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Cerebrospinal fluid kynurenic acid and depressive symptoms in HIV-infected individuals
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Abstracts / Drug and Alcohol Dependence 146 (2015) e34–e117
Financial support: National Institute of Drug Abuse DA024104 and DA02774.
Cerebrospinal fluid kynurenic acid and depressive symptoms in HIV-infected individuals
http://dx.doi.org/10.1016/j.drugalcdep.2014.09.681
Naomi Tanizaki 1 , Adrian Franke 2 , Xingnan Li 2 , Nataliya Holmes 1 , Vanessa Douet 1 , Linda Chang 1
(±)-Modafinil potentiates cocaine self-administration but not the effects on DA levels in rodents Gianluigi Tanda 1,2 , Maddalena Mereu 2 , Takato Hiranita 2 , Amy H. Newman 1,3 , J. Katz 2 1
Medications Development Program, NIDA/IRP, Baltimore, MD, United States 2 Psychobiology Section, NIDA/IRP, Baltimore, MD, United States 3 Medicinal Chemistry Section, NIDA/IRP, Baltimore, MD, United States Aims: While the mechanisms underlying the therapeutic efficacy of (±)-Modafinil (MOD) are not fully understood, actions at the dopamine (DA) transporter (DAT) appear to be involved. With some exceptions, DAT blockers administered in combination potentiate the behavioral and reinforcing effects of psychostimulants (PSY) like cocaine (COC). That potentiation is related to increased accumbens (ACC) DA levels. However, recent clinical studies suggested efficacy of MOD in treating PSY abuse, suggesting a potential reduction of COC use in PSY abusers rather than a potentiation. Methods: Effects of MOD and COC, were tested alone and in combination, on microdialysate ACC DA levels in rats (n = 48), and mice (n = 60), self-administration (SA) (n = 12) in rats, and subjective effects (n = 12) in mice trained to discriminate COC. Results: MOD alone (0.03–10 mg/kg i.v.) did not maintain SA above vehicle levels when substituted for COC, but at those doses increased DA levels dose-dependently. MOD pretreatments (10–32 mg/kg i.p., 5 min prior) also dose-dependently (p < 0.05) potentiated COC SA, but microdialysis studies showed no significant enhancement of the effects of COC (0.03–3.0 mg/kg i.v.) on stimulation of DA levels in ACC in excess of those produced by COC alone. In mice, MOD alone (10–100 mg/kg) produced COClike subjective effects and potentiated the subjective effects of low COC doses (p < 0.05). In mice, MOD elicited significant (p < 0.05) increases in DA levels without significant differences between ACC shell and core, distinguishing MOD from PSYs abused by humans. Conclusions: MOD alone has a reduced PSY profile compared to COC. Our preclinical results suggest it might enhance reinforcing effects when taken in combination with sub-threshold doses of COC, independently from stimulation of DA levels. Based on clinical reports, these effects suggest a basis for use of MOD as a substitution agonist therapy for PSY abuse. Studies are in progress to better address the mechanisms underlying these effects. Financial support: NIDA/IRP. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.682
1 Medicine, University of Hawaii at Manoa, Honolulu, HI, United States 2 University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, United States
Aims: HIV patients have higher rates of depression compared to the general population in the U.S. Although social factors and co-morbid factors (e.g., such as stimulant abuse) may contribute to the depressive symptoms, abnormalities in the kynurenic pathyway may contribute to the symptoms in HIV patients. Increased kynurenic acid (KYNA) levels were reported in cerebrospinal fluid (CSF) of HIV patients, while decreased kynurenic acid levels were reported in CSF of depressed patients. Whether KYNA concentration varies with depressive symptoms differently in those with and without HIV was explored. Methods: 100 participants, 51 seronegative controls (SN) and 49 HIV, were evaluated clinically, provided CSF samples and completed the Center for Epidemiological Studies Depression scale (CES-D). We further evaluated the subjects according to the CESD scores (high ≥16 or low <16). CSF KYNA levels were measured by high performance liquid chromatography (HPLC). Results: SN and HIV subjects had similar age, education and sex proportion. However, HIV subjects had higher CES-D scores. HIV subjects with high and low CES-D had similar CD4 count, nadir CD4, and viral load. Across all subjects, those with higher CES-D had lower KYNA (p = 0.025), but HIV subjects tended to have higher levels than SN (p = 0.06). However, HIV subjects with higher CES-D had lower [KYNA] than HIV with lower CES-D (p = 0.07). SN with higher CES-D scores had similar [KYNA] as those with lower CES-D scores. Conclusions: Consistent with prior studies, those with depressive symptoms had lower CSF KYNA levels. However, this is the first study to evaluate CSF [KYNA] in HIV subjects in relation to depressive symptoms. The trend for higher KYNA in HIV subjects may be related to the greater neuroinflammation. Additional evaluations with CSF and serum inflammatory markers, such as cytokines and chemokines, and other metabolites in the kynurenic pathway will be evaluated. Financial support: Supported by: NIH (2K24-DA16170, U54NS56883, G12-MD007601, P30CA071789). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.683 Chronic, but not acute, low doses of pramipexole increased risk-taking behavior in rats Stephanie E. Tedford 1,3 , Nathan A. Holtz 1,3 , Amanda L. Persons 1,3 , Celeste Napier 1,2,3 1 Pharmacology, RUSH University, Chicago, IL, United States 2 Psychiatry, RUSH University, Chicago, IL, United States 3 Center for Compulsive Behavior and Addiction, RUSH University, Chicago, IL, United States
Aims: Pramipexole (PPX) is a direct-acting dopamine agonist that is used to treat neurological motor disturbances, such as Parkinson’s disease (PD). In a significant portion of PD patients, continuous PPX therapy is associated with behavioral addictions
Abstracts / Drug and Alcohol Dependence 146 (2015) e34–e117
Financial support: National Institute of Drug Abuse DA024104 and DA02774.
Cerebrospinal fluid kynurenic acid and depressive symptoms in HIV-infected individuals
http://dx.doi.org/10.1016/j.drugalcdep.2014.09.681
Naomi Tanizaki 1 , Adrian Franke 2 , Xingnan Li 2 , Nataliya Holmes 1 , Vanessa Douet 1 , Linda Chang 1
(±)-Modafinil potentiates cocaine self-administration but not the effects on DA levels in rodents Gianluigi Tanda 1,2 , Maddalena Mereu 2 , Takato Hiranita 2 , Amy H. Newman 1,3 , J. Katz 2 1
Medications Development Program, NIDA/IRP, Baltimore, MD, United States 2 Psychobiology Section, NIDA/IRP, Baltimore, MD, United States 3 Medicinal Chemistry Section, NIDA/IRP, Baltimore, MD, United States Aims: While the mechanisms underlying the therapeutic efficacy of (±)-Modafinil (MOD) are not fully understood, actions at the dopamine (DA) transporter (DAT) appear to be involved. With some exceptions, DAT blockers administered in combination potentiate the behavioral and reinforcing effects of psychostimulants (PSY) like cocaine (COC). That potentiation is related to increased accumbens (ACC) DA levels. However, recent clinical studies suggested efficacy of MOD in treating PSY abuse, suggesting a potential reduction of COC use in PSY abusers rather than a potentiation. Methods: Effects of MOD and COC, were tested alone and in combination, on microdialysate ACC DA levels in rats (n = 48), and mice (n = 60), self-administration (SA) (n = 12) in rats, and subjective effects (n = 12) in mice trained to discriminate COC. Results: MOD alone (0.03–10 mg/kg i.v.) did not maintain SA above vehicle levels when substituted for COC, but at those doses increased DA levels dose-dependently. MOD pretreatments (10–32 mg/kg i.p., 5 min prior) also dose-dependently (p < 0.05) potentiated COC SA, but microdialysis studies showed no significant enhancement of the effects of COC (0.03–3.0 mg/kg i.v.) on stimulation of DA levels in ACC in excess of those produced by COC alone. In mice, MOD alone (10–100 mg/kg) produced COClike subjective effects and potentiated the subjective effects of low COC doses (p < 0.05). In mice, MOD elicited significant (p < 0.05) increases in DA levels without significant differences between ACC shell and core, distinguishing MOD from PSYs abused by humans. Conclusions: MOD alone has a reduced PSY profile compared to COC. Our preclinical results suggest it might enhance reinforcing effects when taken in combination with sub-threshold doses of COC, independently from stimulation of DA levels. Based on clinical reports, these effects suggest a basis for use of MOD as a substitution agonist therapy for PSY abuse. Studies are in progress to better address the mechanisms underlying these effects. Financial support: NIDA/IRP. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.682
1 Medicine, University of Hawaii at Manoa, Honolulu, HI, United States 2 University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, United States
Aims: HIV patients have higher rates of depression compared to the general population in the U.S. Although social factors and co-morbid factors (e.g., such as stimulant abuse) may contribute to the depressive symptoms, abnormalities in the kynurenic pathyway may contribute to the symptoms in HIV patients. Increased kynurenic acid (KYNA) levels were reported in cerebrospinal fluid (CSF) of HIV patients, while decreased kynurenic acid levels were reported in CSF of depressed patients. Whether KYNA concentration varies with depressive symptoms differently in those with and without HIV was explored. Methods: 100 participants, 51 seronegative controls (SN) and 49 HIV, were evaluated clinically, provided CSF samples and completed the Center for Epidemiological Studies Depression scale (CES-D). We further evaluated the subjects according to the CESD scores (high ≥16 or low <16). CSF KYNA levels were measured by high performance liquid chromatography (HPLC). Results: SN and HIV subjects had similar age, education and sex proportion. However, HIV subjects had higher CES-D scores. HIV subjects with high and low CES-D had similar CD4 count, nadir CD4, and viral load. Across all subjects, those with higher CES-D had lower KYNA (p = 0.025), but HIV subjects tended to have higher levels than SN (p = 0.06). However, HIV subjects with higher CES-D had lower [KYNA] than HIV with lower CES-D (p = 0.07). SN with higher CES-D scores had similar [KYNA] as those with lower CES-D scores. Conclusions: Consistent with prior studies, those with depressive symptoms had lower CSF KYNA levels. However, this is the first study to evaluate CSF [KYNA] in HIV subjects in relation to depressive symptoms. The trend for higher KYNA in HIV subjects may be related to the greater neuroinflammation. Additional evaluations with CSF and serum inflammatory markers, such as cytokines and chemokines, and other metabolites in the kynurenic pathway will be evaluated. Financial support: Supported by: NIH (2K24-DA16170, U54NS56883, G12-MD007601, P30CA071789). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.683 Chronic, but not acute, low doses of pramipexole increased risk-taking behavior in rats Stephanie E. Tedford 1,3 , Nathan A. Holtz 1,3 , Amanda L. Persons 1,3 , Celeste Napier 1,2,3 1 Pharmacology, RUSH University, Chicago, IL, United States 2 Psychiatry, RUSH University, Chicago, IL, United States 3 Center for Compulsive Behavior and Addiction, RUSH University, Chicago, IL, United States
Aims: Pramipexole (PPX) is a direct-acting dopamine agonist that is used to treat neurological motor disturbances, such as Parkinson’s disease (PD). In a significant portion of PD patients, continuous PPX therapy is associated with behavioral addictions