (10-20-fold). Each arrestin demonstrated a unique distribution, although in many areas there was overlap suggesting co-localization. Both arrestins were highly expressed in the cortex and hippocampus. Arrestin2 was abundant in the thalamus, particularly in the anterior, intralaminar, and midline nuclei, while arrestin3 was abundant in the medial habenular. Arrestin3 was relatively abundant in most hypothalamic nuclei and extended amygdala. In the developing brain, arrestin3 was highly expressed in the subventricular zone, whereas arrestin2 was more abundant in differentiated areas. Our data demonstrate that arrestin2 is the major arrestin subtype in the rat brain, although arrestin3 is expressed in specific cell populations including postnatal proliferative zones. Because each arrestin appears to mediate receptor desensitization in a specific way, different kinetics of trafficking of the same receptor should be expected in different cells due to varying arrestin2/arrestin3 ratios. Thus, the response of receptors to specific drugs stimulating or blocking these receptors may depend on complement of arrestins in their target cells.

Aging↗

PubMed2001

Thalamo-cortical afferents control transient expression of the dopamine D(3) receptor in the rat somatosensory cortex.

The D(3) dopamine receptor (D(3)R) is selectively and transiently expressed in the barrel neurons of the somatosensory cortex (SI) between the first and second postnatal weeks. The D(3)R expression starts after the initial ingrowth of thalamocortical afferents (TCAs) into the barrel cortex and could be induced or controlled by them. We show that unilateral electrolytic lesion of the thalamic ventrobasal complex immediately after birth leads to a decrease in the D(3)R mRNA concentration in the lesioned SI 7 days after the lesion, whereas the D(3)R binding is little affected. Fourteen days after the neonatal thalamic lesion, the D(3)R binding and mRNA are drastically reduced and the barrel-like pattern of the D(3)R is absent. Elevation of the D(3) binding normally seen between the first and second postnatal weeks does not occur. Thalamic lesion on P6 differentially affects the D(3)R expression. One day after the lesion, the D(3) binding and mRNA are down-regulated, but the effect is transient. Five days after the lesion the concentration of D(3) mRNA in the lesioned hemisphere returns to the control level. The typical barrel-like pattern of D(3)R expression is evident in the lesioned SI, although TCAs are completely absent. Quantitative analysis demonstrated elevated cellular levels of the D(3) mRNA in barrel neurons 5 days after the lesion. These higher levels are needed, perhaps, to support the increased production of the D(3)R protein appropriate for this age. Age-related dynamics of the D(3)R binding is retained in the lesioned SI, although the concentration of D(3)R sites remains reduced. These data demonstrate that intact thalamic input is essential for the formation of mechanisms responsible for developmental regulation of the D(3)R expression in the SI.

Animals↗

PubMed2000

Dopamine D(3) receptor is selectively and transiently expressed in the developing whisker barrel cortex of the rat.

The rodent primary somatosensory cortex (SI) contains a map of the body surface, the most conspicuous part of which are "barrels," neuronal aggregates in layer IV that receive somatotopic projections from whiskers on the rodent's snout. We report that the D(3) dopamine receptor (D(3)R) is selectively and transiently expressed in SI during the first 2 weeks of postnatal development. D(3)R binding sites and mRNA overlap completely and are limited to layer IV of SI. D(3)R/mRNA are organized in a pattern corresponding to somatotopic representations of the body (e.g., whiskers, jaws, paws, etc.) with the highest expression in the barrel field. D(3) mRNA is first detected at postnatal day (P)4, increases rapidly until P7-10, and sharply decreases after P14. D(3)R binding sites are detectable at P6, peak at P14, and decline afterwards. D(1), D(2), D(4), or D(5) mRNAs display dissimilar expression pattern. D(1) mRNA is mostly confined to infragranular layers throughout the cortex. D(4) mRNA expression in layer IV rises by 4 weeks postnatal, when D(3)R expression is virtually undetectable. Quantitative analysis of D(3) mRNA expression demonstrates that the proportion of D(3) mRNA-positive cells decreases between P7 and P14, whereas mRNA concentration per cell remains stable. Moreover, D(3)R number continues to rise, whereas mRNA levels begin to decline. Thus, a process limiting D(3)R expression to fewer cells may occur that also induces changes in post-transcriptional regulation of D(3)R expression in remaining cells. These findings indicate that dopamine acting via D(3)R may play an important role in the development or function of the SI.

Age Factors↗

PubMed2000

Ontogeny of the dopamine D2 receptor mRNA expressing cells in the human hippocampal formation and temporal neocortex.

The study details the cellular expression of the dopamine D2 receptor mRNA in the human temporal lobe during prenatal development. At 13 embryonic weeks (E13) D2 mRNA was widely expressed in the temporal lobe. At this time point in the dentate gyrus D2 mRNA positive cells first appeared at the outer border of the granular layer and their number increased with development. The CA1 exhibited the highest level of D2 mRNA expression. By E19-25 the hippocampal formation underwent rapid morphological maturation. D2 mRNA expression became more uniform and dense in the ammonic subfield. At all ages the subiculum appeared more mature morphologically but less intensely stained for D2 mRNA than the ammonic fields. In the entorhinal cortex D2 mRNA expression was most conspicuous in the future layer II at all ages. In the temporal neocortex D2 mRNA-positive cells were detected in the subplate and cortical plate. Differentiation of the cortical plate was accompanied by concentration of D2 mRNA-positive cells in layer V. The most conspicuous cells expressing D2 mRNA were found in the marginal zone of all regions and resembled Cajal-Retzius cells in morphology and location. Density of putative Cajal-Retzius cells expressing D2 mRNA decreased with development. They all but disappeared from the hippocampal areas by mid gestation, but in the temporal neocortex occasional cells were seen even at term. Early and widespread but region and cell type specific expression of D2 receptor mRNA suggests an important role of this DA receptor subtype in prenatal development of the human temporal lobe.

Brain Chemistry↗

PubMed2000

Cloning and functional characterization of salamander rod and cone arrestins.

PURPOSE: To clone, localize, and determine functional binding characteristics of rod and cone arrestins from the retina of the tiger salamander (Ambystoma tigrinum). METHODS: Two arrestins from salamander retina were cloned on the basis of their homology to known arrestins from other species. The expression pattern of these arrestins (SalArr1 and SalArr2) in the retina was determined by immunocytochemistry and in situ hybridization. SalArr1 and SalArr2 were expressed and functionally characterized. RESULTS: Both immunocytochemistry and in situ hybridization show that SalArr1 and SalArr2 localized specifically to rod and cone photoreceptors, respectively. SalArr1 demonstrated a characteristic high selectivity for light-activated phosphorylated rhodopsin (P-Rh*) and significant species selectivity, binding preferentially to amphibian rhodopsin over bovine rhodopsin. Mutant constitutively active forms of SalArr1 demonstrated a 2- to 4-fold increase in P-Rh* binding (compared with wild-type protein) and an even more dramatic (up to 25-fold) increase in binding to unphosphorylated Rh* and dark P-Rh. Constitutively active SalArr1 mutants also showed a reduced specificity for amphibian rhodopsin. The ability of Escherichia coli-expressed SalArr1, SalArr2, and an SalArr1-3A (L369A,V370A,F371A) mutant to bind to frog Rh* and P-Rh* and to compete with tritiated SalArr1 for amphibian P-Rh* was compared. SalArr1 and its mutant form bound to amphibian P-Rh* with high affinity (Ki = 179 and 74 nM, respectively), whereas the affinity of SalArr2 for P-Rh* was substantially lower (Ki = 9.1 microM). CONCLUSIONS: SalArr1 and SalArr2 are salamander rod and cone arrestins, respectively. Crucial regulatory elements in SalArr1 are conserved and play functional roles similar to those of their counterparts in bovine rod arrestin. Rod and cone arrestins are relatively specific for their respective receptors.

Ambystoma↗

PubMed1999

D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics.

The mesolimbic dopamine (DA) system and an important target receptor, the D3 receptor, have been implicated in schizophrenia. We have identified, using non-radioactive in situ hybridization histochemistry, that D3 mRNA-positive neurons are highly concentrated in the ventral striatum, efferents of the ventral striatum (globus pallidus internal, ventral palladium, substantia nigra pars reticulata), and in regions projecting to the ventral striatum (medial dorsal thalamus, nucleus basalis, extended amygdala). D3 receptors are also highly enriched in the "limbic" striatal-pallidal-thalamic loop, exhibiting segregation from the D2 receptor-enriched "motor loop." This supports data developed in rats showing that the D3 receptor is a target of the mesolimbic DA system that can modulate the limbic striatal-palladial-thalamic loop. However, D2 and D3 receptors and their mRNAs are co-localized in many sensory regions (lateral and medial geniculate nuclei, basolateral and basomedial amygdala, regions of thalamus), suggesting mechanisms of cross-talk. We have also demonstrated that there are 45% elevations in D3 receptor number in ventral striatal neurons and their striatopalladial targets in schizophrenics that is reduced by concurrent antipsychotic treatment. Chronic haloperidol treatment to rats for 6 months with a 2-month withdrawal does not result in elevated D3 receptor number. We hypothesize that antipsychotic treatment via D3 receptors returns balance to limbic efferents of the ventral striatum. We established that early neonatal damage to the nigrostriatal DA system in rats produces characteristic adaptations in the pre- and post-synaptic components of the mesolimbic DA system that can provide a model to explore regulation by antipsychotics. This includes elevated release of DA from the mesolimbic DA terminals, elevated D3 receptor mRNA in the Islands of Calleja and nucleus accumbens, and enhanced behavioral response to psychostimulants.

Animals↗

PubMed1999

Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons.

The dopamine D2 and D3 receptors are members of the D2 subfamily that includes the D2, D3 and D4 receptor. In the rat, the D3 receptor exhibits a distribution restricted to mesolimbic regions with little overlap with the D2 receptor. Receptor binding and nonisotopic in situ hybridization were used to study the distribution of the D3 receptors and neurons positive for D3 mRNA in comparison to the D2 receptor/mRNA in subcortical regions of the human brain. D2 binding sites were detected in all brain areas studied, with the highest concentration found in the striatum followed by the nucleus accumbens, external segment of the globus pallidus, substantia nigra and ventral tegmental area, medial preoptic area and tuberomammillary nucleus of the hypothalamus. In most areas the presence of D2 receptor sites coincided with the presence of neurons positive for its mRNA. D3 binding sites and D3 mRNA positive neurons were most abundant in the limbic striatum and efferent structures, such as the nucleus accumbens, ventral striatum, substantia nigra, internal segment of the globus pallidus, anteroventral nucleus of the thalamus, and rostral pars reticulata of the substantia nigra. One important difference from the rat is that D3 receptors were virtually absent in the ventral tegmental area. D3 receptor and D3 mRNA positive neurons were observed in sensory, hormonal, and association regions such as the nucleus basalis, anteroventral, mediodorsal, and geniculate nuclei of the thalamus, mammillary nuclei, the basolateral, basomedial, and cortical nuclei of the amygdala. As revealed by simultaneous labeling for D3 and D2 mRNA, D3 mRNA was often expressed in D2 mRNA positive neurons. Neurons that solely expressed D2 mRNA were numerous and regionally widespread, whereas only occasional D3-positive-D2-negative cells were observed. The regions of relatively higher expression of the D3 receptor and its mRNA appeared linked through functional circuits, but co-expression of D2 and D3 mRNA suggests a functional convergence in many regions of the signals mediated by the two receptor subtypes.

Aged↗

PubMed1999

Developmental regulation of expression of the D3 dopamine receptor in rat nucleus accumbens and islands of Calleja.

The dopamine D3 receptor (D3R) belongs to the D2 subfamily and is expressed in the rat brain in targets of the mesolimbic dopaminergic system. Little is known about its normal development and control by dopaminergic innervation. We studied developmental expression of D3R in the rat nucleus accumbens (NAC) and islands of Calleja (ISC). At postnatal day (P) 7, D3 binding sites and mRNA were low in both areas. By P14, D3R and mRNA concentrations were close to adult levels in the ISC, whereas, in the NAC, binding increased until 3 months after birth. Cellular concentrations of D3 mRNA in the ISC increased with age in conjunction with a decrease in the number of D3 positive cells. In the NAC, the number of positive cells increased, whereas cellular levels of expression remained unchanged. Neonatal 6-hydroxydopamine lesion caused age-dependent changes in D3R expression. D3 binding sites did not change at P7 or P14, but there was a reduction in the number of D3 mRNA positive neurons accompanied by an increase in cellular levels of D3 mRNA at P14, suggesting that changes occurred in a subset of neurons. Up-regulation of D3 binding sites in NAC and ISC occurred 1 month after the lesion (P35) concomitant with a decrease in cellular levels of D3 mRNA and the number of D3 mRNA positive cells. At 3 months (P90) after the lesion, an increase in D3 mRNA occurred with no change in D3 binding sites. D3R shows region-specific dynamics in receptor/mRNA expression during development and is sensitive to loss of dopamine in early postnatal development.

Animals↗

PubMed1997

Dopamine D2 receptor mRNA is expressed in maturing neurons of the human hippocampal and subicular fields.

Pyramidal neurons of the adult and fetal hippocampus and subicular fields were shown to express D2 mRNA using non-radioactive in situ hybridization histochemistry. At the earliest developmental stages examined (embryonic week (E) 13), cell packing within the CA1 region is dense and immature neuroblasts express D2 mRNA at high levels, as do more mature pyramid-like neurons in the deep aspect of the pyramidal cell layer. With development (E19 and E24), cell packing density is reduced, maturing neurons of the pyramidal layer are prominently D2 mRNA positive, while the majority of immature cells lining the superficial layer are D2 mRNA negative. In Layer II of the presubiculum there is a high density of immature D2 mRNA negative cells at E13 with D2 mRNA positive cells located on the periphery of the clusters. By E24, the cells in the layer II clusters are larger, express D2 mRNA, and D2 mRNA negative cells are rarely observed. Thus, expression of D2 mRNA in humans is an early and permanent feature of pyramidal neurons of these regions.

Adult↗

PubMed1997

Alterations in the cortical serotonergic system in schizophrenia: a postmortem study.

Previous studies have suggested a disturbance in the cortical serotonergic (5-HT) system in schizophrenia; however, these studies have been confounded by suicide in the patients groups, which in itself is associated with alterations in the 5-HT system. In this study we characterized various components of the 5-HT system in 14 areas of the frontal and parietal cortex in tissue obtained at postmortem from aged chronically hospitalized nonsuicidal schizophrenics compared to age-matched controls. We found no differences between control and schizophrenic subjects in the density of 5-HT uptake sites or other markers of 5-HT innervation. In Brodmann areas 24 and 6 the concentration of 5-HT2A,C receptors was decreased in all schizophrenics regardless of their antipsychotic treatment history. In all other areas examined 5-HT2A,C receptor concentrations were dramatically decreased in schizophrenics patients on drugs at time of death, whereas those off drugs at death showed the same values as control subjects. The density of 5-HT1A receptors was increased in areas 24, 9a (caudal part of area 9), 44, and 6 in subjects with schizophrenia. Antipsychotic treatment did not appear to have a significant effect. Thus, the specific pattern of alterations in the 5-HT system in schizophrenia may depend on the patient population and on antemortem antipsychotic treatment. These data also provide evidence that regulation of the 5-HT2 receptor may be involved in antipsychotic action.

Aged↗

PubMed1997

Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study.

BACKGROUND: The pharmacological properties and distribution of a recently cloned member of the dopamine D2 receptor subfamily, the D3 receptor, has led directly to the hypothesis that it may be the target of antipsychotic action. METHODS: To quantify D3 receptors, we characterized the conditions for selective binding of the radioligand iodine 125-labeled (R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)-amino] tetralin ([125I]trans-7-OH-PIPAT) to the human D3 receptor. We then measured by quantitative autoradiography in postmortem tissue the concentration of D3 receptors in the caudal and rostral basal ganglia regions in patients with schizophrenia and control subjects. RESULTS: We found about 2-fold elevations in the number of D3 receptors in the basal ganglia and ventral forebrain of long-term hospitalized patients with schizophrenia who received no antipsychotic drugs for at least a month before death (n = 7) compared with matched control subjects (n = 15). Patients with schizophrenia receiving antipsychotic drugs less than 72 hours before death (n = 8) had levels similar to those of control subjects. There were no differences in the binding characteristics or affinity of [125I]trans-7-OH-PIPAT binding to D3 receptors between control subjects and patients with schizophrenia. CONCLUSION: In contrast to the previously detected elevation of D2 and D4 receptor levels in schizophrenia, elevation of D3 receptor levels in limbic striatum and its efferents observed in patients with schizophrenia may be reduced by antipsychotic drugs.

Adult↗

PubMed1997

Bulbectomy-induced loss of raphe neurons is counteracted by antidepressant treatment.

1. Bilateral olfactory bulb ablation was performed in C57B1/6j mice (C57). Separate groups of bulbectomized mice were treated with either antidepressants (trazodone, 20 mg/kg i.p., or amitriptyline, 20 mg/kg i.p.) or saline daily for 14 consecutive days starting 14 days after surgery. 2. Celloidine-imbedded 10 microns-thick brain sections containing the nucleus raphe dorsalis (NRD) or locus coeruleus (LC) were stained for Nissl, and the number of functional and pyknotic cells was counted out of 500 total cell count for each animal in every experimental group: sham-operated, bulbectomized treated with saline or one of the two antidepressants. 3. Bulbectomy produced a significant 4 times increase in the proportion of pyknotic cells in NRD as compared to sham-operated control. Both antidepressants reversed the effect bringing the number of pyknotic cells to control level. The proportion of pyknotic cells in LC was also slightly increased (61%) in the bulbectomized mice, but only amitriptyline was able to reverse the effect. 4. Widespread degeneration of the neurons in NRD caused by bulbectomy may be involved in the serotonergic component of the bulbectomy syndrome. The ability of antidepressants to diminish bulbectomy-induced loss of NRD neurons may underlie their restorative effect on the behavior and neurochemical characteristics of bulbectomized animals.

Amitriptyline↗

PubMed1996

Comparison of [3H]paroxetine and [3H]cyanoimipramine for quantitative measurement of serotonin transporter sites in human brain.

Previous studies have demonstrated that [3H]paroxetine and [3H]cyanoimipramine ([3H]CN-IMI) are highly selective ligands for the serotonin (5-HT) transporter. Using membrane preparation from the putamen, we confirmed that in human brain [3H]paroxetine labeled with high affinity one class of site associated with the 5-HT transporter. [3H]CN-IMI labeled two classes of sites in human brain. The one displaceable by 5-HT and with high affinity to 5-HT uptake inhibitors accounts for about 60% of the [3H]CN-IMI binding and, presumably, is associated with the 5-HT transporter. From the competition experiments, citalopram was selected to define [3H]CN-IMI binding to the 5-HT transporter in tissue sections because of its high selectivity to 5-HT transporter sites. A good correlation of the regional distribution patterns for [3H]CN-IMI and [3H]paroxetine was found using quantitative autoradiography. However, [3H]paroxetine underestimated high concentrations of the 5-HT transporter comparing to [3H]CN-IMI. This is likely to be due to the higher specific activity of [3H]CN-IMI. There is a good correlation between the regional distribution of 5-HT transporter sites labeled with either [3H]paroxetine or [3H]CN-IMI and the density of serotonergic innervation. This suggests that the brain areas that receive numerous serotonergic afferents, such as the hypothalamus and basal forebrain, might be common targets of these antidepressant drugs. Pharmacologic similarity of the sites labeled by both ligands as well as their similar distribution in the brain suggests that both antidepressant drugs interact with the same protein, thereby eliciting a similar neurochemical response.

Aged↗

PubMed1994

Antidepressants suppress bulbectomy-induced augmentation of voluntary alcohol consumption in C57B1/6j but not in DBA/2j mice.

Bulbectomy has been previously shown to produce the specific antidepressant-sensitive syndrome in C57Bl/6j, but not DBA/2j mice. The present study examined the effect of the depression on voluntary alcohol consumption. Alcohol consumption and alcohol preference (% of alcohol solution in total liquid) in a free-choice, two-bottle situation was measured in C57BL/6j and DBA/2j mice after sham-operation, anosmia with 10% ZnSO4, or bulbectomy. Both anosmic and bulbectomized mice of both strains consumed more alcohol and showed stronger preference for alcohol than sham-operated mice. In DBA/2j mice both operations altered alcohol consumption of the whole population, and the effect of bulbectomy was stronger. In C57Bl/6j mice bulbectomy and, to a less degree, anosmia seemed to affect predominantly the low-drinking animals. Chronic treatment with antidepressants amitriptyline (20 mg/kg), trazodone (20 mg/kg), and imipramine (10 mg/kg), did not change alcohol consumption in sham-operated C57Bl/6j mice. In anosmic mice antidepressants decreased alcohol preference, but only amitryptyline also decreased alcohol consumption. All antidepressants decreased both alcohol consumption and preference in bulbectomized C57Bl/6j mice. In DBA/2j mice antidepressant treatment either increased, or did not alter alcohol consumption and preference in all groups, though the effects varied among individual antidepressants. The possible connection between the bulbectomy-induced behavioral syndrome and elevated ethanol consumption in C57Bl/6j mice is discussed.

Alcohol Drinking↗