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1.  STREPTOZOTOCIN-INDUCED DIABETES PARTIALLY ATTENUATES THE EFFECTS OF A HIGH-FAT DIET ON LIVER AND BRAIN FATTY ACID COMPOSITION IN MICE 
Lipids  2013;48(9):939-948.
The current study addresses the effects of a high-fat diet on liver and brain fatty acid compositions and the interaction of that diet with diabetes in a type 1 mouse model. Adult, male, normal and streptozotocin-induced diabetic C57BL/6 mice were fed standard (14% kcals from fat) or high-fat (54% kcals from fat, hydrogenated vegetable shortening and corn oil) diets for 8 weeks. Liver and whole brain total phospholipid fatty acid compositions were then determined by TLC/GC. In the liver of non-diabetic mice, the high-fat diet increased the percentages of 18:1n-9, 20:4n-6, and 22:5n-6 and decreased 18:2n-6 and 22:6n-3. Diabetes increased 16:0 in liver, and decreased 18:1n-7 and 20:4n-6. The effects of the high-fat diet on liver phospholipids in diabetic mice were similar to those in non-diabetic mice, or were of smaller magnitude. In the brain, the high-fat diet increased 18:0 and 20:4n-6 of non-diabetic, but not diabetic mice. Brain 22:5n-6 acid was increased by the high-fat diet in both non-diabetic and diabetic mice, but this increase was smaller in diabetic mice. Diabetes alone did not alter the percentage of any individual fatty acid in brain. This indicates that the effects of a high-fat diet on liver and brain phospholipid fatty acid compositions are mitigated by concomitant hyperglycemia with hypoinsulinemia.
doi:10.1007/s11745-013-3817-z
PMCID: PMC3760375  PMID: 23893338
High-fat diet; diabetes; streptozotocin; liver; brain; phospholipid
2.  LOW BRAIN DHA CONTENT WORSENS SENSORIMOTOR OUTCOMES AFTER TBI AND DECREASES TBI-INDUCED TIMP1 EXPRESSION IN JUVENILE RATS 
SUMMARY
The effects of dietary modulation of brain DHA content on outcomes after TBI were examined in a juvenile rat model. Long-Evans rats with normal or diet-induced decreases in brain DHA were subjected to a controlled cortical impact or sham surgery on postnatal day 17. Rats with the greatest decreases in brain DHA had the poorest sensorimotor outcomes after TBI. Ccl2, Gfap, and Mmp 9 mRNA levels, and MMP-2 and −9 enzymatic activities were increased after TBI regardless of brain DHA level. Lesion volume was not affected by brain DHA level. In contrast, TBI-induced Timp1 expression was lower in rats on the Deficient diet and correlated with brain DHA level. These data suggest that decreased brain DHA content contributes to poorer sensorimotor outcomes after TBI through a mechanism involving modulation of Timp1 expression.
doi:10.1016/j.plefa.2013.05.004
PMCID: PMC3753049  PMID: 23796971
3.  N-3 (Omega-3) Polyunsaturated Fatty Acids in the Pathophysiology and Treatment of Depression: Pre-clinical Evidence 
A growing literature suggests the association of low tissue levels and/or dietary intake of n-polyunsaturated fatty acids (PUFA) with depressive illnesses. Animal studies show that low tissue and/or dietary n-3 PUFAs can lead to behaviors and neurobiological effects associated with depression, and can potentiate the consequences of stress. Higher n- 3 PUFA tissue levels or intake have the opposite effect. These data support the involvement of n-3 PUFAs levels in the disease processes underlying depression. In addition, these pre-clinical findings indicate neurobiological mechanisms whereby n-3 PUFAs may contribute to the disease including control of serotonergic and dopaminergic function, modulation of brain-derived neurotrophic factor (BDNF) in the hippocampus, regulation of the hypothalamic-pituitary-adrenal axis, and effects on neuroinflammation. This pre-clinical evidence for a role for n-3 PUFA in the pathophysiology and treatment of depressive illness are reviewed. The implications of these finding for future pre-clinical research and clinical application are discussed.
PMCID: PMC4115447  PMID: 23574159
rain-derived neurotrophic factor; corticosterone; docosahexaenoic acid; dopamine; elevated plus maze; forced swim test; neuroimmune; serotonin
4.  ALTERED NUCLEOLAR MORPHOLOGY IN SUBSTANTIA NIGRA DOPAMINE NEURONS FOLLOWING 6-HYDROXYDOPAMINE LESION IN RATS 
Neuroscience letters  2013;546:26-30.
The nucleolus, the site of ribosomal ribonucleic acid (rRNA) transcription and assembly, is an important player in the cellular response to stress. Altered nucleolar function and morphology, including decreased nucleolar volume, has been observed in Parkinson’s disease; thus the nucleolus represents a potential indicator of neurodegeneration in the disease. This study determined the effects of a partial unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion, which models the dopaminergic loss found in Parkinson’s disease, on the nucleoli of dopaminergic cells in the substantia nigra pars compacta (SNpc). Adult male Long-Evans rats underwent unilateral intrastriatal infusion of 6-OHDA (12.5 μg). Lesions were verified by amphetamine-stimulated rotation 7 days later, and rats were euthanized 14 days after infusion. Coronal sections (50μm) were stained for tyrosine hydroxylase-silver nucleolar (TH-AgNOR) stain using MultiBrain Technology (NeuroScience Associates), which resulted in clearly defined nucleoli and neuronal outlines. Stereological methods were used to compare dopaminergic morphology between lesioned and intact hemispheres in each rat. In cells exhibiting a definable nucleolus, nucleolar volume was decreased by 16% on the ipsilateral side. The ipsilateral SNpc also exhibited an 18% decrease in SNpc planimetric volume, a 46% decrease in total TH-positive neuron number, and an 11% decrease in neuronal body volume (all P<0.05 by paired t-test). These findings suggest that the 6-OHDA lesion alters nucleolar morphology and that these changes are similar to those occurring in Parkinson’s disease.
doi:10.1016/j.neulet.2013.04.033
PMCID: PMC3679339  PMID: 23643997
silver nucleolar stain; 6-hydroxydopamine; stereology; substantia nigra pars compacta; neuronal morphology; nucleolar volume
5.  A NOVEL USE OF COMBINED TYROSINE HYDROXYLASE AND SILVER NUCLEOLAR STAINING TO DETERMINE THE EFFECTS OF A UNILATERAL INTRASTRIATAL 6-HYDROXYDOPAMINE LESION IN THE SUBSTANTIA NIGRA: A STEREOLOGICAL STUDY 
Journal of neuroscience methods  2012;210(2):187-194.
Neurotoxic lesions of the nigrostriatal pathway model the deficits found in Parkinson’s disease. This study used stereology and a novel staining method to examine the effects of a partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion on substantia nigra pars compacta (SNpc) dopamine neuron number and morphology in rats. Adult male Long-Evans rats were subjected to unilateral lesion of the SNpc by intrastriatal microinjection of 6-OHDA (12.5 μg). Lesions were verified by d-amphetamine-stimulated rotation (2.5 mg/kg, sc) by force-plate rotometry 7 days post-surgery. Seven days after rotation testing, rats were euthanized, and brains were prepared for either histology (n = 12) or determination of striatal dopamine content by HPLC-EC (n =20). Brains prepared for histology were stained for tyrosine hydroxylase (TH) combined with a silver nucleolar stain (AgNOR) using a modified protocol developed for stereological assessment. The AgNOR counterstain allowed for precise definition of the nucleolus of the cells, facilitating both counting and qualitative morphometry of TH-positive neurons. Stereological quantitation determined a 54% decrease in TH-positive neuron number (P<0.01), and a 14% decrease in neuron volume (P<0.05) on the lesioned side. Striatal dopamine concentration was decreased by 92% (P<0.01), suggesting that striatal dopamine analysis may overestimate the numbers of SNpc neurons lost. These findings demonstrate that combined use of TH and AgNOR staining provides improved characterization of 6-OHDA-induced pathology. Furthermore, the data suggest that decreased neuronal volume as well as number contributes to the functional deficits observed after unilateral intrastriatal 6-OHDA lesion.
doi:10.1016/j.jneumeth.2012.07.013
PMCID: PMC3443281  PMID: 22850559
silver nucleolar stain; 6-hydroxydopamine; stereology; substantia nigra pars compacta; neuronal volume; neuronal number
6.  High-affinity and selective dopamine D3 receptor full agonists 
We have designed, synthesized and evaluated a series of new compounds with the goal to identify potent and selective D3 ligands. The two most potent and selective new D3 ligands are compounds 38 and 52, which bind to the D3 receptors with a Ki value of <1 nM and display a selectivity of 450–494 times over the D2 receptors and >10,000 times over the D1 receptors. Both 38 and 52 are full agonists with high potency at the D3 receptor in a D3 functional assay.
doi:10.1016/j.bmcl.2012.07.003
PMCID: PMC3461280  PMID: 22871578
Dopamine 3 receptor; Full agonists; Structure-activity-relationships
7.  SENSORIMOTOR BEHAVIORAL TESTS FOR USE IN A JUVENILE RAT MODEL OF TRAUMATIC BRAIN INJURY: ASSESSMENT OF SEX DIFFERENCES 
Journal of neuroscience methods  2011;199(2):214-222.
Modeling juvenile traumatic brain injury (TBI) in rodents presents several unique challenges compared to adult TBI, one of which is selecting appropriate sensorimotor behavioral tasks that enable the assessment of the extent of injury and recovery over time in developing animals. To address this challenge, we performed a comparison of common sensorimotor tests in Long-Evans rats of various sizes and developmental stages (postnatal days 16–45, 35–190 g). Tests were compared and selected for their developmental appropriateness, scalability for growth, pre-training requirements, and throughput capability. Sex differences in response to TBI were also assessed. Grid walk, automated gait analysis, rotarod, beam walk, spontaneous forelimb elevation test, and measurement of motor activity using the force-plate actometer were evaluated. Grid walk, gait analysis, and rotarod failed to meet one or more of the evaluation criteria. Beam walk, spontaneous forelimb elevation test, and measurement of motor activity using the force-plate actometer satisfied all criteria and were capable of detecting motor abnormalities in rats subjected to controlled cortical impact on postnatal day 17. No sex differences were detected in the acute effects of TBI or functional recovery during the 28 days after injury using these tests. This demonstrates the utility of these tests for the evaluation of sensorimotor function in studies using rat models of pediatric TBI, and suggest that pre-pubertal males and females respond similarly to TBI with respect to sensorimotor outcomes.
doi:10.1016/j.jneumeth.2011.05.008
PMCID: PMC3142868  PMID: 21600923
Traumatic brain injury; juvenile; forelimb; hindlimb; actometer; beam walk; controlled cortical impact; sensorimotor
8.  CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist 
ACS medicinal chemistry letters  2011;2(8):620-625.
We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a Ki value of 0.50 nM and displays a selectivity of >5,000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a Ki value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.
doi:10.1021/ml200100t
PMCID: PMC3224040  PMID: 22125662
Dopamine receptors; ligands; agonists; drug abuse
9.  CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist 
ACS Medicinal Chemistry Letters  2011;2(8):620-625.
We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a Ki value of 0.50 nM and displays a selectivity of >5000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a Ki value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.
doi:10.1021/ml200100t
PMCID: PMC3224040  PMID: 22125662
Dopamine receptors; ligands; agonists; drug abuse
10.  DEVELOPMENTAL EFFECTS OF DIETARY N-3 FATTY ACIDS ON ACTIVITY AND RESPONSE TO NOVELTY 
Physiology & behavior  2010;101(1):176-183.
Insufficient availability of n-3 polyunsaturated fatty acids (PUFA) during pre- and neonatal development decreases accretion of docosahexaenoic acid (DHA, 22:6n-3) in the developing brain. Low tissue levels of DHA are associated with neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD). In this study, 1st-and 2nd-litter male Long-Evans rats were raised from conception on a Control diet containing α-linolenic acid (4.20 g/kg diet), the dietarily essential fatty acid precursor of DHA, or a diet Deficient in α-linolenic acid (0.38 g/kg diet). The Deficient diet resulted in a decrease in brain phospholipid DHA of 48% in 1st-litter pups and 65% in 2nd-litter pups. Activity, habituation, and response to spatial change in a familiar environment were assessed in a single-session behavioral paradigm at postnatal days 28 and 70, inclusive. Activity and habituation varied by age with younger rats exhibiting higher activity, less habituation, and less stimulation of activity induced by spatial novelty. During the first and second exposures to the test chamber, 2nd-litter Deficient pups exhibited higher levels of activity than Control rats or 1st-litter Deficient pups and less habituation during the first exposure, but were not more active after introduction of a novel spatial stimulus. The higher level of activity in a familiar environment, but not after introduction of a novel stimulus is consistent with clinical observations in ADHD. The observation of this effect only in 2nd-litter rats fed the Deficient diet suggests that brain DHA content, rather than dietary n-3 PUFA content, likely underlies these effects.
doi:10.1016/j.physbeh.2010.04.038
PMCID: PMC2923479  PMID: 20457171
polyunsaturated fatty acid; omega-3; docosahexaenoic acid; rat; brain; locomotor activity; novelty; habituation; force-plate actometer
11.  Dopamine D2 receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse 
Journal of neurochemistry  2010;114(1):51-61.
Previous research suggests that brain oxidative stress and altered rodent locomotor behavior are linked. We observed bio-behavioral changes in methionine sulfoxide reductase A knockout mice associated with abnormal dopamine signaling. Compromised ability of these knockout mice to reduce methionine sulfoxide enhances accumulation of sulfoxides in proteins. We examined the dopamine D2-receptor function and expression, which has an atypical arrangement and quantity of methionine residues. Indeed, protein expression levels of dopamine D2-receptor were higher in knockout mice compared with wild-type. However, the binding of dopamine D2-receptor agonist was compromised in the same fractions of knockout mice. Coupling efficiency of dopamine D2-receptors to G-proteins was also significantly reduced in knockout mice, supporting the compromised agonist binding. Furthermore, pre-synaptic dopamine release in knockout striatal sections was less responsive than control sections to dopamine D2-receptor ligands. Behaviorally, the locomotor activity of knockout mice was less responsive to the inhibitory effect of quinpirole than wild-type mice. Involvement of specific methionine residue oxidation in the dopamine D2-receptor third intracellular loop is suggested by in vitro studies. We conclude that ablation of methionine sulfoxide reductase can affect dopamine signaling through altering dopamine D2-receptor physiology and may be related to symptoms associated with neurological disorders and diseases.
doi:10.1111/j.1471-4159.2010.06721.x
PMCID: PMC2933736  PMID: 20374422
dopamine; dopamine receptor; locomotor activity; methionine oxidation; oxidative stress; post-translation modification
12.  Behavioral sensitization to cocaine in rats: Evidence for temporal differences in dopamine D3 and D2 receptor sensitivity 
Psychopharmacology  2011;215(4):609-620.
Rationale
Cocaine-induced changes in D2 receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors, however, the influence of D3 receptors is less clear.
Objectives
To characterize the effects of repeated cocaine administration on the sensitivity of rats to D2- and D3-mediated behaviors, as well as the binding properties of ventral striatal D2-like and D3 receptors.
Methods
Pramipexole was used to assess the sensitivity of rats to D3/D2 agonist-induced yawning, hypothermia, and locomotor activity, 24h, 72h, 10d, 21d and 42d after repeated cocaine or saline administration. The locomotor effects of cocaine (42d), and the binding properties of ventral striatal D2-like and D3 receptors (24h and 42d) were also evaluated.
Results
Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72h-42d), and leftward shift of the descending limb (42d) of the pramipexole-induced yawning dose-response curve. Cocaine treatment also decreased Bmax and Kd for D2-like receptors, and increased D3 receptor binding at 42d. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity, or yawning induced by cholinergic or serotonergic agonists.
Conclusions
These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D3 and D2 receptors, with enhancements of D3-mediated behavioral effects observed within 72h, and enhancements of D2-mediated behavioral effects apparent 42d after cocaine. These findings highlight the need to consider changes in D3 receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.
doi:10.1007/s00213-010-2154-7
PMCID: PMC3102773  PMID: 21207013
13.  METHYLPHENIDATE ATTENUATES RATS’ PREFERENCE FOR A NOVEL SPATIAL STIMULUS INTRODUCED INTO A FAMILIAR ENVIRONMENT: ASSESSMENT USING A FORCE PLATE ACTOMETER 
Journal of neuroscience methods  2010;189(1):36-43.
Methylphenidate is a psychostimulant widely used in the treatment of attention deficit hyperactivity disorder (ADHD). Here we report a novel paradigm that affords inferences about habituation and attention to a novel stimulus in a familiar environment in a single test session without prior training of the animals. The paradigm was used to assess the effects of methylphenidate (2.5 and 5.0 mg/kg, sc) in young adult, male, Long-Evans rats. Methylphenidate increased locomotor activity during the initial exposure to the test apparatus in a non-dose-related manner. However, upon introduction of a novel spatial stimulus (an alcove) in the familiar environment, methylphenidate-treatment resulted in dose-related increases in distance traveled and inhibition of long dwell times in the alcove, the latter behavior being characteristic of vehicle-treated rats’ response to the alcove condition. These results demonstrate the utility of this paradigm in the elucidation of the behavioral effects of a drug commonly used in the treatment of ADHD. Findings also suggest that species-typical response preferences in rats (e.g., refuge-seeking) may emerge in experimental settings that add spatial novelty to otherwise featureless test enclosures commonly used to assess locomotor activity.
doi:10.1016/j.jneumeth.2010.03.014
PMCID: PMC2864804  PMID: 20346982
spatial stimulus; novelty; attention; actometer; methylphenidate; rat
14.  N-3 (Omega-3) Fatty Acids in Postpartum Depression: Implications for Prevention and Treatment 
A growing body of clinical and epidemiological evidence suggests that low dietary intake and/or tissue levels of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) are associated with postpartum depression. Low tissue levels of n-3 PUFAs, particularly docosahexaenoic acid (DHA), are reported in patients with either postpartum or nonpuerperal depression. Moreover, the physiological demands of pregnancy and lactation put childbearing women at particular risk of experiencing a loss of DHA from tissues including the brain, especially in individuals with inadequate dietary n-3 PUFA intake or suboptimal metabolic capabilities. Animal studies indicate that decreased brain DHA in postpartum females leads to several depression-associated neurobiological changes including decreased hippocampal brain-derived neurotrophic factor and augmented hypothalamic-pituitary-adrenal responses to stress. Taken together, these findings support a role for decreased brain n-3 PUFAs in the multifactorial etiology of depression, particularly postpartum depression. These findings, and their implications for research and clinical practice, are discussed.
doi:10.1155/2011/467349
PMCID: PMC2989696  PMID: 21151517
15.  Design, Synthesis and Evaluation of Potent and Selective Ligands for the Dopamine 3 (D3) Receptor with a Novel in vivo Behavioral Profile 
Journal of medicinal chemistry  2008;51(19):5905-5908.
A series of compounds structurally related to pramipexole were designed, synthesized and evaluated as ligands for the dopamine 3 (D3) receptor. Compound 12 has a Ki value of 0.41 nM to D3 and a selectivity of >30,000- and 800-fold over the D1-like and D2 receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D3 receptor with no detectable activity at the D2 receptor.
doi:10.1021/jm800471h
PMCID: PMC2662387  PMID: 18785726
16.  DECREASED BRAIN DOCOSAHEXAENOIC ACID CONTENT PRODUCES NEUROBIOLOGICAL EFFECTS ASSOCIATED WITH DEPRESSION: INTERACTIONS WITH REPRODUCTIVE STATUS IN FEMALE RATS 
Psychoneuroendocrinology  2008;33(9):1279-1292.
Summary
Decreased tissue levels of docosahexaenoic acid (DHA; 22:6n-3) are implicated in the etiologies of non-puerperal and postpartum depression. With the aim of determining neurobiological sequelae of decreased brain DHA content, this study examined the effects of a loss of brain DHA content and concurrent reproductive status in adult female Long-Evans rats. An α-linolenic acid-deficient diet and breeding protocols were used to produce virgin and parous female rats with cortical phospholipid DHA levels 23–26% lower than virgin and parous rats fed a control diet containing adequate α-linolenic acid. Parous dams were tested/euthanized at weaning (postnatal day 20) of the second litter; virgin females, during diestrus. Decreased brain DHA was associated with decreased hippocampal BDNF gene expression and increased relative corticosterone response to an intense stressor, regardless of reproductive status. In virgin females with decreased brain DHA, serotonin content and turnover in frontal cortex were decreased compared to virgin females with normal brain DHA. In parous dams with decreased brain DHA, the density of 5-HT1A receptors in the hippocampus was increased, corticosterone response to an intense stressor was increased, and the latency to immobility in the forced swim test was decreased compared to parous dams with normal DHA. These findings demonstrate neurobiological alterations attributable to decreased brain DHA or an interaction of parous status and brain DHA level. Furthermore, the data are consistent with findings in depressed humans, and thus support a role for DHA as a factor in the etiologies of depressive illnesses, particularly postpartum depression.
doi:10.1016/j.psyneuen.2008.06.012
PMCID: PMC2582014  PMID: 18707812
omega-3 polyunsaturated fatty acid; brain-derived neurotrophic factor; serotonin 1A receptor; forced swim; postpartum; corticosterone
17.  Altered dopamine D2-like receptor binding in rats with behavioral sensitization to quinpirole: effects of pre-treatment with Ro 41-1049a 
European journal of pharmacology  2008;592(1-3):67-72.
Repeated treatment with the dopamine D2/D3 receptor agonist quinpirole produces a sensitized behavioral response in rats manifested as an increase in locomotor activity. Pre-treatment with certain monoamine oxidase inhibitors, such as Ro 41-1049 [N-(2-aminomethyl)-5-(3-fluorophenyl)-4-thiazolecarboxamide HCl], changes the sensitized response from locomotion to stationary, self-directed mouthing. In this study, the effects of quinpirole sensitization, with and without pre-treatment with Ro 41-1049, were determined on dopamine D2-like receptors in the nucleus accumbens and the striatum. Long-Evans rats were pre-treated with Ro 41-1049 (1 mg/kg) 90 min prior to administration of quinpirole (0.5 mg/kg, 8 injections, every 3–4 days). Dopamine D2-like receptor binding was determined 3 days after the last injection by ex vivo radioligand assays using [3H]spiperone and [3H]quinpirole. Densities of [3H]spiperone- and [3H]quinpirole-labeled sites were both increased 32% in the nucleus accumbens of rats with demonstrated locomotor sensitization to quinpirole. In contrast, the density of dopamine D2-like receptors in quinpirole-sensitized rats pre-treated with Ro 41-1049 was not different from saline controls. These findings support the involvement of alterations in dopamine D2-like receptors in the development of locomotor sensitization to quinpirole and suggest that modification of these alterations in dopamine D2-like receptors contributes to the change from sensitized locomotion to mouthing observed when rats are pre-treated with Ro 41-1049.
doi:10.1016/j.ejphar.2008.06.101
PMCID: PMC2577911  PMID: 18644362
Dopamine D2 receptor; Sensitization; Quinpirole; Striatum; Nucleus accumbens
18.  REDUCED NUMBERS OF DOPAMINE NEURONS IN THE SUBSTANTIA NIGRA PARS COMPACTA AND VENTRAL TEGMENTAL AREA OF RATS FED AN N-3 POLYUNSATURATED FATTY ACID-DEFICIENT DIET: A STEREOLOGICAL STUDY 
Neuroscience letters  2008;438(3):303-307.
Inadequate dietary n-3 polyunsaturated fatty acid (PUFA) content is associated with altered function of the CNS dopamine systems. In this study, the effects of dietary n-3 PUFA content was determined on dopamine cell number and morphology. Adult (postnatal day 70), male, Long-Evans rats were raised from conception on diets containing adequate (control) or negligible n-3 PUFAs. The number and morphology of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and ventral tegmental area were determined stereologically. The number of tyrosine hydroxylase-positive cells in rats fed the n-3 PUFA-deficient diet was 33.9% lower in the substantia nigra pars compacta and 33.7% lower in the ventral tegmental area than in those fed the control diet (P<0.05); however, the volume of tyrosine hydroxylase-positive cell bodies was not different between diet groups in either brain region. Rats fed the n-3 PUFA-deficient diet also exhibited dendritic depletion and isolation of tyrosine hydroxylase-positive cells compared to rats fed the control diet, which had clustering of tyrosine hydroxylase-positive cells and extensive dendritic arborization. These findings support a role for n-3 PUFAs in the survival of dopamine neurons and suggest that altered dopamine cell number, as well as function, contributes to the behavioral effects observed in rats raised on n-3 PUFA-deficient diets.
doi:10.1016/j.neulet.2008.04.073
PMCID: PMC2493469  PMID: 18499349
omega-3 polyunsaturated fatty acid; docosahexaenoic acid; stereology; tyrosine hydroxylase; substantia nigra pars compacta; ventral tegmental area
19.  BASAL LOCAL CEREBRAL GLUCOSE UTILIZATION IS NOT ALTERED AFTER BEHAVIORAL SENSITIZATION TO QUINPIROLE 
Neuroscience letters  2007;429(2-3):165-168.
Sensitization to psychostimulants results in a behavioral response of a greater magnitude than that produced by a given single dose. Previously, we have shown that sensitization to the D2/D3 dopamine receptor agonist quinpirole produces alterations in quinpirole-stimulated local cerebral glucose utilization (LCGU) in ventral striatal and limbic cortical regions. To determine whether basal neuronal activity is altered in the sensitized animal, this study examined the effects of a sensitizing course of quinpirole on basal neuronal activity using the [14C]-2-deoxyglucose (2-DG) method in rats with verified sensitization. Adult, male Long-Evans rats (n = 7 or 10/group) were subjected to 10 injections of quinpirole (0.5 mg/kg, s.c.) or saline administered every 3rd day. Sensitization was verified on the basis of locomotor activity. The 2-DG procedure was performed in freely moving rats three days after the last quinpirole injection. LCGU was determined by quantitative autoradiography. No alterations in basal LCGU were detected in quinpirole-sensitized rats compared to those treated with saline. The present finding suggests that either the basal activity of very discrete populations of neurons is affected by sensitization to quinpirole or that the neurobiological changes that result in the sensitized behavioral response affect only stimulated, but not basal, neuronal activity.
doi:10.1016/j.neulet.2007.10.006
PMCID: PMC2171330  PMID: 17997222
Sensitization; quinpirole; local cerebral glucose utilization; psychostimulant; [14C]2-deoxyglucose
20.  CLORGYLINE-INDUCED MODIFICATION OF BEHAVIORAL SENSITIZATION TO QUINPIROLE: EFFECTS ON LOCAL CEREBRAL GLUCOSE UTILIZATION 
Brain research  2007;1160:124-133.
Sensitization refers to augmented behavioral responses produced by repeated, intermittent injections of dopaminergic psychostimulants. The locomotor manifestations observed after a sensitizing course of quinpirole, a D2/D3 dopamine agonist, can be modified by the MAOA inhibitor clorgyline, by a mechanism apparently unrelated to its actions on MAOA. Alterations in regional neuronal activity produced by quinpirole in quinpirole-sensitized rats with or without clorgyline pre-treatment were assessed on the basis of LCGU using the [14C]-2-deoxyglucose (2-DG) method. Adult, male Long-Evans rats (180–200 g, n = 9–10/group) were subjected to an injection of either clorgyline (1.0 mg/kg, s.c.) or saline 90 minutes prior to an injection of quinpirole (0.5 mg/kg, s.c.) or saline, 1 set of injections administered every 3rd day for 10 sets. The 2-DG procedure was initiated 60 minutes after an 11th set of injections in freely moving rats. LCGU was determined by quantitative autoradiography. LCGU was decreased in a number of limbic (nucleus accumbens and ventral pallidum) and cortical (medial/ventral orbital and infralimbic) regions and in the raphe magnus nucleus in quinpirole-sensitized rats (P < 0.05 v. saline-saline). Quinpirole-sensitized rats pretreated with clorgyline had similar alterations in LCGU, but LCGU was higher in the locus coeruleus compared to quinpirole alone (P < 0.05), was not decreased in the raphe magnus nucleus, and was decreased in the piriform cortex and septum. This implicates altered activity of the noradrenergic, serotonergic, olfactory, and limbic systems in the modified behavioral response to quinpirole with clorgyline pretreatment.
doi:10.1016/j.brainres.2007.05.035
PMCID: PMC2099299  PMID: 17573047
Behavioral sensitization; [14C]-2-Deoxyglucose; D2/D3 dopamine receptor; Clorgyline; Quinpirole; Obsessive-Compulsive Disorder
21.  Dopamine receptor alterations in female rats with diet-induced decreased brain docosahexaenoic acid (DHA): interactions with reproductive status 
Nutritional Neuroscience  2010;13(4):161-169.
Decreased tissue levels of n-3 (omega-3) fatty acids, particularly docosahexaenoic acid (DHA), are implicated in the etiologies of non-puerperal and postpartum depression. This study examined the effects of a diet-induced loss of brain DHA content and concurrent reproductive status on dopaminergic parameters in adult female Long–Evans rats. An α-linolenic acid-deficient diet and breeding protocols were used to produce virgin and parous female rats with cortical phospholipid DHA levels 20–22% lower than those fed a control diet containing adequate α-linolenic acid. Decreased brain DHA produced a significant main effect of decreased density of ventral striatal D2-like receptors. Virgin females with decreased DHA also exhibited higher density of D1-like receptors in the caudate nucleus than virgin females with normal DHA. These receptor alterations are similar to those found in several rodent models of depression, and are consistent with the proposed hypodopaminergic basis for anhedonia and motivational deficits in depression.
doi:10.1179/147683010X12611460764282
PMCID: PMC2955509  PMID: 20670471
omega-3; polyunsaturated fatty acid; dopamine receptor; postpartum; docosahexaenoic acid; rat

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