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ABSTRACT: The best known neurobehavioral effects of testosterone are on sexual function and aggression. However, testosterone and other androgens may be involved in the pathophysiology of mood disorders and suicidal behavior. This is the first study to examine whether there is a relation between testosterone levels and clinical parameters in bipolar suicide attempters.
Patients with a DSM-IV diagnosis of a bipolar disorder (16 males and 51 females), in a depressive or mixed episode with at least one past suicide attempt were enrolled. Demographic and clinical parameters, including lifetime suicidal behavior, were assessed and recorded. Plasma testosterone was assayed using a double antibody radioimmunoassay procedure.
The number of major depressive episodes, the maximum lethality of suicide attempts, and the testosterone levels were higher in men compared to women. Current suicidal ideation scores were higher in women compared to men. Controlling for sex, we found that testosterone levels positively correlated with the number of manic episodes and the number of suicide attempts.
Our findings are consistent with previous observations of the association between testosterone levels and parameters of mood and behavior. This study suggests that testosterone levels may be related to the course of bipolar disorder and suicidal behavior. Further studies of the role of testosterone in the neurobiology of mood disorders and suicidal behavior are merited.
Journal of psychiatric research 07/2012; 46(10):1267-71. · 3.72 Impact Factor
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ABSTRACT: In utero exposure to tetrahydrocannabinol, the psychoactive component of marijuana, is associated with an increased risk for neurodevelopmental defects in the offspring by interfering with the functioning of the endocannabinoid (eCB) system. At the present time, it is not clearly known whether the eCB system is present before neurogenesis. Using an array of biochemical techniques, we analyzed the levels of CB1 receptors, eCBs (AEA and 2-AG), and the enzymes (NAPE-PLD, DAGLα, DAGLβ, MAGL, and FAAH) involved in the metabolism of the eCBs in chick and mouse models during development. The findings demonstrate the presence of eCB system in early embryo before neurogenesis. The eCB system might play a critical role in early embryogenesis and there might be adverse developmental consequences of in utero exposure to marijuana and other drugs of abuse during this period.
Birth Defects Research Part B Developmental and Reproductive Toxicology 02/2012; 95(2):137-50. · 1.93 Impact Factor
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ABSTRACT: While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors.
The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats.
These findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder.
PLoS ONE 01/2012; 7(5):e36743. · 4.09 Impact Factor
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Elizabeth Ralevski,
Edward B Perry,
D Cyril D'Souza,
Vanessa Bufis,
Jacqueline Elander,
Diana Limoncelli,
Michael Vendetti,
Erica Dean, Thomas B Cooper,
Sherry McKee,
Ismene Petrakis
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ABSTRACT: There are mixed reports on nicotine's effects on alcohol-induced impairment in cognitive performance and behavior in humans. The main objective of this study was to characterize the interactive effects of acute intravenous (IV) alcohol and nicotine administration on behavior and cognition in healthy nonsmokers.
Healthy subjects aged 21-44 years participated in 3 test days. On each test day, they received in a double-blind randomized manner one of three IV alcohol infusion conditions using a "clamp": placebo, targeted breathalyzer of 40 mg%, or targeted breathalyzer of 80 mg%. Alcohol infusion was delivered over 20 min and lasted for 120 min. They also received both placebo and active nicotine in a fixed order delivered intravenously. Placebo nicotine was delivered first over 10 min at the timepoint when the breath alcohol was "clamped"; active nicotine (1.0 mcg/kg/min) was delivered for 10 min, 70 min after the alcohol infusion was clamped. Subjective effects of alcohol were measured using the Biphasic Alcohol Effects Scale and the Number of Drinks Scale. Cognitive inhibition and attention were measured by the Continuous Performance Task-Identical Pairs and working memory by the Rey Auditory Verbal Learning Task (RAVLT).
Nicotine significantly reversed subjective intoxication and sedation of alcohol at the low dose. Alcohol impaired performance on the RAVLT, and nicotine further impaired verbal learning and recall at both doses of alcohol.
The data showed that nicotine had an effect on subjective alcohol effects but did not reverse and actually worsened alcohol-induced deficits in memory.
Nicotine & Tobacco Research 12/2011; 14(5):596-606. · 2.58 Impact Factor
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ABSTRACT: The present study was undertaken to examine whether genetically predetermined differences in components of the endocannabinoid system were present in the brain of Sardinian alcohol-preferring (sP) and Sardinian alcohol-non-preferring (sNP) rats, a pair of rat lines selectively bred for opposite alcohol preference. The effects of acquisition and maintenance of alcohol drinking, alcohol withdrawal, and alcohol re-exposure on the endocannabinoid system was also assessed in the striatum of sP rats. The findings revealed significantly higher density of the CB1 receptors and levels of CB1 receptor mRNA, CB1 receptor-mediated G-protein coupling, and endocannabinoids in the cerebral cortex, hippocampus and striatum of alcohol-naive sP rats than sNP rats. A significantly lower expression of mFAAH enzyme was evident in the hippocampus of alcohol-naive sP rats. Alcohol drinking (during both acquisition and maintenance phases) in sP rats resulted in a significant reduction in striatal CB1 receptor-mediated G-protein coupling whereas alcohol withdrawal attenuated this effect. Alcohol consumption was also associated with markedly increased levels of endocannabinoids in the striatum. Co-administration of the CB1 receptor antagonist, rimonabant (SR141716A) reduced alcohol intake, and reversed alcohol-induced changes in CB1 receptor-mediated G-protein activation. These findings provided a new insight into a potential genetic basis of excessive alcohol consumption, suggesting innate differences in the endocannabinoid system might be associated with higher alcohol preference in sP rats. The data also indicate a modulation of CB1 receptor-mediated signaling following alcohol consumption, and further strengthen the potential of the endocannabinoid system as a target for the treatment of alcohol related behaviors.
Addiction Biology 02/2011; 17(1):62-75. · 4.83 Impact Factor
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ABSTRACT: The role of n-3 polyunsaturated fatty acids (PUFAs) in psychiatric illness is a topic of public health importance. This report describes development and biomarker validation of a 21-item, self-report food frequency questionnaire (FFQ) intended for use in psychiatric research to assess intake of α-linolenic acid (18:3n-3 [ALA]), docosahexaenoic acid (22:6n-3 [DHA]), and eicosapentaenoic acid (20:5n-3 [EPA]). In a cross-sectional study conducted from September 2006 to September 2008, sixty-one ethnically diverse adult participants with (n=34) and without (n=27) major depressive disorder completed this n-3 PUFA FFQ and provided a plasma sample. Plasma levels of n-3 PUFAs EPA and DHA, and n-6 PUFA arachidonic acid (20:4n-6 [AA]) were quantified by gas chromatography. Using Spearman's ρ, FFQ-estimated intake correlated with plasma levels of DHA (r=0.50; P<0.0001) and EPA (r=0.38; P=0.002), but not with ALA levels (r=0.22; P=0.086). Participants were classified into quartiles by FFQ-estimated intake and plasma PUFA concentrations. Efficacy of the FFQ to rank individuals into same or adjacent plasma quartiles was 83% for DHA, 78.1% for EPA, and 70.6% for ALA; misclassification into extreme quartiles was 4.9% for DHA, 6.5% for EPA, and 8.2% for ALA. FFQ-estimated EPA intake and plasma EPA were superior to plasma AA levels as predictors of the plasma AA to EPA ratio. This brief FFQ can provide researchers and clinicians with valuable information concerning dietary intake of DHA and EPA.
Journal of the American Dietetic Association 01/2011; 111(1):117-123.e1-2. · 3.59 Impact Factor
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W Gordon Frankle,
N Scott Mason,
Eugenii A Rabiner,
Khanum Ridler,
Maureen A May,
Deanna Asmonga,
Chi-Min Chen,
Steve Kendro, Thomas B Cooper,
Chester A Mathis,
Rajesh Narendran
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ABSTRACT: The use of PET and SPECT endogenous competition-binding techniques has contributed to the understanding of the role of dopamine (DA) in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of changes in synaptic DA have been restricted to the striatum. The ligands previously used, such as [(11)C]raclopride and [(123)I]IBZM, do not provide sufficient signal-to-noise ratio to quantify D(2) receptors in extrastriatal areas, such as cortex, where the concentration of D(2) receptors is much lower than that in the striatum. Recently, we published a comparison study of the ability of two high-affinity DA D(2) radioligands [(11)C]FLB 457 and [(11)C]fallypride to measure amphetamine-induced changes in DA transmission in the human cortex. Our findings support the use of [(11)C]FLB 457 to measure changes in cortical synaptic DA induced by amphetamine. The goal of this study is to examine the effects of DA depletion with α-methyl-para-tyrosine (α-MPT) on [(11)C]FLB 457 binding in the cortex. Six healthy volunteers underwent two PET scans, first under control conditions and subsequently after DA depletion. The simplified reference tissue model as well as kinetic modeling with an arterial input function was used to derive the binding potential (BP(ND)) in seven cortical regions. We found no effect of DA depletion with α-MPT on [(11)C]FLB 457 binding in any of the regions examined. In contrast to the measurement of DA release, the combination of low D(2) receptor density and low basal DA levels in the cortex greatly reduce the power to detect alterations in [(11)C]FLB 457 binding secondary to DA depletion.
Synapse 12/2010; 64(12):879-85. · 2.94 Impact Factor
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ABSTRACT: A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D(2) receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D(2) receptors is responsible for the antipsychotic action of D(2) receptor antagonists.
To localize dopaminergic hyperactivity within the striatum in schizophrenia.
Case-control study.
Inpatient research unit.
Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight.
Percentage change in dopamine D(2) receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11-labeled raclopride before and during pharmacologically induced dopamine depletion.
In the associative striatum, acute dopamine depletion resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum.
These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.
Archives of general psychiatry 03/2010; 67(3):231-9. · 12.26 Impact Factor
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ABSTRACT: Recent studies in rodents have suggested a role for the central endocannabinoid system in the regulation of mood and alcohol related behaviors. Alcohol use disorder is often associated with suicidal behavior. In the present study, we examined whether abnormalities in the endocannabinoid system in the ventral striatum are associated with alcohol dependence and suicide. The levels of CB1 receptors, receptor-mediated G-protein signaling, and activity and level of the fatty acid amide hydrolase (FAAH) were analyzed postmortem in the ventral striatum of alcohol-dependent nonsuicides (CA, n=9), alcohol-dependent suicides (AS, n=9) and nonpsychiatric controls (C, n=9). All subjects underwent a psychological autopsy, and toxicological and neuropathological examinations. The levels of the CB1 receptors and the CB1 receptor-mediated G-protein signaling were significantly lower in the ventral striatum of CA compared to the control group. However, these parameters were elevated in AS when compared to CA group. The activity of FAAH enzyme was lower in CA compared to the control group while it was found to be significantly higher in AS compared with CA group. These findings suggest that alcohol dependence is associated with the downregulation of the CB1 receptors, while suicide is linked to the upregulation of these receptors in the ventral striatum. Alteration in the activity of FAAH enzyme that regulates the anandamide (AEA) content might in turn explain differences in the CB1 receptor function in alcohol dependence and suicide. These findings may have etiological and therapeutic implications for the treatment of alcohol addiction and suicidal behavior.
Journal of psychiatric research 12/2009; 44(9):591-7. · 3.72 Impact Factor
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Rajesh Narendran,
W Gordon Frankle,
N Scott Mason,
Eugenii A Rabiner,
Roger N Gunn,
Graham E Searle,
Shivangi Vora,
Maralee Litschge,
Steve Kendro, Thomas B Cooper,
Chester A Mathis,
Marc Laruelle
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ABSTRACT: The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [(11)C]raclopride and [(123)I]IBZM, do not provide sufficient signal to noise ratio to quantify D(2) receptors in extrastriatal areas, such as cortex, where the concentration of D(2) receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D(2) radioligands [(11)C]FLB 457 and [(11)C]fallypride to measure amphetamine-induced changes in DA transmission in the human cortex. D(2) receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg(-1), oral), using both [(11)C]FLB 457 and [(11)C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BP(ND)) in eight cortical regions. Under controlled conditions, [(11)C]FLB 457 BP(ND) was 30-70% higher compared with [(11)C]fallypride BP(ND) in cortical regions. Amphetamine induced DA release led to a significant decrease in [(11)C]FLB 457 BP(ND) in five out the eight cortical regions evaluated. In contrast, no significant decrease in [(11)C]fallypride BP(ND) was detected in cortex following amphetamine. The difference between [(11)C]FLB 457 and [(11)C]fallypride ability to detect changes in the cortical D(2) receptor availability following amphetamine is related to the higher signal to noise ratio provided by [(11)C]FLB 457. These findings suggest that [(11)C]FLB 457 is superior to [(11)C]fallypride for measurement of changes in cortical synaptic dopamine.
Synapse 03/2009; 63(6):447-61. · 2.94 Impact Factor
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ABSTRACT: Brain diseases including Alzheimer's and Parkinson's involve the cellular 'unfolded protein' (UPR) stress response. Psychiatric illnesses such as depressive disorders are thought to involve brain stress-response pathways. The XBP1 gene encodes a key transcription factor in the UPR stress response and therefore could be involved in the pathophysiology of depressive disorders. A functional polymorphism (-116C-->G) in the XBP1 promoter was linked in some studies to bipolar disorder. Among 132 adults (mean age 39 yr) who presented with a major depressive episode, this polymorphism was found to be associated with a worse course during 1-yr prospective follow-up. In a subgroup (n=22), the polymorphism was associated with higher plasma levels of the stress hormone cortisol. The results suggest that hypothalamic-pituitary-adrenocortical and cellular stress pathways involving the XBP1 gene may be involved in the pathophysiology of major depressive disorder. These relationships merit further study.
The International Journal of Neuropsychopharmacology 01/2009; 12(2):281-3. · 4.58 Impact Factor
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ABSTRACT: Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB(1) receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB(1) receptor significantly reduced the ethanol preference. Although the stimulation of the CB(1) receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB(1) receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB(1) -/- mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB(1) receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB(1) receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB(1) receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB(1) receptor may have therapeutic potential in the treatment of ethanol dependence.
Synapse 09/2008; 62(8):574-81. · 2.94 Impact Factor
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ABSTRACT: Dysfunction of serotonergic neurotransmission has been implicated in the etiopathogenesis of major depression (MDD) and alcohol use disorders (AUD). To compare serotonin function in MDD with co-occurring AUD (MDD/AUD), MDD without co-occurring AUD (MDD only) and healthy controls (HC) we sought to study differences in prolactin responses to fenfluramine administration in patients with MDD/AUD, patients with MDD only and HC. In all, 169 subjects (62 MDD/AUD, 75 MDD only, and 32 HC) were entered into the study. Controlling for gender, prolactin responses were lower in the MDD/AUD group compared to the MDD only or the HC group. Controlling for gender and aggression, prolactin responses in the MDD/AUD group remained significantly lower compared to the HC group but the difference between the MDD/AUD and the MDD only groups disappeared. The difference in prolactin responses between MDD/AUD and MDD only could be attributed to higher aggression scores in the MDD/AUD group compared to the MDD group.
European Neuropsychopharmacology 07/2008; 18(9):692-9. · 4.05 Impact Factor
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ABSTRACT: Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB1 receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB1 receptor significantly reduced the ethanol preference. Although the stimulation of the CB1 receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB1 receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB1 −/− mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB1 receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB1 receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB1 receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB1 receptor may have therapeutic potential in the treatment of ethanol dependence. Synapse 62:574–581, 2008. Published 2008 Wiley-Liss, Inc.
Synapse 05/2008; 62(8):574 - 581. · 2.94 Impact Factor
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ABSTRACT: Blunted neurohormonal responses to serotonergic agents are found in major depression and suicidal behavior, but there have been no prospective studies of their relationship to later suicide attempt. In this study, healthy volunteers and depressed subjects were administered a fenfluramine (FEN) and placebo challenge test at baseline and then followed for 2 years. Seven subjects made suicide attempts within the follow-up period. Healthy volunteers, depressed non-attempters, depressed past suicide attempters, and depressed future attempters were compared on plasma prolactin and cortisol responses, as well as on mood (Profile of Mood States; POMS) and behavioral measures that were assessed at baseline and at the end of each challenge testing day. Both past and future attempters had lower total prolactin output (area under the curve) in response to FEN relative to non-patients. Future attempters had lower cortisol response relative to all other groups. All subject groups reported a decrease in POMS Fatigue subscale score and increase in finger tapping rate after receiving FEN. Depressed subjects reported a significant decline in POMS Total, Depression, and Tension/Anxiety scores, but future attempters' did not, showing a slight mean increase. Lower cortisol response correlated with greater suicidal ideation 3 months and 1 year post-study. Logistic regression revealed that blunting of cortisol response and worsening of mood after FEN, and younger age could be used to predict later suicide attempt in the majority of cases (4/7). Results suggest that blunted cortisol and unfavorable acute mood response to serotonergic challenge, in the context of the general activating effects of these drugs, may be a risk factor for later suicide attempt.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2008; 35(5):1063-72. · 6.99 Impact Factor
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ABSTRACT: N-Methyl-D-aspartate (NMDA) antagonists induced behavioral and neurochemical changes in rodents that serve as animal models of schizophrenia. Chronic phencyclidine (PCP, 15 mg/(kg day) for 3 weeks via Alzet osmotic pump) administration enhances the amphetamine (AMPH)-induced dopamine (DA) efflux in prefrontal cortex (PFC), similar to that observed in schizophrenia. NMDA/glycine-site agonists, such as glycine (GLY), administered via dietary supplementation, reverse the enhanced effect. The present study investigated mechanisms of glycine-induced reversal of PCP-induced stimulation of AMPH-induced DA release, using simultaneous measurement of DA and AMPH in brain microdialysate, as well as peripheral and tissue AMPH levels. PCP treatment, by itself, increased peripheral and central AMPH levels, presumably via interaction with hepatic enzymes (e.g. cytochrome P450 CYP2C11). GLY (16% diet) had no effect on peripheral AMPH levels in the presence of PCP. Nevertheless, GLY significantly reduced extracellular/tissue AMPH ratios in both PFC and striatum (STR), especially following PCP administration, suggesting a feedback mediated effect on the dopamine transporter. GLY also inhibited acute AMPH (5 mg/kg)-induced DA release in PFC, but not STR. These findings suggest that GLY may modulate DA release in brain by producing feedback regulation of dopamine transporter function, possibly via potentiation of NMDA-stimulated GABA release and presynaptic GABAB receptor activation. The present studies also demonstrate pharmacokinetic interaction between AMPH and PCP, which may be of both clinical and research relevance.
Neurochemistry International 02/2008; 52(1-2):119-29. · 2.86 Impact Factor
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ABSTRACT: We hypothesized that bolus injections of lipid soluble chemotherapeutic drugs during transient cerebral hypoperfusion could significantly boost regional drug delivery. In the first two groups of New Zealand White rabbits we measured brain tissue carmustine concentrations after intravenous infusion, intraarterial infusion with normal perfusion, and after intraarterial injections during transient cerebral hypoperfusion. In the third group of animals we assessed the safety of the technique by assessing electroencephalographic changes for 6 h after flow arrest carmustine administration and subsequent histological examination. The brain tissue carmustine concentrations were fivefold to sevenfold higher when the drug was injected during cerebral hypoperfusion compared to a conventional intracarotid infusion (68.4 +/- 24.5 vs. 14.2 +/- 8.3 microg/g, n = 5 each, respectively, P < 0.0001). The brain tissue carmustine concentrations (y) were a linear function of the bolus dose (x) injected during cerebral hypoperfusion, y = 10.4 x x - 21 (R = 0.84, P < 0.001). Stable EEGs were recorded several hours after flow arrest carmustine exposure and histological examinations did not reveal any gross evidence of cerebral injury. Transient cerebral hypoperfusion during intraarterial bolus injection of carmustine significantly increases drug delivery. Clinical techniques that decrease CBF, such as, transient arterial occlusion by balloon tipped catheters, hyperventilation, hypothermia, induced hypotension, or transient circulatory arrest, could enhance intraarterial drug delivery to the brain. We believe that the mechanisms for improved drug delivery is the decrease in drug dilution by reduced or absent blood flow, decreased protein binding and a longer time for high concentrations of free drugs to transit through the blood brain barrier.
Journal of Neuro-Oncology 02/2008; 86(2):123-32. · 3.21 Impact Factor
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ABSTRACT: Previously, we have shown that ethanol-induced apoptosis in cultured neurons is accompanied by changes in cellular lipid profiles. In the present study, the effects of ethanol on brain lipid metabolism were studied using 7-day-old C57BL/6ByJ mice, which display apoptotic neurodegeneration upon exposure to ethanol. The brain lipids were extracted 4-24 h after the ethanol or saline treatment, and analyzed by TLC. We found that the levels of triglyceride, cholesterol ester, ceramide, and N-acylphosphatidylethanolamine increased significantly in the brains of ethanol-treated mice compared to those of saline-treated mice. Concomitantly, ethanol reduced Thr172 phosphorylation of AMP-activated protein kinase (AMPK) alpha subunits. Ethanol also reduced phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK and a lipogenic enzyme known to be activated by dephosphorylation. In contrast, lipid profiles of 19-day-old mouse brains, which scarcely manifested neurodegeneration upon ethanol exposure, were not significantly affected by ethanol. Also, the basal levels of Thr172-phosphorylated AMPK alpha were lower in these brains than in 7-day-old mouse brains, and no detectable changes in the phosphorylation status were observed by ethanol treatment. Our findings indicate that the ethanol-induced apoptotic neurodegeneration observed in mice during restricted developmental periods is accompanied by alterations in both the lipid content and the activity of AMPK in the brain.
Journal of Neurochemistry 12/2007; 103(3):1208-18. · 4.06 Impact Factor
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ABSTRACT: This is the first study contrasting regional glucose metabolic rate (rCMRglu) responses to a serotonergic challenge in major depressive disorder (MDD) with and without comorbid alcohol dependence. In a university hospital, patients with MDD without a history of alcohol dependence (MDD only) and patients with MDD and comorbid alcohol dependence (MDD/ALC) were enrolled in this study. Subjects with comorbid borderline personality disorder were excluded. A bolus injection of approximately 5 mCi of (18)fluorodeoxyglucose was administered 3 h after the administration of placebo or fenfluramine. We found an anterior medial prefrontal cortical area where MDD/ALC subjects had more severe hypofrontality than MDD only patients. This area encompassed the left medial frontal and left and right anterior cingulate gyri. This group difference disappeared after fenfluramine administration. The fact that the observed group difference disappeared after the fenfluramine challenge suggests that serotonergic mechanisms play a role in the observed differences between the groups.
European Neuropsychopharmacology 10/2007; 17(9):608-15. · 4.05 Impact Factor
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Diana Martinez,
Rajesh Narendran,
Richard W Foltin,
Mark Slifstein,
Dah-Ren Hwang,
Allegra Broft,
Yiyun Huang, Thomas B Cooper,
Marian W Fischman,
Herbert D Kleber,
Marc Laruelle
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ABSTRACT: Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated.
Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [(11)C]raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward.
Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: -1.2% in cocaine-dependent participants versus -12.4% in healthy subjects; associative striatum: -2.6% versus -6.7%, respectively; sensorimotor striatum: -4.3% versus -14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money.
Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to play a critical role in relapse.
American Journal of Psychiatry 04/2007; 164(4):622-9. · 12.54 Impact Factor
