Behavioral and neurochemical effects of neurotensin microinjection into the ventral tegmental area of the rat

Kalivas, Peter W.; Burgess, Susan; Nemeroff, Charles B.; Prange, Arthur J.

doi:10.1016/0306-4522(83)90195-1

Cited by 263 publications

(166 citation statements)

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“…The localization of CRH and its receptors within this system suggests that the peptide may have modulatory effects on dopaminergic neurotransmission. Accordingly, the administration of CRH directly into the VTA results in a timedependent decrease in prefrontal cortical dopamine metabolism with an increase in dopamine turnover in the nucleus accumbens (Kalivas et al 1987). This general pattern of dopaminergic neurotransmission has previously been associated with an enhanced vulnerability to engage in psychomotor stimulant self-adminis-tration (Piazza et al 1991;Goeders and Smith 1993).…”

Section: Discussionmentioning

confidence: 99%

“…However, the effects of intra-VTA CRH are very different from those reported following the icv administration of the peptide. ICV CRH has little or no effect on dopamine in the nucleus accumbens (Kalivas et al 1987;Dunn and Berridge 1990) and actually increases dopamine metabolism in the medial prefrontal cortex (Dunn and Berridge 1990). Nevertheless, in consideration of the putative dual role for the medial prefrontal cortex in the neurobiological response to stress as well as in the initiation of cocaine-seeking behavior (Goeders and Smith 1983;Goeders 1997), it is likely that CRHinduced alterations in dopaminergic neurotransmission play an important role in this peptide's effects on cocaine responsiveness.…”

Section: Discussionmentioning

confidence: 99%

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Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Goeders

Guerin

2000

Neuropsychopharmacology

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The role for corticotropin-releasing hormone (CRH) receptors in the maintenance of intravenous cocaine self-administration in rats was investigated using the centrally active, small molecule CRH1 receptor antagonist 526. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine selfadministration (0.125, 0.25 Self-administration; Rat During the past several years, research from our laboratory has focused on the potential involvement of the hypothalamic-pituitary-adrenal (HPA) axis in cocaine reinforcement. The HPA axis consists of a complex, well-regulated interaction between the brain, the anterior pituitary gland, and the adrenal cortex. The initial step in the activation of the HPA axis is the neuronally regulated secretion of the peptide corticotropin-releasing hormone (CRH) from the parvocellular division of the paraventricular nucleus (PVN) of the hypothalamus. CRH is released by the hypothalamus into the adenohypophyseal portal circulation to act on the pituitary to induce the secretion of adrenocorticotropin hormone (ACTH). ACTH diffuses through the general circulation until it reaches the adrenal glands. There it stimulates the biosynthesis of adrenocorticosteroids, most notably the glucocorticoids, cortisol (in humans) and corticosterone (in rats), which results in their secretion from the adrenal cortex.Cocaine has been reported to stimulate HPA axis activity in a manner analogous to various stressors, which indicates that this system has the potential to influence many of the neurochemical and behavioral effects of the drug. For example, the acute administration of cocaine dose-dependently increases plasma concentrations of corticosterone, ACTH, and ␤ -endorphin in rats (Moldow and Fischman 1987;Rivier and Vale 1987;Borowsky and Kuhn 1991). Cocaine also stimulates the release of ACTH and cortisol in humans (Mendelson et al. 1989;Baumann et al. 1995) and non-human primates (Sarnyai et al. 1996) by increasing the peak amplitude of secretory pulses of these hormones without altering pulse frequency, suggesting that these increases are driven by hypothalamic CRH (Mendelson et al. 1989;Teoh et al. 1994;Sarnyai et al. 1996). Cocaine-induced increases in ACTH and corticosterone in rats can be blocked by pretreatment with the CRH antagonist ␣ -helical CRF 9-41 (Sarnyai et al. 1992a), by immunoneutralization of CRH with an anti-CRH antibody (Rivier and Vale 1987;Sarnyai et al. 1992a), or by bilateral electrolytic lesions of the PVN (Rivier and Lee 1994), indicating that these increases are also mediated by the cocaine-induced release of CRH from parvocellular neurons in the PVN. Accordingly, it has been reported that cocaine administration also results in increases in hypothalamic CRH mRNA (Zhou et al. 1996;Rivier and Lee 1994) and alters CRH receptor binding measured autoradiographically in various regions of the rat brain (Goeders et al. 1990). These data suggest that the complex relationship between cocaine reinforcement and cort...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Goeders

Guerin

2000

Neuropsychopharmacology

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“…Previous studies have shown that exogenous NT can exert opposite effects, depending on whether it is administered in the cell body region or in the projection areas of dopaminergic neurons. Injection of NT into the VTA increases locomotor activity as well as dopamine metabolism and release in the nucleus accumbens (Kalivas et al 1983;Ford and Marsden 1990;Kalivas and Duffy 1990a;Rivest et al 1991). Conversely, when injected into the nucleus accumbens or the cerebral ventricles, NT reduces the hyperactivity elicited by cocaine and amphetamine (Ervin et al 1981;Robledo et al 1993).…”

Section: Discussionmentioning

confidence: 99%

“…The microinjection of NT into the VTA increases locomotion and rearing (Kalivas et al 1983) and enhances dopamine release in the nucleus accumbens (Kalivas and Duffy 1990a). NT also has reinforcing properties, as indicated by studies showing that rats self-administer NT into the VTA (Glimcher et al 1987) and that administration of NT in the same region induces a conditioned place preference (Glimcher et al 1984).…”

Section: Introductionmentioning

confidence: 99%

“…The inhibitory effect of SR 48692 on cocaine-induced motor activity and dopamine release could be mediated via NT receptors located either presynaptically on dopaminergic terminals in the nucleus accumbens or on dopaminergic cell bodies in the VTA. The ability of exogenous NT to stimulate dopaminergic transmission when applied directly on dopamine neurons in the VTA (Kalivas et al 1983; Kalivas and Duffy 1990a) favors the latter possibility. Consistent with this hypothesis, the VTA of the rat brain contains a high density of NT-and dopamine-containing neuronal perikarya, as well as a high density of NT receptors, located predominantly on dopaminergic neurons (Hökfelt et al 1984;Szigethy and Beaudet 1989).…”

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Role of Endogenous Neurotensin in the Behavioral and Neuroendocrine Effects of Cocaine

Betancur¹,

Cabrera²,

Kloet³

et al. 1998

Neuropsychopharmacology

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of endogenous neurotensin in the behavioral and neuroendocrine effects of cocaine.. Neuropsychopharmacology, Nature Publishing Group, 1998, 19 (4), pp.322-32. <10.1016/S0893-133X(98)00028-1>. Role of Endogenous Neurotensin in the Behavioral and Neuroendocrine Effects of CocaineCatalina Betancur, M.D., Ph.D., Ricardo Cabrera,* Ph.D., E. Ronald de Kloet, Ph.D., Didier Pélaprat, Ph.D., and William Rostène, Ph The present experiments were designed to assess the role of endogenous neurotensin (NT) in the behavioral response to acute and daily cocaine, after administration of the NT receptor antagonist, SR 48692. Given that glucocorticoids increase the sensitivity to the psychomotor effects of drugs of abuse, we also investigated the effects of SR 48692 on basal and cocaine-induced corticosterone secretion. Acute administration of SR 48692 (1 mg/kg IP) reduced the number of rearings induced by cocaine (15 mg/kg IP), without modifying horizontal activity. Repeated pretreatment with SR 48692 (1 mg/kg x 5 days) markedly reduced locomotion and rearings after an acute cocaine challenge (day 1), whereas the lower dose of SR 48692 (0.1 mg/kg) had no effect. SR 48692 (1 mg/kg), given daily before cocaine, also decreased cocaine-induced rearing on day 2, but had no effect on the following drug challenges (days 3-10). One week after discontinuing repeated cocaine injections, SR 48692 blocked vertical, but not horizontal, activity induced by an acute cocaine challenge. Rats treated repeatedly with cocaine showed an enhanced behavioral response characterized by the development of stereotypies, which were unaffected by SR 48692. Finally, treatment with SR 48692 did not alter corticosterone circadian secretion nor cocaine-stimulated corticosterone levels, indicating that the attenuation of the behavioral effects of cocaine after NT receptor blockade is not associated with blunted glucocorticoid secretion. These results indicate that administration of SR 48692 attenuates the locomotion and rearing response to cocaine but fails to modify stereotyped behavior, suggesting that SR 48692 modulates the behavioral effects of psychostimulant drugs by acting selectively on the mesolimbic dopaminergic system. Betancur et al. 2 INTRODUCTIONCocaine is a potent psychostimulant drug that binds to the dopamine transporter and blocks dopamine re-uptake, leading to increased extracellular levels of dopamine (Kuhar et al. 1991). The mesolimbic dopaminergic system is considered the main substrate for the motor stimulant and reinforcing effects of cocaine and other drugs of abuse (Koob 1992). Several lines of evidence suggest that neurotensin (NT), a neuropeptide closely associated with dopaminergic systems, both anatomically and functionally (Kasckow and Nemeroff 1991), may be involved in the behavioral effects of cocaine. First, cocaine and other psychostimulants such as amphetamine induce a pronounced increase in NT peptide content (Cain et al. 1993;Gygi et al. 1994) and NT mRNA expression (Castel et al. 1994;Merchant et al. 1994;...

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Neuroblastoma in adolescents

Conte

Parodi

Bernardi

et al. 2006

Cancer

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BACKGROUNDNeuroblastoma (NB) occurs rarely during adolescence, and information is scarce on its characteristics and clinical course in this age group.METHODSPatients with NB who were included in the Italian Neuroblastoma Registry were considered for the current study. The clinical characteristics and survival of adolescents (age at diagnosis between 10 yrs and 18 yrs) were compared with those of children (ages 1–9 yrs). Infants (age < 1 yr) were excluded because of their well known favorable clinical course.RESULTSBetween 1116 children and 53 adolescents who were evaluated, no differences were documented with regard to the primary tumor site and the prevalence of advanced stage at diagnosis. If only patients with Stage IV NB were considered, then adolescents were less likely to be diagnosed with bone/bone marrow metastases (77%) compared with children (94%; P = 0.038), but adolescents were more likely to have metastases at unusual sites, such as the lung parenchyma or the central nervous system (23% vs. 7%, respectively; P = 0.005). With regard to biologic characteristics, adolescents did not differ significantly from children, although they always had a lower prevalence of unfavorable markers. In particular, MYCN amplification was documented in 21% of children and in 11% of adolescents (P = 0.173). At age 10 years, adolescents had a 20% overall survival rate and a 22% event‐free survival rate. Adolescents who had resectable disease had a 73% overall survival rate, which was worse compared with the rate among children with the same disease stage (89%), although the difference did not reach statistical significance (P = 0.159). No differences in survival were observed among patients with Stage IV NB, and adolescents had a probability of survival almost identical to that among children (6% vs. 16%, respectively; P = 0.481). However, when the analysis was restricted to events that occurred after patients developed a recurrence, even if the final outcome was poor for both groups, the difference was statistically significant (P = 0.022) mostly because of the more indolent disease course observed among the adolescents. This effect was even more evident for patients with Stage IV NB. When the 6‐year cut‐off point was used to separate children from adolescents, a significantly worse overall survival rate (P = 0.036) was documented for adolescents who had resectable disease (81% vs. 93% in children).CONCLUSIONSNB in adolescents had clinical and biologic characteristics similar to those observed among children. The clinical course of NB probably is correlated significantly with age at diagnosis, but information is scarce on the role of the biologic risk factors in this age group. The authors were able to identify a group of patients with a cut‐off age between 6 years and 10 years that had a more indolent course but a worse prognosis. Cancer 2006. © 2006 American Cancer Society.

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Behavioral and neurochemical effects of neurotensin microinjection into the ventral tegmental area of the rat

Cited by 263 publications

References 30 publications

Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Role of Endogenous Neurotensin in the Behavioral and Neuroendocrine Effects of Cocaine

Neuroblastoma in adolescents

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