Biomedical subjects

Beth Levant

Publications and source records attributed to Beth Levant.

At least 19 recordsLinked to original sources

PubMed2007

Maternal parity and diet (n-3) polyunsaturated fatty acid concentration influence accretion of brain phospholipid docosahexaenoic acid in developing rats.

The long-chain PUFA, docosahexaenoic acid [22:6(n-3), DHA], a major component of neuronal membrane phospholipids, accumulates in brain during late prenatal and early neonatal development and is essential for optimal attentional and cognitive function. Because all nutrition is supplied to the developing fetus/neonate by the mother and maternal DHA status is affected by parity, this study examined the effects of maternal diet and parity on DHA accretion in the developing brain. Whole brain total phospholipid fatty acid composition was determined by TLC and GC in weanling male Long-Evans rats (n = 5) from the 1st, 2nd, 3rd, or 4th litters of dams fed diets containing alpha-linolenic acid (ALA), containing ALA and preformed DHA (ALA + DHA), or lacking ALA (low-ALA). First-litter low-ALA offspring exhibited a decrease in phospholipid fatty acid DHA content to 68% of 1st-litter ALA pups. DHA in 2nd-litter low-ALA pups was further decreased to 55% of 1st-litter ALA pups, but further decreases were not observed in subsequent litters. DHA levels increased 15-20% in 2nd to 4th-litter ALA + DHA pups and 11% in 4th-litter ALA pups compared with 1st-litter ALA pups. These findings demonstrate that maternal diet and parity interact to affect offspring brain DHA status and suggest that maternal multiparity may place offspring at greater risk of decreased accretion of brain DHA if the maternal diet contains insufficient (n-3) PUFA.

Aging↗

PubMed2007

Specific brain regions of female rats are differentially depleted of docosahexaenoic acid by reproductive activity and an (n-3) fatty acid-deficient diet.

Low tissue levels of (n-3) PUFA, particularly docosahexaenoic acid [DHA, 22:6(n-3)], are implicated in postpartum depression. Brain DHA content is depleted in female rats undergoing pregnancy and lactation when the diet supplies inadequate (n-3) PUFA. In this study, the effects of DHA depletion as a result of reproductive activity and an (n-3) PUFA-deficient diet were examined in 8 specific brain regions of female rats after undergoing 2 sequential reproductive cycles. Virgin females, fed the alpha-linolenic acid (ALA)-containing or deficient (low-ALA) diets for a commensurate duration (13 wk) served as a control for reproduction. Total phospholipid composition of each brain region was determined at weaning (postnatal d 21) by TLC/GC. The regional PUFA composition of ALA virgins was similar to that previously measured in male rats. All brain regions examined were affected by reproductive activity and/or the low-ALA diet; however, the magnitude of the loss of DHA and compensatory incorporation of docosapentaenoic acid [(n-6) DPA, 22:5(n-6)] varied among brain regions. In low-ALA parous dams, frontal cortex (77% of ALA virgin) and temporal lobe (83% of ALA virgin), regions involved in cognition and affect, were among those exhibiting the greatest depletion of DHA. Caudate-putamen also exhibited significant depletion of DHA (82% of ALA virgin), whereas only (n-6) DPA levels were altered in ventral striatum, hypothalamus, hippocampus, and cerebellum. This pattern of changes in regional DHA and (n-6) DPA content suggests that specific neuronal systems may be differentially affected by depletion of brain DHA in the postpartum organism.

Animals↗

PubMed2006

Sex-specific effects of brain LC-PUFA composition on locomotor activity in rats.

Insufficient availability of n-3 polyunsaturated fatty acids (PUFAs) during pre- and neonatal development decreases accretion of docosahexaenoic acid (DHA, 22:6n-3) in the developing brain and is associated with sub-optimal sensory and cognitive function in humans, altered behavior in animals, and may contribute to neurodevelopmental disorders such as attention deficit hyperactivity disorder and schizophrenia. This study examined the effects of variation in dietary availability of n-3 PUFAs on brain fatty acid composition and the consequent effects on locomotor activity in male and female Long-Evans rats. Rats were raised from conception using purified diets and breeding protocols designed to produce four groups with distinct brain phospholipid compositions varying in DHA content and/or the proportion of n-3 and n-6 PUFAs. Locomotor behavior was measured for a 2-h period on postnatal days 28, 42, 56, and 70. In males, decreased brain DHA produced alterations in activity that were most pronounced post-adolescence and with the greatest decrease in DHA. However, the behavioral effects in males were not linearly related to brain DHA level. In contrast, no significant effects of variation in brain fatty acid composition were observed in females. This suggests that variation in brain DHA content produces sex-specific alterations in locomotor activity and that the neurochemical alterations underlying the observed behavioral changes vary depending on the degree of DHA depletion.

Age Factors↗

PubMed2006

Reduced brain DHA content after a single reproductive cycle in female rats fed a diet deficient in N-3 polyunsaturated fatty acids.

BACKGROUND: Low levels of n-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA, 22:6n3), are implicated in postpartum depression. METHODS: The effects of pregnancy and lactation on brain phospholipid fatty acid content were determined in female rats fed diets containing sufficient (control) or negligible (deficient) alpha-linolenic acid (18:3n-3), the dietary precursor of DHA, beginning at conception. Female virgins, fed the diets for 6 weeks, served as control animals. Whole brain total phospholipid composition was determined at weaning by GC. RESULTS: Brain DHA content of postpartum dams fed the deficient diet was decreased by 21% compared with age-matched virgin control animals, with a reciprocal increase in docosapentaenoic acid (22:5n6) to 243%. CONCLUSIONS: Under dietary conditions supplying inadequate n-3 PUFAs, maternal brain DHA content can be reduced after a single reproductive cycle. This depletion may affect neuronal function and thus the sensitivity of the postpartum organism to stress.

Animals↗

PubMed2006

Sub-chronic antipsychotic drug treatment does not alter brain phospholipid fatty acid composition in rats.

Altered membrane phospholipid fatty acid composition is reported in schizophrenia and appears to be reduced by antipsychotic drug treatment. To determine whether antipsychotic drugs have a direct effect on brain phospholipid fatty acid composition, the effects of sub-chronic treatment with a "typical" and an "atypical" antipsychotic drug were determined in adult male Sprague-Dawley rats. Rats were treated with haloperidol (1 mg/kg), clozapine (20 mg/kg) or vehicle daily for 21 days. Whole brain total phospholipid composition was determined by gas chromatography. No alterations in brain phospholipid composition were produced by either drug. This suggests that the apparent normalization of membrane phospholipids observed in drug-treated schizophrenic patients is not due to a direct pharmacological effect of these drugs nor can the pharmacological effects of these drugs occurring in this time frame be attributed to alterations in neuronal membrane fatty acid composition.

Analysis of Variance↗

PubMed2006

Differential effects of modulation of docosahexaenoic acid content during development in specific regions of rat brain.

Variation in brain FA composition, particularly decreased DHA (22:6n-3), affects neurodevelopment, altering visual, attentional, and cognitive functions, and is implicated in several neuropsychiatric disorders. To further understand how specific brain processes and systems are affected by variation in brain DHA content, we sought to determine whether specific brain regions were differentially affected by treatments that alter brain DHA content. Adult male Long-Evans rats were raised from conception using diet/breeding treatments to produce four groups with distinct brain phospholipid compositions. Total phospholipid FA composition was determined in whole brain and 15 brain regions by TLC/GC. Brain regions exhibited significantly different DHA contents, with the highest levels observed in the frontal cortex and the lowest in the substantia nigra/ventral tegmental area. Increased availability of DHA resulted in increased DHA content only in the olfactory bulb, parietal cortex, and substantia nigra/ventral tegmental area. In contrast, treatment that decreased whole-brain DHA levels decreased DHA content in all brain regions except the thalamus, dorsal midbrain, and the substantia nigra/ventral tegmental area. Alterations in DHA level were accompanied by changes in docosapentaenoic acid (n-6 DPA, 22:5n-6) content; however, the change in DHA and n-6 DPA was nonreciprocal in some brain regions. These findings demonstrate that the FA compositions of specific brain regions are differentially affected by variation in DHA availability during development. These differential effects may contribute to the specific neurochemical and behavioral effects observed in animals with variation in brain DHA content.

Animals↗

PubMed2006

Diet (n-3) polyunsaturated fatty acid content and parity interact to alter maternal rat brain phospholipid fatty acid composition.

Low tissue levels of (n-3) polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid [DHA, 22:6(n-3)], are implicated in postpartum depression. The effects of 1-4 sequential reproductive cycles on maternal brain phospholipid fatty acid composition were determined in female rats fed diets containing alpha-linolenic acid (ALA), containing ALA and pre-formed DHA (ALA+DHA), or lacking ALA (low-ALA). Virgin females, fed the diets for commensurate durations served as a control for reproduction. Whole-brain total phospholipid composition was determined at weaning by TLC/GC. A single reproductive cycle on the low-ALA diet decreased brain DHA content by 18% compared to ALA primiparas (P < 0.05), accompanied by incorporation of docosapentaenoic acid ((n-6) DPA, 22:5(n-6)) to 280% of ALA primiparas (P < 0.05). DHA was not further decreased after subsequent cycles; however, there was an additional increase in (n-6) DPA after the second cycle (P < 0.05). Brain DHA of virgin females fed the low-ALA diet for 27 wk decreased 15% (P < 0.05), but was accompanied by a more modest increase in (n-6) DPA than in parous low-ALA dams (P < 0.05). Virgin females and parous dams fed the diet containing ALA+DHA exhibited only minor changes in brain fatty acid composition. These observations demonstrate that brain DHA content of adult animals is vulnerable to depletion under dietary conditions that supply inadequate (n-3) PUFAs, that this effect is augmented by the physiological demands of pregnancy and lactation, and that maternal diet and parity interact to affect maternal brain PUFA status.

Animals↗

PubMed2005

Design of novel hexahydropyrazinoquinolines as potent and selective dopamine D3 receptor ligands with improved solubility.

We have recently reported hexahydropyrazinoquinolines as a new class of dopamine 3 (D(3)) receptor ligands with high-affinity to the D(3) receptor and excellent selectivity over the closely related D(1)-like and D(2)-like receptors. However, our previously reported most potent and selective D(3) ligands have poor aqueous solubility, which greatly hinders our in vivo studies aimed at evaluation of their therapeutic potential in animal models. In this study, we wish to report the design, synthesis, and evaluation of a series of new hexahydropyrazinoquinolines as D(3) ligands with improved solubility. Among them, compound 4g has a K(i) value of 9.7 nM for the D(3) receptor and displays a selectivity of >5000 and 466 times over the D(1)-like and D(2)-like receptors, respectively. Importantly, the hydrochloride salt form of compound 4g has a good aqueous solubility (>50 mg/mL) and represents a promising D(3) ligand for further in vivo evaluations of its therapeutic potential for the treatment of drug abuse, restless legs syndrome, schizophrenia, Parkinson's disease, and depression.

Animals↗

PubMed2005

Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands.

We report the design and synthesis of a series of enantiomerically pure hexahydropyrazinoquinolines as potent and selective ligands for the dopamine 3 subtype receptor using a newly developed synthetic method and using in vitro pharmacological evaluation. Our efforts yielded optically pure ligands with high affinities for the D(3) receptor and outstanding selectivity over closely related D(1)-like and D(2)-like receptors. For example, compound 38a has a K(i) value of 5.7 nM to the D(3) receptor and selectivity greater than 10000- and 1600-fold over the D(1)-like and D(2)-like receptors, respectively, and thus is one of the most selective D(3) ligands reported to date.

Animals↗

PubMed2005

Altered quinpirole-induced local cerebral glucose utilization in anterior cortical regions in rats after sensitization to quinpirole.

Dopaminergic psychostimulants produce behavioral responses of greater magnitude with repeated, intermittent administration, than a single, acute dose, a phenomenon known as "sensitization." Most studies of sensitization have focused on the "motive circuit"; however, some additional anterior cortical regions also appear to be affected. In this study, alterations in regional neuronal activity in anterior cortical brain areas produced by quinpirole, a D(2)/D(3) agonist, were assessed on the basis of local cerebral glucose utilization (LCGU) using the [(14)C]-2-deoxyglucose (2-DG) method. Adult, male Long-Evans rats (180-200 g, n = 7-9/group) were subjected to ten injections of quinpirole (0.5 mg/kg, s.c.) administered every third day; controls and drug-naive rats received saline. Locomotor activity was quantitated after injections one and ten to confirm sensitization. The 2-DG procedure was initiated 60 min after an 11th injection in freely moving rats. LCGU was determined in 11 anterior cortical brain regions by quantitative autoradiography. In drug-naive rats, quinpirole decreased LCGU in the cingulate cortex-area 3 (-16%) and infralimbic cortex (-16%). In sensitized rats, quinpirole decreased LCGU in the cingulate cortex-area 1 (-19%), frontal cortex-area 3 (-19%), lateral orbital cortex (-18%), medial/ventral orbital cortex (-17%), and parietal cortex (-17%) as well as in the cingulate cortex-area 3 (-19%) and infralimbic cortex (-20%); (all P < 0.05 v. control). This suggests that decreased neuronal activity in the cingulate cortex-area 1, frontal cortex-area 3, lateral orbital cortex, medial/ventral orbital cortex, and parietal cortex, in addition to altered activity in the motive circuit, may underlie the augmented behavioral response to quinpirole in sensitized animals.

Animals↗

PubMed2005

Design, synthesis and structure-activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligands.

A hexahydropyrazinoquinoline (compound 5c) was previously discovered as a novel D3 ligand with a moderate binding affinity to the D3 receptor (Ki=304 nM) but no selectivity over the D1-like and D2-like receptors. In this study, we wish to report the design, synthesis and structure-activity relationship studies of a series of novel hexahydropyrazinoquinolines. Our efforts resulted in new compounds with improved binding affinity and selectivity. Among them, compound 12d has a Ki value of 2.6 nM for its binding affinity to the D3 receptor and has >2000- and 99-fold selectivity over the D1-like and D2-like receptors, respectively, representing a potent and selective D3 ligand.

Animals↗

PubMed2004

Design, synthesis, and evaluation of hexahydrobenz[f]isoquinolines as a novel class of dopamine 3 receptor ligands.

We previously identified hexahydrobenz[f]isoquinoline (4a) as a new class of dopamine 3 receptor (D(3)) ligand. Herein, we described the design, synthesis, and preliminary structure-activity relationships of new analogues of 4a as a novel class of D(3) ligands. Among these new analogues, compound 4 h is a potent D(3) ligand (K(i)=6.1 nM) and has a selectivity of 133-fold between D(3)- and D(2)-like receptors, and of 163-fold between D(3)- and D(1)-like receptors, respectively. Thus, compound 4 h represents a promising new lead compound for further design and optimization toward achieving highly potent and selective D(3) ligands.

Animals↗

PubMed2004

Decreased brain docosahexaenoic acid during development alters dopamine-related behaviors in adult rats that are differentially affected by dietary remediation.

Docosahexaenoic acid (DHA) is a major component of neuronal membranes. In rats, low brain levels of DHA during development produce alterations in the mesocortical and mesolimbic dopamine systems. In this study, male Long-Evans rats (n = 6-7 per group) were raised from conception on diets with (control) or without alpha-linolenic acid, the dietary precursor of DHA. The deficient diet reduced brain DHA to 80% of that of control animals at maturity. At weaning (P21), half of the pups from each deficient litter were changed to a remediation diet enriched in DHA by the addition of fish oil. Beginning at P56, rats were subjected to a battery of behavioral tests. Catalepsy induced by haloperidol (3mg/kg, i.p.) in deficient animals was 49% of that observed in control animals (P < 0.05). Catalepsy in remediated animals was similar to that observed for control animals. In a test of locomotor activity in a novel environment, deficient animals exhibited 187% of the activity of control animals (P < 0.05). Locomotor activity stimulated by d-amphetamine (0.5mg/kg, s.c.) in deficient animals was 145% of that observed in control animals (P < 0.05). Basal and amphetamine-stimulated activity of remediated animals was similar to that of deficient animals. Response to a thermal stimulus was not different between groups. These findings demonstrate that rats exposed from conception to a diet that produces a relatively modest decrease in brain DHA content exhibit alterations in adult behavior indicative of altered dopaminergic function. Some of these behavioral alterations were reversed by dietary remediation initiated at weaning.

Amphetamine↗

PubMed2004

Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats.

Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2-deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing doses of morphine (5-25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg (b.i.d.) for 4-7 days. For the 2-DG procedure, rats were injected with saline or ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46 brain regions. In drug-naive animals, ibogaine produced significant increases in LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared to controls consistent with its activity as a hallucinogen and a tremorogen. Morphine-dependent rats had only minor alterations in LCGU at the time assessed in this experiment. However, in morphine-dependent animals, ibogaine produced a global decrease in LCGU that was greatest in brain regions such as the lateral and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell, inferior colliculus, locus coeruleus, and flocculus compared to morphine-dependent animals treated with saline. These findings indicate that ibogaine produces distinctly different effects on LCGU in drug-naive and morphine-dependent rats. This suggests that different mechanisms may underlie ibogaine's hallucinogenic and anti-addictive effects.

Animals↗

PubMed2004

Signaling mechanisms of the D3 dopamine receptor.

A substantial body of evidence shows the capacity of the dopamine D3 receptor to couple functionally to G proteins when expressed in an appropriate milieu in heterologous expression systems. In these systems, activation of D3 receptors inhibits adenylate cyclase, modulates ion flow through potassium and calcium channels, and activates kinases, most notably mitogen-activated protein kinase. Coupling to Gi/Go is implicated in many of these effects, but other G proteins may contribute. Studies with chimeric receptors implicate the third intracellular loop in the mediation of agonist-induced signal transduction. Finally, D3-preferring drugs modulate expression of c-fos in neuronal cultures and brain. Signaling mechanisms of the D3 receptor in brain, however, remain to be definitively determined.

Adenylyl Cyclases↗

PubMed2003

Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor: discovery of novel and potent D3 ligands through a hybrid pharmacophore- and structure-based database searching approach.

The dopamine 3 (D3) subtype receptor has been implicated in several neurological conditions, and potent and selective D3 ligands may have therapeutic potential for the treatment of drug addiction, Parkinson's disease, and schizophrenia. In this paper, we report computational homology modeling of the D3 receptor based upon the high-resolution X-ray structure of rhodopsin, extensive structural refinement in the presence of explicit lipid bilayer and water environment, and validation of the refined D3 structural models using experimental data. We further describe the development, validation, and application of a hybrid computational screening approach for the discovery of several classes of novel and potent D3 ligands. This computational approach employs stepwise pharmacophore and structure-based searching of a large three-dimensional chemical database for the identification of potential D3 ligands. The obtained hits are then subjected to structural novelty screening, and the most promising compounds are tested in a D3 binding assay. Using this approach we identified four compounds with K(i) values better than 100 nM and eight compounds with K(i) values better than 1 microM out of 20 compounds selected for testing in the D3 receptor binding assay. Our results suggest that the D3 structural models obtained from this study may be useful for the discovery and design of novel and potent D3 ligands. Furthermore, the employed hybrid approach may be more effective for lead discovery from a large chemical database than either pharmacophore-based or structure-based database screening alone.

Algorithms↗

PubMed2003

Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration.

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.

Amphetamine↗

PubMed2003

Differences in quinpirole-induced local cerebral glucose utilization between naive and sensitized rats.

Dopaminergic psychostimulants produce behavioral responses of greater magnitude with repeated, intermittent administration, than a single, acute dose, a phenomenon known as 'sensitization'. Alterations in regional neuronal activity produced by quinpirole, a D(2)/D(3) agonist, in quinpirole-naive and quinpirole-sensitized rats were assessed on the basis of local cerebral glucose utilization (LCGU) using the [14C]2-deoxyglucose (2-DG) method. Adult, male Long-Evans rats (180-200 g, n=7-9/group) were subjected to ten injections of quinpirole (0.5 mg/kg, s.c.) administered every 3rd day; controls and quinpirole-naive rats received saline. Locomotor activity was quantitated after injections one and ten to confirm sensitization. The 2-DG procedure was initiated 60 min after an 11th injection in freely moving rats. LCGU was determined in 43 brain regions by quantitative autoradiography. In quinpirole-naive rats, quinpirole decreased LCGU in the caudate/putamen (84% of control), lateral habenula (80% of control), and motor cortex (79% of control). In sensitized rats, quinpirole decreased LCGU in the nucleus accumbens core and shell (77 and 83% of control, respectively) and ventral pallidum (82% of control) as well as in the caudate/putamen (86% of control), lateral habenula (77% of control), and motor cortex (79% of control). This suggests that decreased neuronal activity in the nucleus accumbens and ventral pallidum may underlie the augmented behavioral response to quinpirole in sensitized animals.

Animals↗