Role of drug-associated environmental stimuli in the development of cross-tolerance to the tachycardic effects of nicotine and alcohol in humans. / Papel de los estímulos ambientales asociados a la droga en el desarrollo de tolerancia cruzada a los efectos de taquicardia de la nicotina y el alcohol en humanos.

According to the Pavlovian conditioning model, drug tolerance is modulated by drug-associated environmental cues. This study evaluated the contribution of drug-associated cues in the development of cross-tolerance to the tachycardic effects of nicotine from tobacco and alcohol in human subjects. Forty undergraduate students were recruited for this experiment, and each student was randomly assigned to one of two experimental conditions. Twenty students smoked nicotine-containing cigarettes in context A and placebo cigarettes in context B, and twenty students smoked nicotine-containing cigarettes in context B and placebo cigarettes in context A. A cross-tolerance test was carried out by dividing the subjects in each condition into two subgroups (n = 10). Each subgroup consumed alcohol in both contexts (A and B). The results of this experiment showed that cross-tolerance between nicotine and alcohol was exhibited only if the cross-tolerance test was carried out in the same context where tolerance had developed to the nicotine from tobacco. These results support the hypothesis that drug-associated environmental stimuli play a modulatory role in the development of cross-tolerance between nicotine from tobacco and alcohol.

De acuerdo con el modelo de condicionamiento pavloviano, las claves ambientales asociadas a la droga modulan la tolerancia a las drogas. Este estudio evaluó la contribución de las claves asociadas a la droga en el desarrollo de tolerancia cruzada a los efectos taquicárdicos de la nicotina de tabaco y el alcohol en sujetos humanos. En este experimento participaron cuarenta estudiantes universitarios. Cada estudiante fue asignado aleatoriamente a una de dos condiciones experimentales. Veinte estudiantes fumaron cigarros con nicotina en el Contexto A y placebo en el Contexto B y veinte estudiantes fumaron cigarros con nicotina en el Contexto B y placebo en el Contexto A. La prueba de tolerancia cruzada fue llevada a cabo dividiendo a los participantes de cada condición en dos subgrupos (n = 10), cada subgrupo consumió alcohol en cada uno de los contextos (A y B). Los resultados de este experimento muestran que la tolerancia cruzada entre nicotina y alcohol se presentó únicamente cuando la prueba de tolerancia cruzada se realizó en el mismo contexto donde se desarrolló la tolerancia a la nicotina del tabaco. Estos resultados concuerdan con la hipótesis de que los estímulos ambientales asociados a la droga juegan un papel modulador en el desarrollo de la tolerancia cruzada entre la nicotina del tabaco y el alcohol.

Administration of low doses of the 5-HT1A receptor agonist 8-OH-DPAT attenuates the discriminative signal of amphetamine in the conditioned taste aversion procedure.

Several studies have reported that low doses of the 5-HT1A receptor agonist 8-OH-DPAT reduce cocaine-induced locomotor activity. However, it has also been reported that high doses of 8-OH-DPAT do not substitute for or alter the discriminative signal of cocaine (COC) or amphetamine (AMPH). This study aimed to evaluate the effects of low and high doses of the 5-HT1A agonist 8-OH-DPAT on the discriminative signal of AMPH using conditioned taste aversion as a drug discrimination procedure. Additionally, to establish a correlation between the behavioral effects in drug discrimination and changes in dopamine (DA) and gamma-aminobutyric acid (GABA) concentrations, we evaluated the effect of systemic administration of low or high doses of the 5-HT1A receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist WAY100135 on DA and GABA extracellular concentrations in the nucleus accumbens (nAcc) and ventral tegmental area (VTA), respectively, using cerebral microdialysis. The behavioral results showed that low but not high doses of 8-OH-DPAT produced a reduction in the AMPH-induced discriminative signal, while WAY100135 administration prevented such effects. The microdialysis results showed that a low dose of 8-OH-DPAT decreased extracellular DA concentrations in the nAcc and increased GABA concentrations in the VTA. Pretreatment with WAY100135 prevented these effects. These data support the hypothesis that 5-HT1A receptors modulate the behavioral effects of psychostimulant drugs, such as AMPH, through somatodendritic 5-HT1A autoreceptors in the raphe nucleus indicating that 5-HT1A receptors may be an important target for the development of pharmacological treatments for psychostimulant addiction.

Effect of coadministration of the GABAB agonist baclofen and the 5-HT2C agonist Ro60-0175 on the expression of amphetamine-induced locomotor sensitization.

GABAB and 5-HT2C agonists are effective in attenuating the behavioral effects of psychostimulants. However, they induce adverse side effects when used in high doses. The previous evidence has suggested that the 5HT2C receptor activation effect could be produced by an increased release of GABA in the ventral tegmental area (VTA) and the consequent activation of GABAergic receptors. Therefore, the objective of this study was to evaluate the effects of joint administration of an intermediate dose of the GABAB agonist baclofen (3.0 mg/kg) with different doses of the 5HT2C agonist Ro60-0175 (0.3, 1.0, and 3.0 mg/kg) on the locomotor sensitization expression induced by the repeated administration of amphetamine (1.0 mg/kg). Our results showed an attenuation of the expression of sensitization in a dose-dependent manner with both agonists. In both cases, we observed a complete blockade at the highest dose. In addition, the intermediate dose of baclofen increased the effects of the three doses of Ro60-0175. These results support the role of the joint action of GABAB and 5-HT2C receptors in the effects of psychostimulants. However, it remains to be explored whether the observed effect can be attributed to receptors located in the VTA or the nucleus accumbens.

Mental nerve injury induces novelty seeking behaviour leading to increasing ethanol intake in Wistar rats.

OBJECTIVE: Dental treatment and orofacial surgeries may induce chronic neuropathic orofacial pain (CNOP). This kind of pain affects adaptability to environmental changes in both model animals and humans. Part of the adaptation process depends on the ability to distinguish between familiar and novel stimuli. CNOP induces novelty seeking behaviour as a deficit in environmental adaptation. Alternatively, novelty seeking is a sign for susceptibility to the development of substance abuse. Evidence shows that CNOP leads to alcoholism in animal models. The behavioural relationship between CNOP, novelty seeking behaviour and substance abuse is unknown. In this article, we investigate if CNOP produces an increase in novelty seeking and leads to increasing ethanol intake. DESIGN: Firstly, we used mental nerve injury as a neuropathic orofacial pain model to evaluate both thermal and mechanical allodynia. We used the novel recognition task to determine novelty seeking behaviour and the drink in darkness protocol to assess ethanol intake. RESULTS: Our results show that mental nerve constriction increases novelty seeking behaviour (p = 0.01) and correlates with ethanol binge consumption (r2 = 0.68, p = 0.0008). CONCLUSIONS: The present study demonstrates, for the first time, that trigeminal nerve injury, which induces CNOP, is enough to provide novelty seeking behaviour and lead to increasing ethanol intake. The increase of novelty seeking behaviour can serve as a predictor of risk of developing substance abuse. The treatment of CNOP involves a high risk of producing addiction. The level of novelty seeking evaluation in patients with neuropathic pain before treatment is critical.

Multidimensional study of orofacial chronic neuropathic pain: an experimental study in rats

Orofacial neuropathic chronic pain (NCP) is frequently attributed to lesions caused by orofacial surgeries and dental treatments. there are many experimental models available to study orofacial NCP, however, many are extremely painful for the animal due to the amplitude of the innervated region. a previously proposed mental nerve constriction model, mNC, was used in this project. forty wistar rats were randomly divided into two groups: one group included rats with mNC (n=20), and another rats with sham lesions (n=20). through the use of the fixed ratio program and the progressive program, a decrease of motivation for a sweet substance, caused by the lesion, was evaluated. the possibility of alterations in cognitive learning and adaptation abilities was also assessed using the go/no-go behavioral task. the mNC group showed low induced and spontaneously evoked pain responses, as well as a decrease in the motivation for sucrose, a sign of anhedonia. this decrease does not depend on taste processing. finally, although no alterations in the learning-memory process were observed, the mNC group did show alterations when adapting to a new rule.

El agonista del receptor de serotonina-2C Ro 60-0175 decrementa la expresión de la sensibilización locomotora inducida por etanol / Serotonin-2C receptor agonist Ro 60-0175 decreases the expression of ethanol-induced locomotor sensitization

Resumen: El objetivo principal de la presente investigación fue evaluar los efectos del agonista 5-HT2C Ro 60-0175 en la expresión de la sensibilización locomotora inducida por la administración de etanol. Además, también se evaluaron los efectos del antagonista 5-HT2C SB 242084 sobre los efectos del Ro 60-0175 en la sensibilización locomotora producida por etanol para determinar si los efectos del Ro 60-0175 resultan de una acción específica sobre los receptores 5-HT2C. Diferentes grupos de ratas se sometieron al desarrollo de sensibilización locomotora producida por etanol. En las pruebas de expresión de la sensibilización locomotora se evaluaron los efectos del Ro 60-0175 y del SB 242084 sobre la sensibilización locomotora producida por etanol. Adicionalmente se evaluó el pretratamiento con SB 242084 sobre los efectos del Ro 60-0175 en la sensibilización locomotora producida por etanol. Los resultados mostraron que el Ro 60-0175 disminuyó la sensibilización locomotora producida por etanol y que este efecto fue prevenido por el pretratamiento con SB 242084. Estos resultados sugieren que los receptores 5-HT2C juegan un papel modulatorio en la sensibilización locomotora producida por etanol.

Abstract: The main goal of the present research was to evaluate the effects of 5-HT2C receptor agonist Ro 60-0175 on the expression of ethanol-induced locomotor sensitization. In order to determine if these effects result from a specific action of Ro 60-0175 on 5-HT2C receptors, we also examined the effects of the selective 5-HT2C receptor antagonist SB 242084 on Ro 60-0175's effects on the ethanol-induced locomotor sensitization. Different groups of rats were subjected to development of ethanol-induced locomotor sensitization. On the expression tests of the locomotor sensitization the effects of the Ro 60-0175 and SB 242084 on the ethanol-induced locomotor sensitization were evaluated. In addition, the pretreatment with SB 242084 on the effects of Ro 60-0175 on the ethanol-induced locomotor sensitization was also evaluated. The results showed that Ro 60-0175 produced a dose-dependent prevention of the expression of ethanol-induced locomotor sensitization. This effect was reversed by administration of SB 242084. These data suggest that 5-HT2C receptors play a regulatory role on ethanol-induced locomotor sensitization.

La administración del antagonista GABA A bicuculina previene los efectos de la administración del agonista 5-HT 1A 8-OH-DPAT en las propiedades discriminativas de la anfetamina / Administration of GABA A receptor antagonist bicuculline prevents the effects of administration of 5-HT 1A receptor agonist on the discriminative properties of amphetamine

Resumen En esta investigación se evaluaron los efectos de la administración sistémica del antagonista GABAA bicuculina sobre los efectos del agonista 5-HT1A 8-OH-DPAT en las propiedades discriminativas de la anfetamina (ANF) utilizando el condicionamiento de aversión a los sabores. Los resultados mostraron que ni el 8-OH-DPAT, ni la bicuculina, sustituyeron la señal discriminativa de la ANF. Sin embargo, la administración del 8-OH-DPAT disminuyó la señal discriminativa de la ANF, y la administración de la bicuculina, previa a la administración del 8-OH-DPAT más una dosis de ANF, previno el efecto del 8-OH-DPAT sobre la señal discriminativa de la ANF. Estos datos apoyan la hipótesis de que las conductas relacionadas con la adicción a las drogas, como la ANF, involucran diferentes sistemas de neurotransmisión como la DA, la 5-HT y el GABA.

Abstract In this research, the effects of systemic administration of the GABAA receptor antagonist bicuculline on the effects of 5-HT1A receptor agonist 8-OH-DPAT on the discriminative properties of the AMPH using the conditioned taste aversion procedure were evaluated. The results showed that neither 8-OH-DPAT nor bicuculline administration did not substitute for AMPH. However, the 8-OH-DPAT administration decreased the discriminative signal of AMPH and the bicuculline administration, prior to the 8-OH-DPAT administration plus a dose of AMPH prevented the effect of the 8-OH-DPAT on discriminative signal of AMPH. These data support the hypothesis that addiction-related behaviors of drugs such as AMPH involve several neurotransmitter systems such as DA, 5-HT and GABA.

Effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric modulator of the GABAB receptor, CGP7930, on the development and expression of amphetamine-induced locomotor sensitization in rats.

BACKGROUND: Several of the behavioral effects of amphetamine (AMPH) are mediated by an increase in dopamine neurotransmission in the nucleus accumbens. However, evidence shows that γ-aminobutyric acid B (GABAB) receptors are involved in the behavioral effects of psychostimulants, including AMPH. Here, we examined the effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric modulator of the GABAB receptor, CGP7930, on AMPH-induced locomotor sensitization. METHODS: In a series of experiments, we examined whether baclofen (2.0, 3.0 and 4.0 mg/kg), CGP7930 (5.0, 10.0 and 20.0 mg/kg), or co-administration of CGP7930 (5.0, 10.0 and 20.0 mg/kg) with a lower dose of baclofen (2.0 mg/kg) could prevent the development and expression of locomotor sensitization produced by AMPH (1.0 mg/kg). RESULTS: The results showed that baclofen treatment prevented both the development and expression of AMPH-induced locomotor sensitization in a dose-dependent manner. Furthermore, the positive allosteric modulator of the GABAB receptor, CGP7930, increased the effects of a lower dose of baclofen on AMPH-induced locomotor sensitization under both conditions. CONCLUSION: These data provide further evidence that GABAB receptor ligands may modulate psychostimulant-induced behaviors.

The GABA-B antagonist 2-hydroxysaclofen reverses the effects of baclofen on the discriminative stimulus effects of D-amphetamine in the conditioned taste aversion procedure.

Some of the behavioral effects of d-amphetamine (d-AMPH) are mediated by an increase in dopamine neurotransmission in the nucleus accumbens. However, there is evidence that gamma-amino-butyric-acid-B (GABA-B) receptors are involved in some behavioral effects of D-AMPH and cocaine. Here, we examined the effects of baclofen on the discriminative stimulus properties of D-AMPH, using conditioned taste aversion (CTA) as the drug discrimination procedure. Male Wistar rats were deprived of water and trained in the CTA procedure. They received D-AMPH (1 mg/kg, i.p.) before gaining access to saccharin, which was followed by an injection of LiCl. On alternate days, the subjects received saline before and after the access to saccharin. After the rats learned the D-AMPH-saline discrimination, the standard dose of D-AMPH was replaced by different doses of D-AMPH, baclofen (a GABA-B receptor agonist), 2-hydroxysaclofen (a GABA-B receptor antagonist), a combination of baclofen+D-AMPH, or a combination of 2-hydroxysaclofen+baclofen+D-AMPH. Baclofen did not substitute for D-AMPH, but, when combined with D-AMPH, it produced a small but significant decrease in the discriminative stimulus effects of D-AMPH. This effect was reversed by administration of 2-hydroxysaclofen. These data suggest that GABA-B receptors play a regulatory role in the discriminative stimulus effects of D-AMPH.

Modulatory role of 5-HT1B receptors in the discriminative signal of amphetamine in the conditioned taste aversion paradigm.

Drugs of abuse, such as amphetamine (AMPH), share the ability to activate the mesolimbic dopamine (DA) system. The behavioral effects of AMPH are largely mediated by increased DA neurotransmission in the nucleus accumbens. However, there is evidence that serotonin (5-hydroxytryptamine - 5-HT) systems may regulate forebrain DA function. We examined the role of 5-HT1B receptors on the discriminative stimulus properties of AMPH using conditioned taste aversion (CTA) as the drug discrimination procedure. Male Wistar rats were deprived of water and trained in the CTA procedure. They received the administration of AMPH (1.0 mg/kg) before a 10 min period of access to saccharin solution and followed by an injection of LiCl; on alternate days, rats received saline before and after the access to saccharin solution. In generalization and combination tests, the training dose of AMPH was substituted by 5-HT1B receptor ligands RU24969 (5-HT1B agonist: 0.1, 0.3 and 1.0 mg/kg), CP94253 (5-HT1B agonist: 1.0, 3.0 and 5.6 mg/kg) and GR127935 (5-HT1B antagonist: 0.3, 1.0 and 3.0 mg/kg) or a combination of RU24969 (0.1, 0.3 and 1.0 mg/kg), CP94253 (1.0, 3.0 and 5.6 mg/kg) or GR127935 (0.3, 1.0 and 3.0 mg/kg) with AMPH (0.3 mg/kg) or GR127935 (0.3, 1.0 and 3.0 mg/kg) and CP94253 (5.6 mg/kg) with AMPH (0.3 mg/kg). The results showed that 5-HT1B agonists RU24969 and CP94253 produced partial generalization of 48% and 60%, respectively, and the 5-HT1B antagonist GR127935 neither substituted for AMPH nor affected the discriminative cue of AMPH; however, when RU24969 or CP94253 were administrated in combination with AMPH, they increased the discriminative cue of AMPH. This effect was reversed by the administration of 5-HT1B antagonist GR127935. These data suggest that 5-HT1B receptors play a modulatory role in the discriminative cue of AMPH.