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- Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus. [JOURNAL ARTICLE]
- Neuropsychopharmacology 2014 Aug 28.
The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and behavioral responses to reward omission, aversive and fear-eliciting stimuli, and certain drugs of abuse. Insofar as previous studies implicate ventral mesencephalic dopamine neurons as an essential component of locomotor activation, we hypothesized that the RMTg also should modulate locomotion activation. We observed that bilateral infusions into the RMTg of the GABAA agonist, muscimol, indeed activate locomotion. Alternatively, bilateral RMTg infusions of the GABAA receptor antagonist, bicuculline, suppress robust activations of locomotion elicited in two distinct ways:  by disinhibitory stimulation of neurons in the lateral preoptic area and  by return of rats to an environment previously paired with amphetamine administration. The possibility that suppressive locomotor effects of RMTg bicuculline infusions were due to unintended spread of drug to the nearby VTA was falsified by a control experiment showing that bilateral infusions of bicuculline into the VTA produce activation rather than suppression of locomotion. These results objectively implicate the RMTg in the regulation of locomotor activation. The effect is important because much evidence reported in the literature suggests that locomotor activation can be an involuntary behavioral expression of expectation and/or want without which the willingness to execute adaptive behaviors is impaired.Neuropsychopharmacology accepted article preview online, 28 August 2014. doi:10.1038/npp.2014.223.
- Gene expression profiling in the striatum of amphetamine-treated spontaneously hypertensive rats which showed amphetamine conditioned place preference and self-administration. [JOURNAL ARTICLE]
- Arch Pharm Res 2014 Aug 28.
Attention-deficit/hyperactivity disorder (ADHD), the most commonly diagnosed neurobehavioral disorder of childhood, is usually treated with psychostimulants (e.g., amphetamine). Little is known about the neuronal and behavioral consequences of chronic amphetamine use or abuse in individuals with ADHD. Of all ADHD animal models, the spontaneously hypertensive rat (SHR) is the most validated and widely used. Here, we analyzed striatal transcriptomes in amphetamine-pretreated SHRs (5 mg/kg, i.p. for 7 days [twice daily]), which showed a conditioned place preference to and self-administration of amphetamine. Microarray analyses revealed increased mRNA expression of 55 genes (>1.65-fold increase), while 17 genes were downregulated (<0.6-fold) in the striatum of SHRs. The main functional categories overrepresented among the differentially expressed genes in the striatum include those involved in transcription (e.g., Cebpb, Per2), genes associated with angiogenesis (e.g., Kdr, Klf5), cell adhesion (e.g., Col11a1, Ctgf), apoptosis (e.g., Nfkbia, Perp) and neuronal development (e.g., Egr2, Nr4a3). In conclusion, we dissected the striatal transcriptional responses to the reinforcing effects of repeated amphetamine treatment in the SHR model of ADHD. Future studies should determine the influence of these altered transcripts on amphetamine reinforcement in amphetamine-treated SHRs, and the clinical relevance of the present findings with regard to amphetamine use/abuse in ADHD individuals.
- Decision-making in stimulant and opiate addicts in protracted abstinence: evidence from computational modeling with pure users. [JOURNAL ARTICLE]
- Front Psychol 2014.:849.
Substance dependent individuals (SDI) often exhibit decision-making deficits; however, it remains unclear whether the nature of the underlying decision-making processes is the same in users of different classes of drugs and whether these deficits persist after discontinuation of drug use. We used computational modeling to address these questions in a unique sample of relatively "pure" amphetamine-dependent (N = 38) and heroin-dependent individuals (N = 43) who were currently in protracted abstinence, and in 48 healthy controls (HC). A Bayesian model comparison technique, a simulation method, and parameter recovery tests were used to compare three cognitive models: (1) Prospect Valence Learning with decay reinforcement learning rule (PVL-DecayRI), (2) PVL with delta learning rule (PVL-Delta), and (3) Value-Plus-Perseverance (VPP) model based on Win-Stay-Lose-Switch (WSLS) strategy. The model comparison results indicated that the VPP model, a hybrid model of reinforcement learning (RL) and a heuristic strategy of perseverance had the best post-hoc model fit, but the two PVL models showed better simulation and parameter recovery performance. Computational modeling results suggested that overall all three groups relied more on RL than on a WSLS strategy. Heroin users displayed reduced loss aversion relative to HC across all three models, which suggests that their decision-making deficits are longstanding (or pre-existing) and may be driven by reduced sensitivity to loss. In contrast, amphetamine users showed comparable cognitive functions to HC with the VPP model, whereas the second best-fitting model with relatively good simulation performance (PVL-DecayRI) revealed increased reward sensitivity relative to HC. These results suggest that some decision-making deficits persist in protracted abstinence and may be mediated by different mechanisms in opiate and stimulant users.
- First detection of ethylphenidate in human fatalities after ethylphenidate intake. [JOURNAL ARTICLE]
- Forensic Sci Int 2014 Jul 25.:126-129.
Methylphenidate, a psychostimulant drug from the group of amphetamines is, among others, established in the treatment of attention deficit hyperactivity disorder and narcolepsy. It is also known to have a certain potential of abuse. In combination with alcohol, the metabolite ethylphenidate was detected in human plasma in small amounts. However, ethylphenidate is sold as "research chemical" via the Internet. It was put under German narcotics law in July 2013. In a recent case, where a deceased person was found in his apartment, the police seized a plastic bag with the inscription "ethylphenidate". An autopsy of the 32-year-old man yielded a mitral valve endocarditis, which must have persisted a while before death, in combination with a pneumonia. At the Forensic Toxicological Centre (FTC) in Munich femoral blood, liver, pericardium fluid, urine, stomach content and hair of the deceased were analyzed for ethylphenidate after sample preparation by an LC-Triple TOF 5600. Calibration curves were spiked with a methanolic 1mg/mL solution of ethylphenidate (substance provided by the State Office of Criminal Investigation in Munich) in whole blood in comparison to liver and femoral blood, in serum in comparison to pericardium fluid and in urine in comparison to urine and stomach content, respectively. Ethylphenidate was detected in all analyzed matrices. The spectrums of the human specimen were compared to those obtained from the calibration curves and identified as ethylphenidate. The measured concentrations were for femoral blood 110ng/mL, for liver 180ng/g, for pericardium fluid 131ng/mL, for urine 987ng/mL and for stomach content 20.7ng/mL, respectively. The stomach contained 200mL of a brownish-coloured liquid, resulting in a total amount of 4000ng ethylphenidate. The lowest calibrator for whole blood and serum was 1ng/mL and for urine 10ng/mL. As far as it is known to the authors, these are the first ethylphenidate levels measured in a case of ethylphenidate intake. Therefore these results can only be compared to methylphenidate concentrations with therapeutic levels ranging from 5 to 60ng/mL in serum. As the toxic levels for methylphenidate start from approximately 500ng/mL serum, we estimate that ethylphenidate in the concentrations mentioned above is not in a directly lethal range. But it has to be considered, that amphetamine-like drugs as methylphenidate are known for their cardiovascular side effects (like tachycardia and arrhythmia) and might therefore have contributed to death, which was attributed to endocarditis in combination with pneumonia.
- Central dopamine action modulates neuropeptide-controlled appetite via the hypothalamic PI3K/NFκB-dependent mechanism. [JOURNAL ARTICLE]
- Genes Brain Behav 2014 Aug 27.
Hypothalamic neuropeptides, including neuropeptide Y (NPY) and proopiomelanocortin (POMC), have been found to control the appetite-suppressing effect of amphetamine (AMPH). In the present study, we have examined whether dopamine receptor (DAR), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-κB) are involved in AMPH's action. We administered AMPH to rats once a day for 4 days and assessed and compared changes in hypothalamic NPY, melanocortin receptor 4 (MC4R), PI3K, pAkt, and NF-κB expression. We found that the inhibition of DAR increased NPY, but decreased MC4R, PI3K, and NF-κB expression, compared to AMPH-treated rats. Moreover, MC4R, PI3K, pAkt, and NF-κB increased with the maximum response on Day 2, which was consistent with the response of feeding behavior but was opposite the expression of NPY. Furthermore, we found that the intracerebroventricular infusion of the PI3K inhibitor or NF-κB antisense could attenuate AMPH-induced anorexia, and partially reverse the expression of NPY, MC4R, PI3K, Akt and NF-κB back toward a normal level. We therefore suggest that DAR-PI3K-NFκB signaling in the hypothalamus plays functional roles in the modulation of NPY and POMC neurotransmissions and in the control of AMPH-evoked appetite suppression.
- Intracerebral Hemorrhage Associated with Oral Phenylephrine Use: A Case Report and Review of the Literature. [JOURNAL ARTICLE]
- J Stroke Cerebrovasc Dis 2014 Aug 23.
Prior reports have linked both ischemic and hemorrhagic stroke to use of sympathomimetic drugs including phenylephrine. The purpose of this study is to describe the first case, to our knowledge of intracerebral hemorrhage (ICH) after oral use of phenylephrine and to systematically review the literature on phenylephrine and acute stroke.A case report and review of the literature.A 59-year-old female presented with thunderclap headache, right hemiparesis, aphasia, and left gaze deviation. Head computed tomography (CT) showed a left frontal ICH with intraventricular and subarachnoid extension. She had no significant past medical history. For the previous 30 days, the patient was taking multiple common cold remedies containing phenylephrine to treat sinusitis. CT and magnetic resonance angiography showed no causative vascular abnormality. Catheter cerebral angiography supported reversible cerebral vasoconstriction syndrome (RCVS). Phenylephrine was determined to be the most likely etiology for her hemorrhage. A review of the literature, found 7 cases describing phenylephrine use with acute stroke occurrence: female, 5 of 7 (71%); route of administration, nasal (n = 3), ophthalmic (n = 2), intravenous (n = 1), intracorporeal injection (n = 1). Stroke types were subarachnoid hemorrhage (n = 5), ICH (n = 4), and ischemic (n = 1). One case reported RCVS after phenylephrine use.It is scientifically plausible that phenylephrine may cause strokes, consistent with the pharmacologic properties and adverse event profiles of similar amphetamine-like sympathomimetics. As RCVS has been well described in association with over-the-counter sympathomimetics, a likely, although not definitive, causal relationship between phenylephrine and ICH is proposed.
- Improved identification of multiple drugs of abuse and relative metabolites in urine samples using liquid chromatography/triple quadrupole mass spectrometry coupled with a library search. [Journal Article]
- Rapid Commun Mass Spectrom 2014 Oct 15; 28(19):2043-53.
Although two multiple reaction monitoring (MRM) transitions per compound are used for identification performed using liquid chromatography/triple quadrupole mass spectrometry (LC/QqQ-MS/MS), differences in identification criteria among several regulations may lead to misidentification. We demonstrated that the use of two MRM transitions and product ion spectra improves compound identification.The scan cycle time was reduced using time-scheduled MRM (tMRM), data-dependent product ion scanning, and dynamic exclusion. The quantification and identification performance for 13 drugs of abuse and their metabolites were evaluated.Deuterated internal standards compensated for ion suppression. All analytes exhibited intra- and interday precision <12.11%, accuracy of -10.31% to +10.10%, and no carryover. The LC/QqQ-MS/MS and reference gas chromatography/MS methods were equally precise, accurate, and specific. Several regulatory organizations include two MRM transitions, their ratio, and retention time as identification criteria. In 28 samples, the relative ion ratio variation was >10% and product ion spectral matches with >94% probabilities improved drug and metabolite identification.The LC/QqQ-MS/MS method is a comprehensive assay in which tMRM and the product ion scan are combined in a single run by using a QqQ mass analyzer to simultaneously quantify amphetamine, ketamine, morphine, and their relative metabolites in urine. The proposed method can be applied in forensic science. Copyright © 2014 John Wiley & Sons, Ltd.
- Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats. [JOURNAL ARTICLE]
- Mol Psychiatry 2014 Aug 26.
Gpr88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinson's disease or schizophrenia (SZ). This study investigated the relevance of Gpr88 to SZ-associated behavior by knocking down Gpr88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of Gpr88 and of Drd2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically Gpr88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of Gpr88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for Gpr88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex.Molecular Psychiatry advance online publication, 26 August 2014; doi:10.1038/mp.2014.92.
- A longitudinal study of self-reported psychopathology in early ecstasy and amphetamine users. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Aug 27.
It still remains unclear whether psychopathological abnormalities described in human 3,4-methylenedioxymethamphetamine users (MDMA users) and d-amphetamine users (AMPH users) existed before the beginning of regular use or if they develop with ongoing use.The present study was conducted in order to assess this relationship and to overcome previous methodological shortcomings.A longitudinal cohort study in 96 beginning MDMA and d-amphetamine users between 2006 and 2011 with a follow-up duration of 24 months. In order to explore the impact of MDMA and AMPH use on self-reported psychopathology (measured by the Symptom Checklist-90-Revised), mixed models for repeated measures were fitted. In order to examine the impact of previous psychopathology on subsequent use, partial correlation analyses and linear regression analyses were applied.Over the course of the 2-year follow-up period, 31 subjects used neither MDMA nor AMPH (non-users); 65 subjects used both MDMA and AMPH: 37 subjects used between 1 and 14 tablets of MDMA and 28 subjects used 15 or more tablets of MDMA. Thirty-three subjects used between 1 and 14 g of AMPH, and 32 subjects used 15 g or more. No associations concerning MDMA/AMPH use and development of self-reported psychopathology were found. However, there was a significant relationship between globally increased self-reported psychopathology-particularly psychoticism-at the beginning of the study and subsequent AMPH use.The data of the present study suggest that a certain psychopathological profile could form a risk factor for later use of amphetamines.
- Methamphetamine Self-administration in Humans During D-Amphetamine Maintenance. [JOURNAL ARTICLE]
- J Clin Psychopharmacol 2014 Aug 22.
Agonist replacement may be a viable treatment approach for managing stimulant use disorders. This study sought to determine the effects of D-amphetamine maintenance on methamphetamine self-administration in stimulant using human participants. We predicted that D-amphetamine maintenance would reduce methamphetamine self-administration. Eight participants completed the protocol, which tested 2 D-amphetamine maintenance conditions in counterbalanced order (0 and 40 mg/d). Participants completed 4 experimental sessions under each maintenance condition in which they first sampled 1 of 4 doses of intranasal methamphetamine (0, 10, 20, or 30 mg). Participants then had the opportunity to respond on a computerized progressive-ratio task to earn portions of the sampled methamphetamine dose. Subject-rated drug effect and physiological measures were completed at regular intervals prior to and after sampling methamphetamine. Methamphetamine was self-administered as an orderly function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects on 12 items of the drug-effects questionnaires, 8 of which were attenuated by D-amphetamine maintenance (eg, increased ratings were attenuated on items such as Any Effect, Like Drug, and Willing to Take Again on the Drug Effect Questionnaire). Methamphetamine produced significant increases in systolic blood pressure, which were attenuated by D-amphetamine maintenance compared to placebo maintenance. Methamphetamine was well tolerated during D-amphetamine maintenance and no adverse events occurred. Although D-amphetamine attenuated some subject-rated effects of methamphetamine, the self-administration results are concordant with those of clinical trials showing that D-amphetamine did not reduce methamphetamine use. Unique pharmacological approaches may be needed for treating amphetamine use disorders.