Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

Negus, S. Stevens; Miller, Laurence L.

doi:10.1124/pr.112.007419

Cited by 203 publications

(305 citation statements)

References 373 publications

(536 reference statements)

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“…Moreover, selectivity of these MCAT analogs in both in vitro and in vivo neurochemical procedures correlates both with 1) the volume of the para substituent on the MCAT scaffold, and 2) the efficacy to produce abuserelated behavioral effects in an ICSS procedure Sakloth et al, 2015). Given the positive correlation between ICSS facilitation and other preclinical and clinical measures of abuse potential (Negus and Miller, 2014), the present results provide evidence for a mechanism whereby molecular features of a drug molecule (in this case the steric volume of the para substituent of the MCAT scaffold) can determine neurochemical selectivity to act at DAT and SERT and ultimately influence behavioral measures of abuse potential. Fig.…”

Section: Discussionmentioning

confidence: 99%

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Suyama

Sakloth

Kolanoś

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuserelated behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH 3, and 4-OCH 3 ) produced dose-and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r 5 0.89, P 5 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r 5 0.95, P , 0.01); and 3) molecular volume of the para substituent (r 5 20.85, P 5 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.

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Section: Discussionmentioning

confidence: 99%

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Suyama

Sakloth

Kolanoś

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Utilizando este tipo de paradigma, los animales realizan una respuesta operante que les permite autoadministrarse cortos pulsos eléctricos en diferentes áreas cerebrales relacionadas con el refuerzo (Koob et al, 2014;Negus y Miller, 2014), ya que generalmente los electrodos están colocados en el haz prosencefálico medial a nivel del hipotálamo lateral o en el núcleo accumbens, áreas pertenecientes al sistema de recompensa cerebral. Se manipula la frecuencia o la amplitud de la estimulación de estas estructuras para generar una amplia gama de tasa de respuesta (Negus y Miller, 2014).…”

Section: Autoestimulación Eléctrica Intracraneal (Aeic)unclassified

“…Se manipula la frecuencia o la amplitud de la estimulación de estas estructuras para generar una amplia gama de tasa de respuesta (Negus y Miller, 2014). Se sabe que la administración aguda de drogas disminuye el umbral de AEIC de forma que el animal necesita menor estimulación para percibir la sensación reforzante, mientras que la abstinencia los aumenta (Koob et al, 2014;Negus y Miller, 2014). Esto significa que si una droga disminuye el umbral de AEIC es porque se trata de una droga con un alto poder reforzante, pues los animales no necesitan tanta estimulación para sentir el refuerzo.…”

Section: Autoestimulación Eléctrica Intracraneal (Aeic)unclassified

Modelos animales de adicción a las drogas

et al. 2017

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Resumen Abstract adicciones vol. 29, nº 4 · 2017 revisión Modelos animales de adicción a las drogas Animal Models of Drug AddictionMaría Pilar García Pardo*,**; Concepción Roger Sánchez*; José Enrique de la Rubia Ortí**; María Asunción Aguilar Calpe*. En los últimos años los modelos han incorporado modificaciones metodológicas para incluir el estudio de los procesos de extinción, reinstauración y reconsolidación o para modelar aspectos concretos de la conducta adictiva como puede ser la motivación para consumir la droga, el consumo compulsivo o la búsqueda de la droga bajo situaciones de castigo. Otros modelos interrelacionan diferentes componentes del refuerzo o modelan la motivación voluntaria por consumir (modelos de "two-bottle choice" o "drinking in the dark").En definitiva, las innovaciones en estos modelos contribuyen al avance en el conocimiento científico de los diferentes factores que llevan a tomar una droga y a desarrollar un consumo compulsivo, ofreciendo una vía para identificar futuros tratamientos para la adicción.Palabras clave: Refuerzo; Adicción; Modelos animales; Drogas de abuso.

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“…Реакция самостимуляции латерального гипо-таламуса у крыс является одной из перспективных моделей для изучения фармакологических препара-тов, потенциально способных купировать развитие патологических зависимостей [4].…”

Section: Introductionunclassified

“…Известно, что при активации дофаминергической системы фенамином происходит значительное уси-ление реакции самостимуляции [4]. В наших преды-дущих исследованиях показано, что локальное вве-дение препарата SB-408124 в ядро ложа конечной полоски (ЯЛКП) блокирует это поведение [2].…”

Section: Introductionunclassified

Blockade of orexin receptors in the bed nucleus of stria terminalis increases serotonin level only in the left hypothalamus

Karpova

Владимировна²,

Bychkov

et al. 2018

Rev Clin Pharm Drug Ther

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The aim of investigation was to study the role of the hypothalamic serotoninergic system in mechanisms of blocking action of the orexin receptor antagonist on amphetamine-induced self-stimulation in rats. Methods. 27 male Wistar rats weighing 250-300 g were the object of the investigation. One week before the experiment, the microelectrodes were implanted into the lateral hypothalamus for self-stimulation and microcannulas into the bad nucleus of stria terminalis (BNST) for microinjections. The electrodes were implanted bilaterally and cannulas unilaterally (right or left). Intact rats and rats treated with amphetamine were controls. On the day of the experiment, amphetamine 1 mg/kg i.p. was injected, and then SB-408124 1 µg in 1 µl was administered into the BNST in 10 min. The rats were decapitated in 15 min after microinjection of SB-408124. The level of serotonin (Ser) and its metabolite 5-HIAA was determined in the right and the left hypothalamus by HPLC with electrochemical detection. Results. In intact rats, the 5-HIAA level in the left hypothalamus was higher than in the right one (p < 0.05). After systemic administration of amphetamine the ratio of 5-HIAA/Ser was significantly decreased both in the left (p < 0.05) and the right (p < 0.05) hypothalamus. The levels of Ser and 5-HIAA stated symmetrical. It is important that effects of orexin antagonist after amphetamine administration appeared only on the side contralateral to microinjection being significantly only in the left hypothalamus. After administration of orexin antagonist into the right BNST, the level of Ser in the left hypothalamus increased compared both to intact rats (p < 0.05) and rats treated with amphetamine (p < 0.05). Conclusion. The results suggest that the left hypothalamus plays a leading role in developing of self-stimulation reaction and support the hypothesis that the serotoninergic system is involved in mechanism of blocking action of orexin receptors antagonist on self-stimulation activated with amphetamine. (For citation: Karpova IV, Bychkov ER, Lebedev AA, Shabanov PD. Blockade of orexin receptors in the bed nucleus of stria terminalis increases serotonin level only in the left hypothalamus. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(2):33-36. doi: 10.17816/RCF16233-36).

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Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

Cited by 203 publications

References 373 publications

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Modelos animales de adicción a las drogas

Blockade of orexin receptors in the bed nucleus of stria terminalis increases serotonin level only in the left hypothalamus

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