RESUMEN
Methcathinone (MCAT) is a psychostimulant of abuse that can cause both persistent striatal dopaminergic and serotonergic, as well as hippocampal serotonergic, deficits. Evidence suggests that the rapid effects of stimulants that are structurally and mechanistically similar to MCAT on monoamine transporter function may contribute to the abuse liability and/or persistent monoaminergic deficits caused by these agents. Thus, effects of MCAT on 1) striatal dopamine (DA) transporter (DAT); and 2) striatal and hippocampal serotonin transporter (SERT) function, as determined in tissues from adult male rats, were assessed. As reported previously, a single administration of MCAT rapidly (within 1 hr) decreases striatal [3 H]DA uptake. Similarly, incubation of rat synaptosomes with MCAT at 37â (but not 4ËC) decreased striatal [3 H]DA uptake. Incubation with MCAT likewise decreased [3 H]5HT but not vesicular [3 H]DA uptake. MCAT incubation in vitro was without effect on [3 H]DA uptake in striatal synaptosomes prepared from MCAT-treated rats. The decrease in [3 H]DA uptake caused by MCAT incubation: (a) reflected a decrease in Vmax , with minimal change in Km , and (b) was attenuated by co-incubation with the cell-permeable calcium chelator, N,N'-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]-1,1'-bis[(acetyloxy)methyl] ester-glycine (BAPTA-AM), as well as the non-selective protein kinase-C (PKC) inhibitors bisindolylmaleimide-1 (BIM-1) and 2-[1-3(Aminopropyl)indol-3-yl]-3(1-methyl-1H-indol-3-yl)maleimide (or Bisindolylmaleimide VIII; Ro-31-7549). Taken together, these results suggest that in vitro MCAT incubation may model important aspects of MCAT administration in vivo, and that calcium and PKC contribute to the in vitro effects of MCAT on DAT.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/fisiología , Propiofenonas/farmacología , Proteína Quinasa C/fisiología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Sinaptosomas/efectos de los fármacos , Sinaptosomas/fisiologíaRESUMEN
Methylenedioxypyrovalerone (MDPV) is an abused synthetic cathinone, commonly referred to as a "bath salt." Because the dopamine (DA) transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) are key regulators of both the abuse and neurotoxic potential of structurally and behaviorally related agents, the impact of MDPV on these transporters was investigated. Results revealed that a single in vivo MDPV administration rapidly (within 1 hour) and reversibly increased both rat striatal DAT and VMAT-2 activity, as assessed via [3H]DA uptake in synaptosomes and synaptic vesicles, respectively, prepared from treated rats. There was no evidence of an MDPV-induced increase in plasmalemmal membrane DAT surface expression. Plasma concentrations of MDPV increased dose-dependently as assessed 1 hour after 2.5 and 5.0 mg/kg (s.c.) administration and returned to levels less than 10 ng/ml by 18 hours after 2.5 mg/kg (s.c.). Neither pretreatment with a D1 receptor (SCH23390), a D2 receptor (eticlopride), nor a nicotinic receptor (mecamylamine) antagonist attenuated the MDPV-induced increase in DAT activity. In contrast, eticlopride pretreatment attenuated both the MDPV-induced increase in VMAT-2-mediated DA uptake and an associated increase in cytoplasmic-associated vesicle VMAT-2 immunoreactivity. SCH23390 did not attenuate the MDPV-induced increase in VMAT-2 activity. Repeated MDPV injections did not cause persistent DAergic deficits, as assessed 7 to 8 days later. The impact of MDPV on striatal and hippocampal serotonergic assessments was minimal. Taken together, these data contribute to a growing pharmacological rubric for evaluating the ever-growing list of designer cathinone-related stimulants. The profile of MDPV compared with related psychostimulants is discussed. SIGNIFICANCE STATEMENT: Pharmacological characterization of the synthetic cathinone, 3,4-methylenedioxypyrovalerone (MDPV; commonly referred to as a "bath salt"), is critical for understanding the abuse liability and neurotoxic potential of this and related agents. Accordingly, the impact of MDPV on monoaminergic neurons is described and compared with that of related psychostimulants.
Asunto(s)
Benzodioxoles/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Drogas de Diseño/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Pirrolidinas/farmacología , Trastornos Relacionados con Sustancias/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Benzodioxoles/farmacocinética , Temperatura Corporal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacocinética , Drogas de Diseño/farmacocinética , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Femenino , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Pirrolidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Cathinona SintéticaRESUMEN
Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/fisiología , Dopamina/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/farmacología , Proteínas de Transporte Vesicular de Monoaminas/fisiología , Inhibidores de Captación Adrenérgica/farmacología , Animales , Enfermedades del Sistema Nervioso Central/fisiopatología , Dopaminérgicos/farmacología , Glicosilación , Humanos , Fosforilación/fisiología , Transducción de Señal , Transmisión Sináptica , Proteínas de Transporte Vesicular de Monoaminas/clasificaciónRESUMEN
Investigator-administered nicotine alters neurotensin and substance P levels in Sprague-Dawley rats. This finding suggested a role of the dopamine-related endogenous neuropeptides in nicotine addiction. We sought to extend this observation by determining the responses of neurotensin and substance P systems (assessed using radioimmunoassay) in male and female rats following nicotine self-administration (SA). Male and female Sprague-Dawley were trained to self-administer nicotine, or receive saline infusions yoked to a nicotine-administering rat during daily sessions (1-h; 21 days). Brains were extracted 3 h after the last SA session. Nicotine SA increased tissue levels of neurotensin in the males in the anterior and posterior caudate, globus pallidus, frontal cortex, nucleus accumbens core and shell, and ventral tegmental area. Nicotine SA also increased tissue levels of neurotensin in the females in the anterior caudate, globus pallidus, nucleus accumbens core and shell, but not in the posterior caudate, frontal cortex, or ventral tegmental area. There were fewer sex differences observed in the substance P systems. Nicotine SA increased tissue levels of substance P in both the males and females in the posterior caudate, globus pallidus, frontal cortex, nucleus accumbens shell, and ventral tegmental area. A sex difference was observed in the nucleus accumbens core, where nicotine SA increased tissue levels of substance P in the males, yet decreased levels in the females. The regulation of neuropeptides following nicotine SA may play a role in the susceptibility to nicotine dependence in females and males. Synapse 70:336-346, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Encéfalo/efectos de los fármacos , Neurotensina/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Sustancia P/metabolismo , Animales , Encéfalo/metabolismo , Femenino , Masculino , Neurotensina/genética , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Autoadministración , Factores Sexuales , Sustancia P/genéticaRESUMEN
Preclinical studies demonstrate that repeated, high-dose methamphetamine administrations rapidly decrease plasmalemmal dopamine uptake, which may contribute to aberrant dopamine accumulation, reactive species generation, and long-term dopaminergic deficits. The present study extends these findings by demonstrating a heretofore unreported, epitope-specific modification in the dopamine transporter caused by a methamphetamine regimen that induces these deficits. Specifically, repeated, high-dose methamphetamine injections (4 × 10 mg/kg/injection, 2-h intervals) rapidly decreased immunohistochemical detection of striatal dopamine transporter as assessed 1 h after the final methamphetamine exposure. In contrast, neither a single high dose (1 × 10 mg/kg) nor repeated injections of a lower dose (4 × 2 mg/kg/injection) induced this change. The high-dose regimen-induced alteration was only detected using antibodies directed against the N-terminus. Immunohistochemical staining using antibodies directed against the C-terminus did not reveal any changes. The high-dose regimen also did not alter dopamine transporter expression as assessed using [(125) I]RTI-55 autoradiography. These data suggest that the repeated, high-dose methamphetamine regimen alters the N-terminus of the dopamine transporter. Further, these data may be predictive of persistent dopamine deficits caused by the stimulant. Future studies of the signaling cascades involved should provide novel insight into potential mechanisms underlying the physiological and pathophysiological regulation of the dopamine transporter.
Asunto(s)
Dopaminérgicos/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Metanfetamina/farmacología , Secuencia de Aminoácidos , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopaminérgicos/administración & dosificación , Dopaminérgicos/toxicidad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Epítopos/metabolismo , Masculino , Metanfetamina/administración & dosificación , Metanfetamina/toxicidad , Datos de Secuencia Molecular , Unión Proteica , Dominios Proteicos , Ratas , Ratas Sprague-DawleyRESUMEN
Preclinical studies have demonstrated that oral nicotine exposure attenuates long-term dopaminergic damage induced by toxins, including repeated, high doses of methamphetamine. It is suggested that alterations in nicotinic acetylcholine receptor (nAChR) expression, including α4ß2* and α6ß2* subtypes, likely contribute to this protection. The current study extended these findings by investigating whether nicotine self-administration in male, Sprague-Dawley rats (a) attenuates short-term dopaminergic damage induced by methamphetamine and (b) causes alterations in levels of α4ß2* and α6ß2* nAChR subtypes. The findings indicate that nicotine self-administration (0.032 mg/kg/infusion for 14 days) per se did not alter α4ß2* and α6ß2* nAChR expression or dopamine transporter (DAT) expression and function. Interestingly, prior nicotine self-administration attenuated methamphetamine-induced decreases in DAT function when assessed 24 h, but not 1 h, after methamphetamine treatment (4×7.5 mg/kg/injection). The ability of nicotine to attenuate the effects of methamphetamine on DAT function corresponded with increases in α4ß2*, but not α6ß2*, nAChR binding density. Understanding the role of nAChRs in methamphetamine-induced damage has the potential to elucidate mechanisms underlying the etiology of disorders involving dopaminergic dysfunction, as well as to highlight potential new therapeutic strategies for prevention or reduction of dopaminergic neurodegeneration.
Asunto(s)
Metanfetamina/toxicidad , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Receptores Nicotínicos/metabolismo , Administración Oral , Animales , Dopamina/metabolismo , Dopaminérgicos/toxicidad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Ratas , Ratas Sprague-Dawley , Autoadministración , Factores de TiempoRESUMEN
Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4ß2 and α6ß2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4ß2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6ß2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4ß2 and/or α6ß2 expression, and that both age of onset and duration of nicotine exposure affect this protection.
Asunto(s)
Inhibidores de Captación de Dopamina/farmacología , Dopamina/deficiencia , Metanfetamina/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Edad de Inicio , Envejecimiento/efectos de los fármacos , Animales , Autorradiografía , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina/farmacocinética , Interacciones Farmacológicas , Masculino , Metanfetamina/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismoRESUMEN
BACKGROUND: Previous studies have demonstrated that methamphetamine abuse leads to memory deficits and these are associated with relapse. Furthermore, extensive evidence indicates that nicotine prevents and/or improves memory deficits in different models of cognitive dysfunction and these nicotinic effects might be mediated by hippocampal or cortical nicotinic acetylcholine receptors. The present study investigated whether nicotine attenuates methamphetamine-induced novel object recognition deficits in rats and explored potential underlying mechanisms. METHODS: Adolescent or adult male Sprague-Dawley rats received either nicotine water (10-75 µg/mL) or tap water for several weeks. Methamphetamine (4 × 7.5mg/kg/injection) or saline was administered either before or after chronic nicotine exposure. Novel object recognition was evaluated 6 days after methamphetamine or saline. Serotonin transporter function and density and α4ß2 nicotinic acetylcholine receptor density were assessed on the following day. RESULTS: Chronic nicotine intake via drinking water beginning during either adolescence or adulthood attenuated the novel object recognition deficits caused by a high-dose methamphetamine administration. Similarly, nicotine attenuated methamphetamine-induced deficits in novel object recognition when administered after methamphetamine treatment. However, nicotine did not attenuate the serotonergic deficits caused by methamphetamine in adults. Conversely, nicotine attenuated methamphetamine-induced deficits in α4ß2 nicotinic acetylcholine receptor density in the hippocampal CA1 region. Furthermore, nicotine increased α4ß2 nicotinic acetylcholine receptor density in the hippocampal CA3, dentate gyrus and perirhinal cortex in both saline- and methamphetamine-treated rats. CONCLUSIONS: Overall, these findings suggest that nicotine-induced increases in α4ß2 nicotinic acetylcholine receptors in the hippocampus and perirhinal cortex might be one mechanism by which novel object recognition deficits are attenuated by nicotine in methamphetamine-treated rats.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Metanfetamina/toxicidad , Nicotina/administración & dosificación , Nootrópicos/administración & dosificación , Receptores Nicotínicos/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Administración Oral , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Envejecimiento/psicología , Animales , Región CA1 Hipocampal/crecimiento & desarrollo , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/patología , Giro Dentado/efectos de los fármacos , Giro Dentado/crecimiento & desarrollo , Giro Dentado/metabolismo , Giro Dentado/patología , Agua Potable , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Agonistas Nicotínicos/administración & dosificación , Ratas Sprague-Dawley , Reconocimiento en Psicología/fisiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/crecimiento & desarrollo , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patologíaRESUMEN
Administration of methamphetamine (METH) alters limbic-related (LR) neurotensin (NT) systems. Thus, through a D1-receptor mechanism, noncontingent high doses (5-15 mg kg(-1)), and likely self-administration, of METH appears to reduce NT release causing its accumulation and an elevation of NT-like immunoreactivity (NTLI) in limbic-related NT pathways. For comparison, we tested the effect of low doses of METH, that are more like those used in therapy, on NTLI in the core and shell of the nucleus accumbens (NAc and NAs), prefrontal cortex (PFC), ventral tegmental area (VTA), the lateral habenula (Hb) and basolateral amygdala (Amyg). METH at the dose of 0.25 mg kg(-1) in particular, but not 1.00 mg kg(-1), decreased NTLI concentration in all of the LR structures studied, except for the prefrontal cortex; however, these effects were rapid and brief being observed at 5 h but not at 24 h after treatment. In all of the LR areas where NTLI levels were reduced after the low dose of METH, the effect was blocked by pretreatment with either a D1 or a D2 antagonist. Thus, opposite to high doses like those associated with abuse, the therapeutic-like low-dose METH treatment induced reduction in NT tissue levels likely reflected an increase in NT release and a short-term depletion of the levels of this neuropeptide in LR structures, manifesting features comparable to the response of basal ganglia NT systems to similar low doses of METH.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Metanfetamina/farmacología , Neurotensina/metabolismo , Animales , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Radioinmunoensayo , Ratas Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismoRESUMEN
Mephedrone (4-methylmethcathinone) is a synthetic cathinone designer drug that alters pre-synaptic dopamine (DA) activity like many psychostimulants. However, little is known about the post-synaptic dopaminergic impacts of mephedrone. The neuropeptide neurotensin (NT) provides inhibitory feedback for basal ganglia and limbic DA pathways, and post-synaptic D1 -like and D2 -like receptor activity affects NT tissue levels. This study evaluated how mephedrone alters basal ganglia and limbic system NT content and the role of NT receptor activation in drug consumption behavior. Four 25 mg/kg injections of mephedrone increased NT content in basal ganglia (striatum, substantia nigra and globus pallidus) and the limbic regions (nucleus accumbens core), while a lower dosage (5 mg/kg/injection) only increased striatal NT content. Mephedrone-induced increases in basal ganglia NT levels were mediated by D1 -like receptors in the striatum and the substantia nigra by both D1 -like and D2 -like receptors in the globus pallidus. Mephedrone increased substance P content, another neuropeptide, in the globus pallidus, but not in the dorsal striatum or substantia nigra. Finally, the NT receptor agonist PD149163 blocked mephedrone self-administration, suggesting reduced NT release, as indicated by increased tissue levels, likely contributing to patterns of mephedrone consumption.
Asunto(s)
Ganglios Basales/efectos de los fármacos , Drogas de Diseño/toxicidad , Sistema Límbico/efectos de los fármacos , Metanfetamina/análogos & derivados , Neurotensina/efectos de los fármacos , Animales , Ganglios Basales/patología , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Sistema Límbico/patología , Masculino , Metanfetamina/toxicidad , Neurotensina/análogos & derivados , Neurotensina/farmacología , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Neurotensina/agonistas , Receptores de Neurotensina/metabolismo , Autoadministración , Sustancia P/metabolismo , Sustancia P/fisiologíaRESUMEN
Preclinical studies suggest that prior treatment with escalating doses of methamphetamine (METH) attenuates the persistent deficits in hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter (SERT) function resulting from a subsequent 'binge' METH exposure. Previous work also demonstrates that brain-derived neurotrophic factor (BDNF) exposure increases SERT function. The current study investigated changes in hippocampal BDNF protein and SERT function in rats exposed to saline or METH self-administration prior to a binge exposure to METH or saline. Results revealed that METH self-administration increased hippocampal mature BDNF (mBDNF) immunoreactivity compared to saline-treated rats as assessed 24 h after the start of the last session. Further, mBDNF immunoreactivity was increased and SERT function was not altered in rats that self-administered METH prior to the binge METH exposure as assessed 24 h after the binge exposure. These results suggest that prior exposure to contingent METH increases hippocampal mBDNF, and this may contribute to attenuated deficits in SERT function.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Metanfetamina/administración & dosificación , Metanfetamina/farmacología , Animales , Hipocampo/diagnóstico por imagen , Masculino , Proteínas de Unión al ARN/metabolismo , Cintigrafía , Ratas , Autoadministración , Serotonina/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , TritioRESUMEN
Mephedrone (4-methymethcathinone) is a synthetic cathinone designer drug that disrupts central nervous system (CNS) dopamine (DA) signaling. Numerous central neuropeptide systems reciprocally interact with dopaminergic neurons to provide regulatory counterbalance, and are altered by aberrant DA activity associated with stimulant exposure. Endogenous opioid neuropeptides are highly concentrated within dopaminergic CNS regions and facilitate many rewarding and aversive properties associated with drug use. Dynorphin, an opioid neuropeptide and kappa receptor agonist, causes dysphoria and aversion to drug consumption through signaling within the basal ganglia and limbic systems, which is affected by stimulants. This study evaluated how mephedrone alters basal ganglia and limbic system dynorphin content, and the role of DA signaling in these changes. Repeated mephedrone administrations (4 × 25 mg/kg/injection, 2-h intervals) selectively increased dynorphin content throughout the dorsal striatum and globus pallidus, decreased dynorphin content within the frontal cortex, and did not alter dynorphin content within most limbic system structures. Pretreatment with D1 -like (SCH-23380) or D2 -like (eticlopride) antagonists blocked mephedrone-induced changes in dynorphin content in most regions examined, indicating altered dynorphin activity is a consequence of excessive DA signaling. Synapse 68:634-640, 2014. © 2014 Wiley Periodicals, Inc.
RESUMEN
Methylphenidate (MPD) is clinically effective in treating the symptoms of attention-deficit hyperactivity disorder; however, its relatively widespread availability has raised public health concerns on nonmedical use of MPD among certain adult populations. Most preclinical studies investigate whether presumed therapeutically relevant doses of MPD alter sensitivity to the reinforcing effects of other drugs, but it remains unclear whether doses of MPD likely exceeding therapeutic relevance impact the subsequent reinforcing effects of drugs. To begin to address this question, the effect of prior MPD self-administration (0.56 mg/kg/infusion) on the subsequent reinforcing effects of methamphetamine (METH, 0.032 or 0.1 mg/kg/infusion) was investigated in male Sprague-Dawley rats. For comparison, it was also determined whether prior experimenter-administered MPD, injected daily at a presumed therapeutically relevant dose (2 mg/kg), altered the subsequent reinforcing effects of METH. Results indicated that, under the current conditions, only a history of MPD self-administration increased sensitivity to the subsequent reinforcing effects of METH. Furthermore, MPD did not impact food-maintained responding, suggesting that the effect of MPD might be specific to drug reinforcers. These data suggest that short-term, nonmedical use of MPD might alter the positive reinforcing effects of METH in a manner relevant to vulnerability to drug use in humans.
Asunto(s)
Estimulantes del Sistema Nervioso Central/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Metanfetamina/administración & dosificación , Metilfenidato/administración & dosificación , Refuerzo en Psicología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Privación de Alimentos , Masculino , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Because of persistent social problems caused by methamphetamine (METH), new therapeutic strategies need to be developed. Thus, we investigated the response of central nervous system neurotensin (NT) systems to METH self-administration (SA) and their interaction with basal ganglia dopamine (DA) pathways. Neurotensin is a peptide associated with inhibitory feedback pathways to nigrostriatal DA projections. We observed that NT levels decreased in rats during extinction of METH SA when lever pressing resulted in intravenous infusions of saline rather than METH. Thus, 6 h after the first session of extinction, NT levels were 53, 42, and 49% of corresponding controls in the anterior dorsal striatum, posterior dorsal striatum, and globus pallidus, respectively. NT levels were also significantly reduced in corresponding yoked rats in the anterior dorsal striatum (64% of control), but not the other structures examined. The reductions in NT levels in the anterior dorsal striatum particularly correlated with the lever pressing during the first session of extinction (r =s; 0.745). These, and previously reported findings, suggest that the extinction-related reductions in NT levels were mediated by activation of D2 receptors. Finally, administration of the neurotensin receptor 1 (NTR1) agonist [PD149163 [Lys(CH2NH)Lys-Pro,Trp-tert-Leu-Leu-Oet]; 0.25 or 0.5 mg/kg] diminished lever pressing during the first extinction session, whereas the NTR1 antagonist [SR48692 [2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-imethoxyphenyl)pyrazol-3-yl)carbonylamino]tricyclo(3.3.1.1.(3.7))decan-2-carboxylic acid]; 0.3 mg/kg per administration] attenuated the reduction of lever pressing during the second to fourth days of extinction. In summary, these findings support the hypothesis that some of the endogenous basal ganglia NT systems contribute to the elimination of contingent behavior during the early stages of the METH SA extinction process.
Asunto(s)
Ganglios Basales/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Extinción Psicológica , Metanfetamina/farmacología , Neurotensina/metabolismo , Animales , Ganglios Basales/metabolismo , Estimulantes del Sistema Nervioso Central/administración & dosificación , Condicionamiento Operante , Masculino , Metanfetamina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Neurotensina/agonistas , Receptores de Neurotensina/antagonistas & inhibidores , Recompensa , AutoadministraciónRESUMEN
Preclinical models suggest that repeated high-dose methamphetamine (METH) exposures, administered in a "binge-like" pattern, acutely decrease norepinephrine (NE), and acutely and persistently decrease serotonin (5-hydroxytryptamine; 5HT) content in the frontal cortex. However, the impact of METH self-administration on this region is unknown. Because of the importance of the monoaminergic neurons in the frontal cortex to a variety of cognitive and addictive processes, effects of METH self-administration on cortical NE and 5HT content were assessed. Results revealed several novel findings. First, METH self-administration decreased cortical NE content as assessed 24 h after last exposure. Consistent with previous preclinical reports after a binge METH regimen, this decrease was reversed 8 days after the final METH exposure. Second, and in contrast to our previous reports involving the hippocampus or striatum, METH self-administration caused persistent decreases in 5HT content as assessed 8 days after the final METH exposure. Of note, the magnitude of this decrease (≈ 20%) was less than that observed typically after a binge METH treatment. Third, prior METH self-administration attenuated METH-induced serotonergic deficits as assessed 7 days, but not 1 h, following a neurotoxic METH regimen. No protection was observed when the binge exposure occurred 15 days after the last self-administration session. Taken together, these data demonstrate important and selective alterations in cortical serotonergic neuronal function subsequent to METH self-administration. These data provide a foundation to investigate complex questions involving "resistance" to the persistent deficits caused by neurotoxic METH exposure and frontal cortical function.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Metanfetamina/farmacología , Norepinefrina/deficiencia , Serotonina/deficiencia , Animales , Corteza Cerebral/química , Masculino , Metanfetamina/administración & dosificación , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Autoadministración , Serotonina/metabolismoRESUMEN
Amphetamine (AMPH) and methamphetamine (METH) alter dopamine transporter (DAT) function. In vitro heterologous cell line and synaptosome studies demonstrate AMPH-induced DAT internalization, implicating relocalization in reduced DAT uptake following drug exposure. However, few studies have evaluated DAT localization following in vivo AMPH/METH administration. To determine DAT subcellular localization following drug administration, a centrifugation technique was developed to isolate striatal synaptosomal membrane and vesicle fractions. DAT was distributed between the synaptosomal membrane (60%) and endosomal vesicles (40%), and in vitro application of the protein kinase C activator phorbol 12-myristate 13-acetate to striatal synaptosomes caused DAT internalization into the vesicle fractions. In contrast, neither single nor repeated in vivo AMPH and/or METH administrations altered DAT localization 5, 15, 30, or 60 min post-treatment, despite reduced DAT uptake. Importantly, repeated METH injections uniformly decreased total DAT immunoreactivity within all fractions 7 days post-treatment. These findings suggest that factors other than internalization can contribute to the observed acute and persistent DAT dysfunction and dopaminergic deficits following in vivo AMPH or METH administration.
Asunto(s)
Anfetamina/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/fisiología , Metanfetamina/farmacología , Animales , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Sinaptosomas/efectos de los fármacos , Sinaptosomas/fisiologíaRESUMEN
Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a "binge" treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. Accordingly, the present study investigated the impact of METH self-administration on dopaminergic neuronal function. Results revealed that self-administration of METH, given according to a regimen that produces brain METH levels comparable with those reported postmortem in human METH abusers (0.06 mg/infusion; 8-h sessions for 7 days), decreased striatal dopamine transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 days after the last self-administration session. Increasing the METH dose per infusion did not exacerbate these deficits. These deficits were similar in magnitude to decreases in DAT densities reported in imaging studies of abstinent METH abusers. It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of binge-induced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Tolerancia a Medicamentos/fisiología , Metanfetamina/administración & dosificación , Metanfetamina/farmacología , Automedicación/efectos adversos , Animales , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Condicionamiento Clásico , Cuerpo Estriado/citología , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas Dopaminérgicas/metabolismo , Relación Dosis-Respuesta a Droga , Fiebre/inducido químicamente , Masculino , Metanfetamina/metabolismo , Metanfetamina/farmacocinética , Proteínas del Tejido Nervioso/metabolismo , Ratas , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
Numerous preclinical studies have demonstrated that noncontingent methamphetamine (METH) administration rapidly decreases both dopamine (DA) transporter (DAT) and vesicular monoamine-2 transporter (VMAT-2) function. Because of the importance of transporter function to the abuse and neurotoxic liabilities of METH, and previous research indicating that the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure, the present study examined the acute impact of METH self-administration on these transporters. Results revealed that five days of METH self-administration (4 h/session; 0.06 mg/infusion) decreased DAT and VMAT-2 activity, as assessed in synaptosomes and vesicles, respectively, prepared from striatal tissue 1 h after the final self-administration session. METH self-administration increased core body temperatures as well. Brain METH and amphetamine (AMPH) levels, assessed 1 h after the final self-administration session, were approximately twice greater in high-pressing rats compared to low-pressing rats despite similar changes in DAT function. In conclusion, the present manuscript is the first to describe transporter function and METH/AMPH levels after self-administration in rodents. These data provide a foundation to investigate complex questions including how the response of dopaminergic systems to METH self-administration contributes to contingent-related processes such as dependence.
Asunto(s)
Dopaminérgicos/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Metanfetamina/farmacología , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Anfetamina/administración & dosificación , Anfetamina/farmacología , Animales , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Masculino , Metanfetamina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Autoadministración , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidoresRESUMEN
Methylphenidate (MPD) is a psychostimulant widely used to treat behavioral problems such as attention deficit hyperactivity disorder. MPD competitively inhibits the dopamine (DA) transporter. Previous studies demonstrated that stimulants of abuse, such as cocaine (COC) and methamphetamine differentially alter rat brain neurotensin (NT) systems through DA mechanisms. As NT is a neuropeptide primarily associated with the regulation of the nigrostriatal and mesolimbic DA systems, the effect of MPD on NT-like immunoreactivity (NTLI) content in several basal ganglia regions was assessed. MPD, at doses of 2.0 or 10.0 mg/kg, s.c., significantly increased the NTLI contents in dorsal striatum, substantia nigra and globus pallidus; similar increases in NTLI were observed in these areas after administration of COC (30.0 mg/kg, i.p.). No changes in NTLI occurred within the nucleus accumbens, frontal cortex and ventral tegmental area following MPD treatment. In addition, the NTLI changes in basal ganglia regions induced by MPD were prevented when D(1) (SCH 23390) or D(2) (eticlopride) receptor antagonists were coadministered with MPD. MPD treatment also increased dynorphin (DYN) levels in basal ganglia structures. These findings provide evidence that basal ganglia, but not limbic, NT systems are significantly affected by MPD through D(1) and D(2) receptor mechanisms, and these NTLI changes are similar, but not identical to those which occurred with COC administration. In addition, the MPD effects on NT systems are mechanistically distinct from the effects of methamphetamine.
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Ganglios Basales/efectos de los fármacos , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Metilfenidato/farmacología , Neurotensina/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Dinorfinas/metabolismo , Masculino , Radioinmunoensayo/métodos , Ratas , Ratas Sprague-DawleyRESUMEN
Methamphetamine (METH) dependence causes alarming personal and social damage. Even though many of the problems associated with abuse of METH are related to its profound actions on dopamine (DA) basal ganglia systems, there currently are no approved medications to treat METH addiction. For this reason, we and others have examined the METH-induced responses of neurotensin (NT) systems in the basal ganglia. This neuropeptide is associated with inhibitory feedback pathways to nigrostriatal DA projections, and NT tissue levels are elevated in response to high doses of noncontingent METH because of its increased synthesis in the striatonigral pathway. The present study reports the contingent responses of NT in the basal ganglia to self-administration of METH (SAM). Intravenous infusions of METH linked to appropriate lever-pressing behavior by rats significantly elevated NT content in both dorsal striatum (210%) and substantia nigra (202%). In these same structures, NT levels were also elevated in yoked METH animals (160 and 146%, respectively) but not as much as in the SAM rats. These effects were blocked by a D1, but not D2, antagonist. A NT agonist administered before the day 5 of operant behavior blocked lever-pressing behavior in responding rats, but a NT antagonist had no significant effect on this behavior. These are the first reports that NT systems associated with striatonigral pathway are significantly altered during METH self-administration, and our findings suggest that activation of NT receptors during maintenance of operant responding reduces the associated lever-pressing behavior.