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Items: 17

1.
Psychopharmacology (Berl). 2018 Aug 3. doi: 10.1007/s00213-018-4991-8. [Epub ahead of print]

Dissociation between hypothermia and neurotoxicity caused by mephedrone and methcathinone in TPH2 knockout mice.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, R&D Service (11R), 4646 John R, Detroit, MI, 48201, USA.
2
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
3
Department of Chemistry, Wayne State University, Detroit, MI, 48201, USA.
4
Research & Development Service, John D. Dingell VA Medical Center, R&D Service (11R), 4646 John R, Detroit, MI, 48201, USA. donald.kuhn@wayne.edu.
5
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA. donald.kuhn@wayne.edu.

Abstract

RATIONALE:

Mephedrone is a commonly abused constituent of "bath salts" and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear.

OBJECTIVES:

Mephedrone elicits a transient hypothermia which may provide intrinsic neuroprotection against methamphetamine-like toxicity to dopamine nerve endings. Furthermore, evidence in the literature suggests that this hypothermia is mediated by serotonin. By utilizing transgenic mice devoid of brain serotonin, we determined the contribution of this neurotransmitter to changes in core body temperature as well as its possible role in protecting against neurotoxicity. The effects of methcathinone and 4-methyl-methamphetamine, two structural analogs of mephedrone and methamphetamine, were also evaluated in these mice.

RESULTS:

The hypothermia induced by mephedrone and methcathinone in wild-type mice was not observed in mice lacking brain serotonin. Despite preventing drug-induced hypothermia, the lack of serotonin did not alter the neurotoxic profiles of the test drugs.

CONCLUSIONS:

Serotonin is a key mediator of pharmacological hypothermia induced by mephedrone and methcathinone, but these body temperature effects do not contribute to dopamine nerve ending damage observed in mice following treatment with mephedrone, methcathinone or 4-methyl-methamphetamine. Thus, the key component of methamphetamine neurotoxicity lacking in mephedrone remains to be elucidated.

KEYWORDS:

4-methyl-methamphetamine; Dopamine; Hypothermia; Mephedrone; Methcathinone; Neurotoxicity

2.
Neuropharmacology. 2018 May 15;134(Pt A):46-56. doi: 10.1016/j.neuropharm.2017.08.033. Epub 2017 Aug 26.

Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
2
Department of Chemistry, Wayne State University, Detroit, MI, USA.
3
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: donald.kuhn@wayne.edu.

Abstract

Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a β-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the β-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4-methylmethamphetamine. To test this hypothesis, l-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by l-DOPA. Mephedrone remained non-neurotoxic when combined with either l-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4-methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to β-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

KEYWORDS:

4-Methylmethamphetamine; Dopamine; Mephedrone; Methamphetamine; Methcathinone; Neurotoxicity

3.
Concussion. 2016 Dec;1(3). doi: 10.2217/cnc-2015-0001. Epub 2016 May 25.

Repeated mild traumatic brain injury causes focal response in lateral septum and hippocampus.

Author information

1
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
2
John D Dingell VA Medical Center and Wayne State University School of Medicine, Detroit, MI 48201, USA.
3
Department of Biological Engineering, Cornell University, Ithaca, NY 14853, USA.
4
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA ; Institute for Brain and Cognitive Sciences, University of Connecticut, Storrs, CT 06269, USA.

Abstract

AIM:

To advance our understanding of regional and temporal cellular responses to repeated mild traumatic brain injury (rmTBI), we used a mouse model of rmTBI that incorporated acceleration, deceleration and rotational forces.

MATERIALS & METHODS:

A modified weight-drop method was used to compare two inter-injury intervals, rmTBI-short (five hits delivered over 3 days) and rmTBI-long (five hits delivered over 15 days). Regional investigations of forebrain and midbrain histological alterations were performed at three post-injury time points (immediate, 2 weeks and 6 weeks).

RESULTS:

The rmTBI-short protocol generated an immediate, localized microglial and astroglial response in the dorsolateral septum and hippocampus, with the astroglial response persisting in the dorsolateral septum. The rmTBI-long protocol showed only a transitory astroglial response in the dorsolateral septum.

CONCLUSION:

Our results indicate that the lateral septum and hippocampus are particularly vulnerable regions in rmTBI, possibly contributing to memory and emotional impairments associated with repeated concussions.

KEYWORDS:

concussion; gliosis; hippocampus; microglia; mouse model; rmTBI; rotational force; septum

PMID:
28078102
4.
J Pharmacol Exp Ther. 2017 Mar;360(3):417-423. doi: 10.1124/jpet.116.237768. Epub 2016 Dec 30.

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone.

Author information

1
Research and Development Service, John D. Dingell VA Medical Center, Detroit, Michigan (J.H.A., M.A.-P., D.M.K.); Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan (J.H.A., M.A.-P., D.M.K.); Department of Chemistry, Wayne State University, Detroit, Michigan (G.C.S., D.C.).
2
Research and Development Service, John D. Dingell VA Medical Center, Detroit, Michigan (J.H.A., M.A.-P., D.M.K.); Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan (J.H.A., M.A.-P., D.M.K.); Department of Chemistry, Wayne State University, Detroit, Michigan (G.C.S., D.C.) donald.kuhn@wayne.edu.

Abstract

Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. Although MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared with METH. The addition of a β-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, two analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significant reductions in all markers of DA nerve-ending damage over a range of doses. These results lead to the conclusion that ring substitution at the 4-position profoundly reduces the neurotoxicity of METH, whereas the β-keto group has much less influence on this property. Although the mechanism(s) by which the 4-methyl substituent reduces METH-induced neurotoxicity remains unclear, it is speculated that this effect is mediated by a loss of DA-releasing action in MEPH and 4MM at the synaptic vesicle monoamine transporter, an effect that is thought to be critical for METH-induced neurotoxicity.

PMID:
28039330
PMCID:
PMC5325074
DOI:
10.1124/jpet.116.237768
[Indexed for MEDLINE]
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5.
Am J Pathol. 2016 Nov;186(11):2869-2886. doi: 10.1016/j.ajpath.2016.07.013. Epub 2016 Sep 20.

Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy-Like Pathology in White Matter Despite Transient Behavioral Abnormalities.

Author information

1
Research and Development Service, John D. Dingell VA Medical Center, Detroit, Michigan; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan. Electronic address: dbriggs@med.wayne.edu.
2
Research and Development Service, John D. Dingell VA Medical Center, Detroit, Michigan; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan.

Abstract

Repetitive mild traumatic brain injury (rmTBI), resulting from insults caused by an external mechanical force that disrupts normal brain function, has been linked to the development of neurodegenerative diseases, such as chronic traumatic encephalopathy and Alzheimer disease; however, neither the severity nor frequency of head injury required to trigger adverse behavioral outcomes is well understood. In this study, the administration of 30 head impacts using two different weights to lightly anesthetized, completely unrestrained mice established a paradigm that simulates the highly repetitive nature of sports- and military-related head injury. As the number of head impacts increases, the time to recover consciousness diminishes; however, both the sensorimotor function and behavioral outcomes of impacted mice evolve during the ensuing weeks. Postmortem analyses reveal robust Alzheimer disease and chronic traumatic encephalopathy-like conditions that manifest in a singular manner throughout the white matter concomitant with evidence of chronic oligodendrogenesis. Our data suggest that latency to recover the righting reflex may be an inadequate measure of injury severity and imply that exposure to repeated head impacts may mask the severity of an underlying and developing neuropathologic condition that does not manifest itself until long after head collisions cease. In addition, our data indicate that there is a cumulative and dose-dependent effect of repetitive head impacts that induces the neurobehavioral and neuropathologic outcomes seen in humans with a history of rmTBI.

PMID:
27662795
DOI:
10.1016/j.ajpath.2016.07.013
[Indexed for MEDLINE]
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6.
Curr Top Behav Neurosci. 2017;32:209-230. doi: 10.1007/7854_2016_21.

Neurotoxicology of Synthetic Cathinone Analogs.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, 48201, USA. maperez@med.wayne.edu.
2
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA. maperez@med.wayne.edu.
3
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, 48201, USA.
4
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, 48201, USA.

Abstract

The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methylone, and methylenedioxypyrovalerone (MDPV), four synthetic cathinones most commonly found in "bath salts." Cathinones are β-keto analogs of the commonly abused amphetamines and display pharmacological effects resembling cocaine and amphetamines, but despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce unique effects. Among the similarities of synthetic cathinones with their non-keto analogs are their targeting of monoamine systems, the release of neurotransmitters, and their stimulant properties. Most of the literature on synthetic cathinones has focused on describing their properties as psychostimulants, their behavioral effects on locomotion, memory, and potential for abuse, whereas descriptions of their neurotoxic properties are not abundant. The biochemical gauges of neurotoxicity induced by non-keto analogs are well studied in humans and experimental animals and include their ability to induce neuroinflammation, oxidative stress, excitotoxicity, temperature alterations as well as dysregulation of neurotransmitter systems and induce changes in monoamine transporters and receptors. These neurotoxicity gauges will serve as parameters to discuss the effects of the four previously mentioned synthetic cathinones alone or in combination with either another cathinone or with some of their non-keto analogs. Bath salts are not a defined combination of drugs and may consist of one synthetic cathinone compound or combinations of more cathinones. Furthermore, this review also presents some of the mechanisms that are thought to underlie this toxicity. A better understanding of the cellular and molecular mechanisms involved in the synthetic cathinones-induced neurotoxicity should contribute to generate modern therapeutic approaches to prevent or attenuate the adverse consequences of use of these drugs in humans.

KEYWORDS:

MDPV; Mephedrone; Methcathinone; Methylone; Neurotoxicity; Synthetic cathinones

PMID:
27753008
DOI:
10.1007/7854_2016_21
[Indexed for MEDLINE]
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7.
J Appl Physiol (1985). 2016 Aug 1;121(2):545-57. doi: 10.1152/japplphysiol.00448.2016. Epub 2016 Jul 8.

Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system.

Author information

1
John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan; Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan;
2
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
3
John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan; and.
4
John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan; Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan; jmateika@med.wayne.edu.

Abstract

We examined the effect of repeated daily exposure to intermittent hypoxia (IH) on the recovery of respiratory and limb motor function in mice genetically depleted of central nervous system serotonin. Electroencephalography, diaphragm activity, ventilation, core body temperature, and limb mobility were measured in spontaneously breathing wild-type (Tph2(+/+)) and tryptophan hydroxylase 2 knockout (Tph2(-/-)) mice. Following a C2 hemisection, the mice were exposed daily to IH (i.e., twelve 4-min episodes of 10% oxygen interspersed with 4-min normoxic periods followed by a 90-min end-recovery period) or normoxia (i.e., sham protocol, 21% oxygen) for 10 consecutive days. Diaphragm activity recovered to prehemisection levels in the Tph2(+/+) and Tph2(-/-) mice following exposure to IH but not normoxia [Tph2(+/+) 1.3 ± 0.2 (SE) vs. 0.3 ± 0.2; Tph2(-/-) 1.06 ± 0.1 vs. 0.3 ± 0.1, standardized to prehemisection values, P < 0.01]. Likewise, recovery of tidal volume and breathing frequency was evident, although breathing frequency values did not return to prehemisection levels within the time frame of the protocol. Partial recovery of limb motor function was also evident 2 wk after spinal cord hemisection. However, recovery was not dependent on IH or the presence of serotonin in the central nervous system. We conclude that IH promotes recovery of respiratory function but not basic motor tasks. Moreover, we conclude that spontaneous or treatment-induced recovery of respiratory and motor limb function is not dependent on serotonin in the central nervous system in a mouse model of spinal cord injury.

KEYWORDS:

diaphragm muscle activity; non-rapid eye movement sleep; repeated daily intermittent hypoxia; respiratory plasticity; telemetry

PMID:
27402561
DOI:
10.1152/japplphysiol.00448.2016
[Indexed for MEDLINE]
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8.
NMR Biomed. 2015 Nov;28(11):1480-8. doi: 10.1002/nbm.3409. Epub 2015 Sep 28.

Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

Author information

1
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
2
Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.
4
Research and Development Service, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA.
5
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
6
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence.

KEYWORDS:

behavioral sensitization; calcium; cocaine; dopamine transporter; magnetic resonance imaging; manganese; nucleus accumbens; striatum

PMID:
26411897
PMCID:
PMC4618766
DOI:
10.1002/nbm.3409
[Indexed for MEDLINE]
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9.
Behav Pharmacol. 2015 Sep;26(6):595-606. doi: 10.1097/FBP.0000000000000157.

Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin.

Author information

1
aResearch & Development Service, John D. Dingell VA Medical Center bDepartment of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

Abstract

Much of the social behavior in which rodents engage is related to reproduction, such as maintaining a breeding territory, seeking mates, mating, and caring for their young. Rodents belong to the internally fertilizing species that require sexual behavior for reproduction. The dyadic, heterosexual patterns of most mammalian species are sexually dimorphic, but they also share mutual components in both sexes: sexual attraction is reciprocal, sexual initiative is assumed, appetitive behavior is engaged in, and mating involves consummatory and postconsummatory phases in females as well as in males. Serotonin, a phylogenetically ancient molecule, is the most widely distributed neurotransmitter in the brain and its signaling pathways are essential for numerous functions including sexual behavior. Since the late 1960s, brain serotonergic neurotransmission has been considered to exert an inhibitory influence on the neural mechanisms mediating sexual behavior. This contention was based mainly on the observations that a decrease in central serotonergic activity facilitated the elicitation of sexual behavior, whereas an increase in central serotonergic activity attenuated it. However, the discovery of over 14 types of serotonin receptors has added numerous layers of complexity to the study of serotonin and sexual behavior. Evidence shows that, upon activation, certain receptor subtypes facilitate, whereas some others suppress, sexual behavior, as well as sexual arousal and motivation. Furthermore, the role of these receptors has been shown to be different in the male and female sexes. The use of serotonergic pharmacological interventions, mouse strains with genetic polymorphisms causing alterations in the levels of brain serotonin, and animal models with genetic manipulations of various serotonin effectors has helped delineate the fundamental role of this neurotransmitter in the regulation of sexual behavior. This review aims to examine the basics of the components of female and male sexual behavior and the participation of the serotonin system in the modulation of these behaviors, with emphasis on rodents.

PMID:
26110223
PMCID:
PMC4777293
DOI:
10.1097/FBP.0000000000000157
[Indexed for MEDLINE]
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10.
PLoS One. 2015 Feb 23;10(2):e0118603. doi: 10.1371/journal.pone.0118603. eCollection 2015.

Brain serotonin signaling does not determine sexual preference in male mice.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, Michigan, United States of America; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, United States of America.

Abstract

It was reported recently that male mice lacking brain serotonin (5-HT) lose their preference for females (Liu et al., 2011, Nature, 472, 95-100), suggesting a role for 5-HT signaling in sexual preference. Regulation of sex preference by 5-HT lies outside of the well established roles in this behavior established for the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). Presently, mice with a null mutation in the gene for tryptophan hydroxylase 2 (TPH2), which are depleted of brain 5-HT, were tested for sexual preference. When presented with inanimate (urine scents from male or estrous female) or animate (male or female mouse in estrus) sexual stimuli, TPH2-/- males show a clear preference for female over male stimuli. When a TPH2-/- male is offered the simultaneous choice between an estrous female and a male mouse, no sexual preference is expressed. However, when confounding behaviors that are seen among 3 mice in the same cage are controlled, TPH2-/- mice, like their TPH2+/+ counterparts, express a clear preference for female mice. Female TPH2-/- mice are preferred by males over TPH2+/+ females but this does not lead to increased pregnancy success. In fact, if one or both partners in a mating pair are TPH2-/- in genotype, pregnancy success rates are significantly decreased. Finally, expression of the VNO-specific cation channel TRPC2 and of CNGA2 in the MOE of TPH2-/- mice is normal, consistent with behavioral findings that sexual preference of TPH2-/- males for females is intact. In conclusion, 5-HT signaling in brain does not determine sexual preference in male mice. The use of pharmacological agents that are non-selective for the 5-HT neuronal system and that have serious adverse effects may have contributed historically to the stance that 5-HT regulates sexual behavior, including sex partner preference.

PMID:
25706994
PMCID:
PMC4338231
DOI:
10.1371/journal.pone.0118603
[Indexed for MEDLINE]
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11.
J Neurochem. 2015 Apr;133(2):211-22. doi: 10.1111/jnc.13048. Epub 2015 Mar 2.

3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: β-ketoamphetamine modulation of neurotoxicity by the dopamine transporter.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, Michigan, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA.

Abstract

Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of 'bath salts' and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS. Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity. METH (a) enters DA nerve endings via the DAT, causes leakage of DA into the cytoplasm and then into the synapse via DAT-mediated reverse transport. Methylone (METHY) and mephedrone (MEPH; b), like METH, are substrates for the DAT but release DA from cytoplasmic pools selectively. When METH is combined with METHY or MEPH (c), DA efflux and neurotoxicity are enhanced. MDPV (d), which is a non-substrate blocker of the DAT, prevents METH uptake and efflux of DA. Therefore, bath salts that are substrates for the DAT and release DA (METHY, MEPH) accentuate METH neurotoxicity, whereas those that are non-substrate blockers of the DAT (MDPV) are neuroprotective.

KEYWORDS:

dopamine nerve ending; dopamine transporter; neurotoxic amphetamines; neurotoxicity; β-ketoamphetamines

PMID:
25626880
PMCID:
PMC4759647
DOI:
10.1111/jnc.13048
[Indexed for MEDLINE]
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12.
Neurotransmitter (Houst). 2015;2. pii: e615. Epub 2015 Mar 2.

Neuronal serotonin in the regulation of maternal behavior in rodents.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Abstract

Maternal behavior is probably the most important pro-social behavior in female mammals, ensuring both the development and survival of her offspring. Signals driving maternal behaviors are complex and involve several brain areas, most of which are innervated by serotonin. Serotonin transmission influences maternal processes indirectly through release of maternally-relevant hormones such as prolactin, oxytocin and vasopressin, but it can also have more direct effects on survival and the growth rate of offspring, as well as on maternal care, aggression and pup killing. This article aims to examine the basics of the components of maternal behaviors in rodents and the neural systems underpinning these maternal responses with special emphasis on the role of neural serotonin in the regulation of these behaviors.

KEYWORDS:

TPH2; TPH2 knockout; maternal behavior; mice; rats; serotonin

13.
J Vis Exp. 2014 Dec 8;(94). doi: 10.3791/51820.

A novel model of mild traumatic brain injury for juvenile rats.

Author information

1
Alberta Children's Hospital Research Institute, University of Calgary; r.mychasiuk@uleth.ca.
2
Alberta Children's Hospital Research Institute, University of Calgary.
3
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine & John D. Dingell VA Medical Center.

Abstract

Despite growing evidence that childhood represents a major risk period for mild traumatic brain injury (mTBI) from sports-related concussions, motor vehicle accidents, and falls, a reliable animal model of mTBI had previously not been developed for this important aspect of development. The modified weight-drop technique employs a glancing impact to the head of a freely moving rodent transmitting acceleration, deceleration, and rotational forces upon the brain. When applied to juvenile rats, this modified weight-drop technique induced clinically relevant behavioural outcomes that were representative of post-concussion symptomology. The technique is a rapidly applied procedure with an extremely low mortality rate, rendering it ideal for high-throughput studies of therapeutics. In addition, because the procedure involves a mild injury to a closed head, it can easily be used for studies of repetitive brain injury. Owing to the simplistic nature of this technique, and the clinically relevant biomechanics of the injury pathophysiology, the modified weight-drop technique provides researchers with a reliable model of mTBI that can be used in a wide variety of behavioural, molecular, and genetic studies.

PMID:
25548960
PMCID:
PMC4396946
DOI:
10.3791/51820
[Indexed for MEDLINE]
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14.
Am J Physiol Regul Integr Comp Physiol. 2015 Jan 1;308(1):R10-7. doi: 10.1152/ajpregu.00400.2014. Epub 2014 Nov 12.

The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin.

Author information

1
John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan; Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan;
2
John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan.
3
John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan; Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan; jmateika@med.wayne.edu.

Abstract

We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:12-h light-dark cycle and determined whether temperature and motor activity are directly responsible for potential disruptions to arousal state. Telemetry transmitters were implanted in 24 wild-type mice (Tph2(+/+)) and 24 mice with a null mutation for tryptophan hydroxylase 2 (Tph2(-/-)). After surgery, electroencephalography, core body temperature, and motor activity were recorded for 24 h. Temperature for a given arousal state (quiet and active wake, non-rapid eye movement, and paradoxical sleep) was similar in the Tph2(+/+) and Tph2(-/-) mice across the light-dark cycle. The percentage of time spent in active wakefulness, along with motor activity, was decreased in the Tph2(+/+) compared with the Tph2(-/-) mice at the start and end of the dark cycle. This difference persisted into the light cycle. In contrast, the time spent in a given arousal state was similar at the remaining time points. Despite this similarity, periods of non-rapid-eye-movement sleep and wakefulness were less consolidated in the Tph2(+/+) compared with the Tph2(-/-) mice throughout the light-dark cycle. We conclude that the depletion of serotonin does not disrupt the diurnal variation in the sleep-wake cycle, motor activity, and temperature. However, serotonin may suppress photic and nonphotic inputs that manifest at light-dark transitions and serve to shorten the ultraradian duration of wakefulness and non-rapid-eye-movement sleep. Finally, alterations in the sleep-wake cycle following depletion of serotonin are unrelated to disruptions in the modulation of temperature.

KEYWORDS:

electroencephalography; electromyography; non-rapid-eye-movement sleep; paradoxical sleep; telemetry

PMID:
25394829
PMCID:
PMC4890646
DOI:
10.1152/ajpregu.00400.2014
[Indexed for MEDLINE]
Free PMC Article
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15.
J Neurochem. 2014 Jun;129(6):916-31. doi: 10.1111/jnc.12690. Epub 2014 Mar 19.

Animal models of sports-related head injury: bridging the gap between pre-clinical research and clinical reality.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA; Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

Sports-related head impact and injury has become a very highly contentious public health and medico-legal issue. Near-daily news accounts describe the travails of concussed athletes as they struggle with depression, sleep disorders, mood swings, and cognitive problems. Some of these individuals have developed chronic traumatic encephalopathy, a progressive and debilitating neurodegenerative disorder. Animal models have always been an integral part of the study of traumatic brain injury in humans but, historically, they have concentrated on acute, severe brain injuries. This review will describe a small number of new and emerging animal models of sports-related head injury that have the potential to increase our understanding of how multiple mild head impacts, starting in adolescence, can have serious psychiatric, cognitive and histopathological outcomes much later in life. Sports-related head injury (SRHI) has emerged as a significant public health issue as athletes can develop psychiatric and neurodegenerative disorders later in life. Animal models have always been an integral part of the study of human TBI but few existing methods are valid for studying SRHI. In this review, we propose criteria for effective animal models of SRHI. Movement of the head upon impact is judged to be of primary importance in leading to concussion and persistent CNS dysfunction.

KEYWORDS:

Sports-related head injury; animal models; cognitive dysfunction; neuropathological disorders; psychiatric outcomes; repetitive mild traumatic brain injury

PMID:
24673291
PMCID:
PMC4797983
DOI:
10.1111/jnc.12690
[Indexed for MEDLINE]
Free PMC Article
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16.
J Vis Exp. 2013 Dec 24;(82):50978. doi: 10.3791/50978.

Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice.

Author information

1
Research and Development Service, John D. Dingell VA Medical Center and Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine.

Abstract

Obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASD) are serious and debilitating psychiatric conditions and each constitutes a significant public health concern, particularly in children. Both of these conditions are highlighted by the repeated expression of meaningless behaviors. Individuals with OCD often show checking, frequent hand washing, and counting. Children with ASDs also engage in repetitive tapping, arm or hand flapping, and rocking. These behaviors can vary widely in intensity and frequency of expression. More intense forms of repetitive behaviors can even result in injury (e.g. excessive grooming, hand washing, and self-stimulation). These behaviors are therefore very disruptive and make normal social discourse difficult. Treatment options for repetitive behaviors in OCD and ASDs are somewhat limited and there is great interest in developing more effective therapies for each condition. Numerous animal models for evaluating compulsive-like behaviors have been developed over the past three decades. Perhaps the animal models with the greatest validity and ease of use are the marble burying test and the nestlet shredding test. Both tests take advantage of the fact that the target behaviors occur spontaneously in mice. In the marble burying test, 20 marbles are arrayed on the surface of clean bedding. The number of marbles buried in a 30 min session is scored by investigators blind to the treatment or status of the subjects. In the nestlet shredding test, a nestlet comprised of pulped cotton fiber is preweighed and placed on top of cage bedding and the amount of the nestlet remaining intact after a 30 min test session is determined. Presently, we describe protocols for and show movie documentation of marble burying and nestlet shredding. Both tests are easily and accurately scored and each is sensitive to small changes in the expression of compulsive-like behaviors that result from genetic manipulations, disease, or head injury.

PMID:
24429507
PMCID:
PMC4108161
DOI:
10.3791/50978
[Indexed for MEDLINE]
Free PMC Article
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17.
Life Sci. 2014 Feb 27;97(1):31-6. doi: 10.1016/j.lfs.2013.07.015. Epub 2013 Jul 24.

Effects of combined treatment with mephedrone and methamphetamine or 3,4-methylenedioxymethamphetamine on serotonin nerve endings of the hippocampus.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
2
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: donald.kuhn@wayne.edu.

Abstract

AIMS:

Mephedrone is a stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Although mephedrone does not damage dopamine nerve endings it increases the neurotoxicity of amphetamine, methamphetamine and MDMA. The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood, with some investigators reporting damage while others conclude it does not. Presently, we investigate if mephedrone given alone or with methamphetamine or MDMA damages 5HT nerve endings of the hippocampus.

MAIN METHODS:

The status of 5HT nerve endings in the hippocampus of female C57BL mice was assessed through measures of 5HT by HPLC and by immunoblot analysis of serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2), selective markers of 5HT nerve endings. Astrocytosis was assessed through measures of glial fibrillary acidic protein (GFAP) (immunoblotting) and microglial activation was determined by histochemical staining with Isolectin B4.

KEY FINDINGS:

Mephedrone alone did not cause persistent reductions in the levels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mild reductions in 5HT but did not change SERT and TPH2 levels. Combined treatment with mephedrone and methamphetamine or MDMA did not change the status of 5HT nerve endings to an extent that was different from either drug alone.

SIGNIFICANCE:

Mephedrone does not cause toxicity to 5HT nerve endings of the hippocampus. When co-administered with methamphetamine or MDMA, drugs that are often co-abused with mephedrone by humans, toxicity is not increased as is the case for dopamine nerve endings when these drugs are taken together.

KEYWORDS:

Bath salts; MDMA; Mephedrone; Methamphetamine; Neurotoxicity; Serotonin

PMID:
23892197
PMCID:
PMC3858458
DOI:
10.1016/j.lfs.2013.07.015
[Indexed for MEDLINE]
Free PMC Article
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