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L Stinus

Publications and source records attributed to L Stinus.

At least 37 records · Page 2Linked to original sources
PubMed1996

Evidence for selective involvement of dopamine D1 receptors of the ventral tegmental area in the behavioral sensitization induced by intra-ventral tegmental area injections of D-amphetamine.

The induction of behavioral sensitization to D-amphetamine (AMPH) is known to result at least in part from an action of the drug in the ventral tegmental area (VTA), which contains the dopamine (DA) A10 cell bodies. To specify the cellular mechanisms through which AMPH acts in the VTA and leads to behavioral sensitization after repeated intra-VTA injections, the involvement of VTA DA D1 and D2 and serotonin2 receptors in this phenomenon was investigated in independent experiments. The results reported here confirm that repeated intra-VTA AMPH injections (four injections of 5 micrograms/0.5 microliter every other day) induce behavioral sensitization, as revealed by the potentiation of the locomotor response to peripheral challenges with AMPH (0.5 mg/kg) 4 or 15 days after treatment. This behavioral sensitization induced by intra-VTA administration of AMPH cross-reacts with morphine (1 microgram/0.5 microliter) administered into the VTA 7 days after treatment. We demonstrated that the D1 receptor antagonist (R)-(+)-8-chloro-2,3,4, 5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (0, 0.01, 0.1 and 1 microgram/ 0.5 microliter) coadministered in the VTA with AMPH dose-dependently prevents the behavioral sensitization to peripheral AMPH challenges (at either 4 or 15 days after treatment) as well as the cross-sensitization with intra-VTA morphine. Neither DA D2 nor serotonin2 receptor blockade, using sulpiride (10 micrograms/0.5 microliters) and ketanserin (1 micrograms/0.5 microliters), respectively, had any effect on the induction of behavioral sensitization. In conclusion, these results demonstrate the selective involvement of VTA DA D1 receptors in the process by which AMPH acts in the VTA to induce behavioral sensitization.

Animals↗
PubMed1995

Short and long-term changes in dopamine and serotonin receptor binding sites in amphetamine-sensitized rats: a quantitative autoradiographic study.

The biochemical changes in DA and 5HT systems were investigated in amphetamine (AMPH)-sensitized rats, 1 and 15 days after cessation of treatment (5 mg/kg AMPH, i.p., twice a day for 6 days). At both times, AMPH-treated rats exhibited behavioral sensitization, as revealed by an enhancement of the stereotypic response to a challenge dose of 2 mg/Kg, ip. AMPH. Basal dopamine (DA) and serotonin (5-HT) metabolism was not significantly modified in different brain areas of AMPH-sensitized rats. Quantitative autoradiographic analysis of DA and serotonin 5-HT receptor subtypes was performed in the following brain regions: medial prefrontal cortex, nucleus accumbens, striatum, substantia nigra, ventral tegmental area, dorsal and median raphe nuclei. A significant increase of [3H]SCH 23390 binding to D1 DA receptors was observed in the substantia nigra pars reticulata 1 day but not 15 days after the cessation of AMPH treatment, whereas [3H]8-OH-DPAT binding to 5-HT1A sites was found to be significantly enhanced in the dorsal raphe nucleus at both time points. No change in D2 DA nor in 5-HT1B or 5-HT2A receptors was found in any of the brain structures examined at either time point. The obtained results suggest that DA and 5-HT systems are differently and time-dependently involved in AMPH-induced behavioral sensitization.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Social deprivation enhances the vulnerability of male Wistar rats to stressor- and amphetamine-induced behavioral sensitization.

The aim of the present study was to assess the influence of experiential factors on the vulnerability of rats to develop amphetamine (AMPH)- and stressor-induced behavioral sensitization. Young male Wistar rats with previous social experience were isolated from their peers for 2 weeks. 1) The effect of this short-lasting social deprivation were: a) a reduced tendency to explore a fearful environment; b) a prolonged exploratory activity in response to a novel but little fearful environment; and c) a dose-dependent increase in the psychomotor stimulation induced by systemic AMPH injection. 2) After repeated AMPH injections (injection every other day for 10 days), isolated rats exhibited behavioral sensitization at lower doses (0.5 and 0.75 mg/kg) than those required for group-housed rats (1 mg/kg). 3) After being submitted to a repeated stressor (3, 7 or 14 footshock sessions, with 2 days between sessions), the isolated rats exhibited a greater increase in the behavioral responsivity to a subsequent AMPH challenge (1 mg/kg) than did the group-housed rats regardless of the number of stress sessions. In conclusion, these results suggest that experiential factors such as privation of contact with peers (social isolation) may make rats more vulnerable to the long-term repercussions of chronic environmental and pharmacological challenges.

Amphetamine↗
PubMed1995

Ethopharmacological analysis of naloxone-precipitated morphine withdrawal syndrome in rats: a newly-developed "etho-score".

The intensity of opiate withdrawal syndrome in rats is usually quantified on the basis of selected physical signs or global scores. However, the selection criteria of signs and scores have not been subjected to an ethological discussion, hence they appear to be somewhat arbitrary. The objectives of this study were thus: i) to analyse the rat's behaviour during the naloxone-precipitated morphine withdrawal syndrome, ii) to evaluate the validity of classic methods, and iii) to design a new "etho-score". Ten rats were implanted with morphine pellets (75 mg x 2, SC), all receiving different naloxone doses following a within-subject design (0, 0.01, 0.05, 0.1, 0.5, 1 mg/kg SC). Twenty unexperienced rats and 20 with placebo pellets were injected with either saline or naloxone. Behaviour was videotaped and later analysed by computer-based ethological techniques. The ethogram encompassed 16 patterns displayed by rats during morphine withdrawal. Frequency, duration and latency of each pattern was measured, and a cluster analysis allowed discerning the structure of behaviour. Several physical signs and the Gellert-Holtzman score were also evaluated. The data revealed that writhing responses linearly changed in a dose-related fashion, and mastication was also enhanced after naloxone. Wet-dog shakes and jumping changed following an U-shaped curve. Significant changes in weight loss were found to be dose-dependent, and highly correlated to diarrhea. Learning effects were found to reliably affect exploration, writhing responses and some physical signs. The Gellert-Holtzman score was gradually enhanced after naloxone, being affected by learning as well. Naloxone affected lying and self-care responses in placebo rats. To sum up, the data indicated that: i) classic signs are useful, although most of them are disrupted by high naloxone or affected by learning effects, ii) the Gellert-Holtzman score was validated in this study, and iii) mastication and weight loss are good indicators of naloxone-precipitated morphine withdrawal, representing the basis of an "etho-score" which is herein proposed.

Animals↗
PubMed1995

Changes in CNS neuropeptide FF-like material, pain sensitivity, and opiate dependence following chronic morphine treatment.

Tolerance and dependence to opiates may be an adaptive process that limits excessive effects of morphine on the CNS. Because no consistent opiate receptor reduction in chronically treated rats seems to underlie the hyposensitivity to morphine, an alternative hypothesis has postulated a role of "antiopioid" peptides. It is possible to speculate that the administration of morphine stimulates antiopioid systems such as neuropeptide FF (NPFF), as part of an homeostatic mechanism contributing to the development of tolerance. To test this hypothesis, pain sensitivity, opiate dependence, and CNS NPFF-IR levels were estimated at different times after implantation of morphine pellets (2 x 75 mg; NIDA). Three hours after morphine pellet treatment the analgesic effect was maximum and it decreased rapidly during the following 12 h. Naloxone-precipitated withdrawal syndrome was detected as soon as 3 h after morphine pellet implantation and was maximal after 24 h. NPFF-IR levels were measured in the spinal cord, brain stem, and hypothalamus. A significant decrease of NPFF-IR was observed 1 h after morphine pellet implantation (-25% to -45% depending on the structures) followed by a drastic increase of NPFF-IR levels (+60 to +140%) between 3 and 6 h. NPFF-IR levels rapidly returned to baseline after 24-36 h. It is suggested that the activity of these NPFF-IR neurones may increase gradually as a consequence of the continuous stimulation of opiate receptors and be part of an adaptive process that is able to counteract morphine effects and to induce dependence and tolerance to the analgesic effects of opiates.

Adaptation, Biological↗
PubMed1995

Neuropeptide FLFQRFamide receptors within the ventral mesenchephalon and dopaminergic terminal areas: localization and functional antiopioid involvement.

The neuropeptide FLFQPQRF amide is a FMRFamide-like peptide with some anti-opiate properties. Neuropeptide FLFQPQRFamide receptors are present in the mammalian central nervous system and have been clearly identified as different from opiate receptors. Autoradiography has revealed neuropeptide FLFQPQRFamide receptor localization within the ventral mesencephalon, where opiate receptors are also located. In order to delineate anatomical localization of neuropeptide FLFQPQRFamide receptors, we used selective chemical lesions of dopaminergic cells and intrinsic perikarya of the ventral mesencephalon, coupled with in vitro autoradiographic techniques. We show that: (i) unilateral lesions of dopaminergic perikarya produced by 6-hydroxydopamine did not affect either ipsi or contralateral neuropeptide FLFQPQRFamide receptor density within the mesencephalon; (ii) unilateral lesions of intrinsic perikarya by ibotenic acid injected into the ventral tegmental area produced a significant reduction of neuropeptide FLFQPQRFamide receptors (40%) in this region; (iii) in the substantia nigra pars compacta, ibotenic acid unilateral lesions did not affect the density of neuropeptide FLFQPQRF-amide receptors; (iv) unilateral 6-hydroxydopamine or ibotenic acid lesions failed to affect neuropeptide FLFQPQRFamide binding in the dopaminergic projection areas. These results suggest that, like opiate receptors, the neuropeptide FLFQPQRFamide binding sites are not localized on dopaminergic neurons but are distributed on both soma of non dopaminergic cells in the ventral tegmental area and on fibers afferent to the ventral tegmental area and substantia nigra pars compacta. To evaluate the possibility that the stimulation of neuropeptide FLFQPQRFamide receptors may affect the opioid modulation of mesocorticolimbic dopaminergic neuron activity, we tested the effects of neuropeptide FLFQPQRFamide ventral tegmental area infusion (0.25-10 micrograms) on the behavioral activation induced by intra-ventral tegmental area morphine infusion. We observed that in the ventral tegmental area, the stimulation of neuropeptide FLFQPQRFamide receptors inhibits morphine-induced locomotor hyperactivity. These results suggest that in the ventral tegmental area, neuropeptide FLFQPQRFamide may participate, via an indirect mechanism, to the control of the mesocorticolimbic dopaminergic system activity by counteracting the effect of opioids.

Animals↗
PubMed1995

Evidence of a complete independence of the neurobiological substrates for the induction and expression of behavioral sensitization to amphetamine.

The repeated administration of amphetamine in rats produces behavioral sensitization which is characterized either by a progressive enhancement of the locomotor activity induced by the drug or by an enduring behavioral hypersensitivity to the drug after the cessation of the treatment. Some authors have suggested that the action of amphetamine at the level of the nucleus accumbens is responsible for the expression of behavioral sensitization, whereas the action of amphetamine at the level of the dopamine cell bodies in the ventral tegmental area induces some changes responsible for the initiation of the phenomenon. The present study fully tested this hypothesis. In two separate experiments, the effects of different doses of amphetamine repeatedly administered in the ventral tegmental area or in the nucleus accumbens were tested on the later behavioral reactivity to the administration of amphetamine in the nucleus accumbens. Independent groups of rats received five repeated administrations (one injection every other day) of different doses of amphetamine either in the ventral tegmental area (0, 1, 2.5, 5 micrograms/0.5 microliters per side) or in the nucleus accumbens (0, 1, 3, 10 micrograms/l microliters per side). Two days following the last intracerebral amphetamine injection, each group received a phosphate buffer solution challenge directly into the nucleus accumbens followed two days later by an amphetamine challenge (1 microgram/l microliters per side) in the nucleus accumbens and two days later by a peripheral challenge with amphetamine (0.5 mg/kg, s.c.). Locomotor responses were recorded following each injection. Results showed that injections of amphetamine into the nucleus accumbens induced a dose-dependent increase in locomotor activity which remained identical with the repetition of the injections. No difference between the different intra-accumbens pretreated groups was observed following the diverse phosphate-buffered saline solution and amphetamine challenges. In contrast, intra-ventral tegmental area administration of amphetamine did not produce any modification of locomotor activity. However, whereas no difference between the differently pretreated groups was observed following phosphate-buffered saline administration into the nucleus accumbens, a potentiation of the locomotor response to a challenge dose of amphetamine into the nucleus accumbens was observed which was dependent on the dose of amphetamine pretreatment into the ventral tegmental area. Similar potentiation was observed following peripheral challenge with amphetamine. Finally, cross-sensitization was observed when a challenge dose of cocaine (10 micrograms/1 microliter per side) was injected into the nucleus accumbens, as well as when a peripheral challenge dose of morphine (2.5 mg/kg, s.c.) was administered to the ventral tegmental area-pretreated groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphetamine↗
PubMed1995

Acute and chronic amphetamine treatments differently regulate neuropeptide messenger RNA levels and Fos immunoreactivity in rat striatal neurons.

Repeated administration of amphetamine results in the well known phenomenon of reverse tolerance or sensitization. However, little is known about cellular and molecular mechanisms underlying acute versus chronic response to amphetamine. In this paper, we investigated the effects of acute (1.5 or 5 mg/kg) and chronic (5 mg/kg/day for 14 days) amphetamine treatment on locomotor activity, stereotypy, Fos immunoreactivity and messenger RNA levels of molecules implicated in dopamine transmission in the rat striatum and substantia nigra. In agreement with other studies, acute amphetamine induced a dose dependent increase in locomotor activity and stereotypy. Also, a comparison between the behavior observed after the first injection and the last injection of amphetamine in chronically treated rats showed sensitization as demonstrated by a higher rating of stereotypy. We have found that acute and chronic amphetamine treatments differently modulate the activity of several output neurons. A double labeling procedure with Fos immunohistochemistry coupled with in situ hybridization demonstrated that acute amphetamine treatment induces Fos immunoreactivity predominantly in striatal neurons expressing substance P messenger RNA (77.07 +/- 1.42%). Only 32.6 +/- 2.07% of Fos immunoreactive neurons expressed preproenkephalin A messenger RNA. In chronic amphetamine treated rats, 56.21 +/- 1.32% of the Fos immunoreactive neurons expressed substance P messenger RNA while 52.12 +/- 1.84% expressed preproenkephalin A messenger RNA. Statistical analysis revealed that this difference is mainly due to a decrease in the density of substance P immunoreactive neurons in chronically treated rats in comparison to acute. Amphetamine treatments induced Fos immunoreactivity in the substantia nigra in non-dopamine neurons. As measured by quantitative in situ hybridization, acute amphetamine induced an increase in substance P, preproenkephalin A and dynorphin messenger RNA levels (+23 +/- 0.05%, +45 +/- 0.07% and +24 +/- 0.05%, respectively). No difference in these increases was observed in relation with the dose injected (1.5 or 5 mg/kg). Chronic amphetamine treatment enhanced only substance P and dynorphin messenger RNA levels (+23 +/- 0.04% and +42 +/- 0.04%, respectively). Neither acute nor chronic amphetamine treatment had any effects on D1 or D2 dopamine receptor messenger RNA levels. Our main conclusions are: (1) in acutely treated rats Fos is essentially expressed by substance P neurons; (2) in chronically treated rats, Fos immunoreactivity is expressed by the two efferent striatal populations (i.e. preproenkephalin A and substance P neurons) and the number of Fos immunoreactive neurons is reduced as compared with acute; (3) neuropeptide messenger RNA levels, but not dopamine receptor messenger RNAs, are affected in the response to acute or chronic treatment with amphetamine.

Amphetamine↗
PubMed1995

Amphetamine-induced conditioned activity in rats: comparison with novelty-induced activity and role of the basolateral amygdala.

A within-subject design was used to investigate the behavioral and neural basis of the conditioned activity induced by amphetamine in male Wistar rats. In this design, conditioned activity was inferred when the activity of a given rat following a vehicle injection was greater in its amphetamine-paired environment (CS+) than in its vehicle-paired environment (CS-). Conditioned activity (a) did not change in magnitude with the number of conditioning sessions, (b) did not differ from the level of activity recorded during the first exposure to the CS- (novelty), (c) had an extinction rate that was similar to the rate of habituation to the CS-, and (d) was not impaired by a bilateral excitotoxic lesion of the basolateral amygdala. Results are discussed in light of the incentive conditioning and habituation theories of conditioned activity.

Animals↗
PubMed1995

Chronic dopamine antagonism facilitates opiate-induced feeding.

Chronic interference with dopamine (DA) transmission has been found to facilitate opiate reward and opiate-induced behavioral activation derived from the nucleus accumbens. This study was aimed at determining the extent to which these effects are generalizable to opiate-induced feeding. Rats were tested for their feeding response to morphine following chronic interference with DAergic transmission with the long-acting neuroleptic, flupenthixol decanoate (FLU). It was found that FLU-treated animals showed an enhanced feeding response to morphine following three and four weeks of DA blockade, but not on weeks 1 and 2. Neither morphine treatment in FLU-control animals nor chronic FLU treatment alone produced any such time-dependent facilitation in feeding. The results indicate that the increased sensitivity to the rewarding effects of opiates following chronic DA blockade is generalizable to opiate-induced feeding.

Animals↗
PubMed1994

Prolonged tolerance, dependence and abstinence following subcutaneous morphine pellet implantation in the rat.

Opiate withdrawal is a common occurrence in human opiate addicts that is no life threatening but is hypothesized to be a significant factor which may contribute to drug taking behavior in these opiate dependent individuals. The purpose of this study was to compare the time course for the development of tolerance, dependence and abstinence using a rat model. Rats were made dependent by implantation of 2 morphine pellets s.c. (75 mg morphine base). Morphine implanted rats exhibited analgesia as measured in a tail-dip assay, for up to 12 h post-implant after which the development of tolerance resulted in tail-flick latencies returning to the level of control rats. Withdrawal was evaluated by injection of the opiate antagonist, naloxone (1 mg/kg s.c.). Rating of the abstinence syndrome revealed significant withdrawal signs by 3 h post-implant which became increasingly intense up to 24 h post-implant. Withdrawal could be precipitated for at least 13 days post-implant, while by 18 days post-implant almost no abstinence signs were observed. Plasma morphine levels following implantation of 2 pellets remained relatively stable from 3-12 days post-implantation. These results further extend the characterization of opiate abstinence following subcutaneous pellet implantation. These results also suggest that opiate abstinence develops within the first 24 h and follows the time course of the development of tolerance. The characterization of the evolution of opiate tolerance, physical dependence and abstinence under similar experimental conditions is critical to the design of future studies to examine the neural bases for these phenomena.

Analgesia↗
PubMed1994

Effects of morphine and naloxone on behaviour in the hot plate test: an ethopharmacological study in the rat.

The objectives of this study were: i) to analyse the effects of morphine and naloxone on the rat's behaviour in the hot plate test using an ethological approach, and ii) to compare the effectiveness of repeated versus single test paradigms. Animals received either morphine (0, 3, 6 or 9 mg/kg SC) or naloxone (0, 0.01, 0.1 or 1 mg/kg SC). For repeated hot plate measures, rats were tested before and 60, 120, 180 and 240 min following morphine treatment, as well as 30, 60, 90 and 120 min after naloxone injection. For the single test schedule, rats were tested only once 60 min after morphine or 30 min after naloxone administration, or at 60, 120, 180, 240 and 300 min after 9 mg/kg morphine treatment. Behaviour was videotaped and analysed by an ethogram and ethological techniques. A cluster analysis revealed that the most frequently displayed patterns could be categorised into exploratory sniffing reactions (walk-sniff, immobile-sniff) and noxious-evoked elements, including primary (paw-licking, stamping), escape (jumping, leaning posture) and independent (hindleg-withdrawal) patterns. During repeated tests, morphine treatment induced: i) a maximum hypoalgesic effect 60 min post-injection (noxious-evoked patterns were significantly reduced), and ii) an unexpected "thermal hyperreactivity rebound effect" after 120 min (paw-licking and hindleg-withdrawal were enhanced), although changes in hindpaw-licking are more indicative of a hyperalgesic rebound effect. Most changes were quite similar during the single test schedule at 60 and 120 min after morphine injection. With regard to naloxone treatment, jumping latency was significantly decreased during the repeated test schedule, but not on single exposure to the plate. Other elements were facilitated, however, in the single test (stamping, leaning posture, hindleg-withdrawal). The results indicated that both repeated and single tests paradigms are of value for testing the effects of morphine and naloxone on rats. However, under our conditions the single test paradigm gave a better picture of the overall effects of the drug. Learning as well as habituation and sensitization may mask certain effects during repeated tests. In conclusion, an ethological analysis of the rat's behaviour in the hot plate test following administration of morphine and naloxone has been validated in this study.

Animals↗
PubMed1994

Real-time sleep-wake scoring in the rat using a single EEG channel.

A new method of analysis of sleep in the rat based on the electrocorticogram (ECoG) is described. Three states, awake (W), nonrapid eye movement (NREM) and rapid eye movement (REM) sleep are automatically classified by the system. After amplification of the ECoG over a restricted bandwidth (3.18-25 Hz) and sampling at 512 Hz, the data are processed in 8-second epochs by a microcomputer, which generates three statistical and two harmonic variables. Each 8-second epoch is thus compressed into five numerical values occupying 10 bytes of memory. Epochs for each state of vigilance are identified by an expert observer to produce three reference models. The program classifies each epoch into the appropriate state by the least quadratic distance. The system was validated by comparing the results with a visual analysis of polygraph recordings. The agreement between the program and the two independent scorers for 24-hour tracings of six rats was 83% for REM sleep, 96% for W and 97% for NREM sleep.

Animals↗
PubMed1994

Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis.

In addition to classic somatic signs of opiate withdrawal, a number of behavioral measures are known to be sensitive, reliable indices of naloxone-precipitated opiate withdrawal in rats. It has been suggested that some behavioral indices of withdrawal may be more sensitive to precipitation by naloxone than some somatic signs of withdrawal. The purpose of the present study was to permit a quantitative assessment of the relative sensitivity to naloxone of a variety of behavioral and somatic indices of opiate withdrawal. Male Wistar rats were implanted s.c. with either two morphine (each 75 mg of base) or two placebo pellets. No sooner than 3 days after implantation, naloxone dose-response functions were determined with several behavioral paradigms and ratings of a variety of somatic withdrawal signs. In dependent rats, very low (0.004 or 0.01 mg/kg) doses of naloxone produced the following behavioral effects: 1) a reduction in spontaneous locomotor activity, 2) a disruption of schedule-controlled (fixed ratio 15) operant responding for food, 3) an elevation in intracranial self-stimulation thresholds and 4) a conditioned place aversion. These same doses of naloxone produced no significant effects in nondependent (placebo pellet-implanted) rats. The ED50 values for naloxone precipitation of all behavioral signs of withdrawal were below 0.013 mg/kg; the ED50 values for naloxone precipitation of most somatic withdrawal signs were higher. The behavioral measures used in these studies therefore represent highly sensitive indices of opiate withdrawal.

Animals↗
PubMed1993

The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat.

Rats readily learn to self-administer ethanol using a procedure where ethanol is introduced in the presence of a sweetener. After gradual removal of the sweetener, sufficient quantities of ethanol are self-administered in non fluid-, non food-deprived rats to produce reliable blood ethanol concentrations. Previous studies using this self-administration model have shown that dopamine receptor antagonists injected systemically or directly into the terminal regions of the mesolimbic dopamine system decrease lever pressing for ethanol, suggesting an important role for dopamine in ethanol reinforcement. The purpose of the present study was to test the hypothesis that the mesolimbic dopamine system is a critical substrate for ethanol reinforcement. Results of this study show that 6-hydroxydopamine (6-OHDA)-induced lesions of the mesolimbic dopamine system, sufficient to produce a 93% depletion of dopamine in the nucleus accumbens, an 85% depletion in the olfactory tubercle, an 82% depletion in the frontal cortex and a 78% depletion in the amygdala, failed to alter ethanol self-administration as measured by the total lever presses. However, the 6-OHDA lesion rats showed an altered pattern of responding for ethanol: an increase in the slope of the regression line of cumulative responses vs. time and an increase in the frequency of responding at inter-response intervals of 4-6 and 6-8 s post 6-OHDA lesion; suggesting that this lesion produced a subtle change in motor or attentional function. The results of this study indicate that while the mesolimbic dopamine system may contribute to the reinforcing actions of ethanol, it is not critical for maintaining ethanol reinforcement.

Administration, Oral↗
PubMed1993

Central administration of corticotropin releasing factor induces long-term sensitization to D-amphetamine.

Corticotropin releasing factor (CRF) has been shown to initiate neuroendocrine and behavioral responses to stress. As stress and amphetamine (AMPH) show cross-sensitization, we investigated the role of endogenous CRF in behavioral sensitization to D-AMPH. In order to evaluate the participation of the central action and the pituitary-adrenocortical (PA) stimulatory effect of CRF, we compared the effects of repeated intracerebroventricular (i.c.v.) administration of CRF (0, 0.5, 2.5 micrograms/2 microliters), which have central and neuroendocrine consequences, with those of repeated subcutaneous administration of CRF (0, 0.1, 0.5, 2.5 micrograms/250 microliters), doses which only stimulate the PA axis, on the development of sensitization to AMPH-induced motor activation administered 1 week later. Repeated i.c.v. administration of CRF induced a long-lasting enhancement of the hyperactivity induced by 0.75 mg/kg peripheral administration of D-AMPH, whereas no sensitization to D-AMPH was observed following repeated subcutaneous administration of CRF. These results favor the hypothesis that a centrally mediated action of CRF is involved in the cross-sensitization of psychostimulants and stress.

Animals↗
PubMed1992

Corticotropin-releasing factor induces a place aversion independent of its neuroendocrine role.

The purpose of the present experiment was to test the hypothesis that corticotropin-releasing factor (CRF), a polypeptide of 41 amino acids, when administered either intracerebroventricularly (i.c.v.) or subcutaneously (s.c.), has aversive properties in the conditioned place-preference paradigm. Five doses of CRF (0, 0.005, 0.05, 0.5, 5 micrograms) were tested. i.c.v. CRF induced a specific dose-dependent reduction of the amount of time spent in the environment previously paired with the administration of CRF. Furthermore, this CRF-induced place aversion was prevented by pretreatment with alpha-helical-CRF(9-41), a specific CRF antagonist, administered i.c.v. In order to test whether the aversive effects induced by i.c.v. CRF could result from the stimulation of the HPA axis accompanying i.c.v. CRF injection, the reinforcing properties of s.c. CRF were studied using the same dose range. Only the higher s.c. dose was effective in producing a place aversion suggesting that the aversive effects of CRF could not be due solely to the stimulation of the pituitary-adrenocortical system, measured by plasmatic levels of adrenocorticotropic hormone (ACTH) and corticosterone, because the lower doses consistently activate the pituitary-adrenocortical system without producing any behavioral changes. Altogether, these data indicate that the non-neurosecretory CRF neurons may mediate the aversive state occurring during stress.

Animals↗