Biomedical subjects

P P Rompré

Publications and source records attributed to P P Rompré.

At least 19 recordsLinked to original sources

PubMed2001

Effects of neurotensin receptor activation on brain stimulation reward in Fischer 344 and Lewis rats.

The effects of intracerebroventricular injections of 18 nmol/10 microl of neurotensin, [D-Tyr(11)]neurotensin, or saline on operant responding for brain stimulation reward were investigated in Fischer 344 (F344) and Lewis (LEW) rats using the curve-shift paradigm. [D-Tyr(11)]neurotensin, but not neurotensin, decreased reward threshold in F344 rats while it increased thresholds in LEW rats. Both peptides suppressed maximal rates of responding; this effect was of greater magnitude and longer lasting in LEW than in F344 rats. These findings show that F344 and LEW rat strains are differentially sensitive to activation of central neurotensin receptors that modulate reward-relevant circuitry.

Animals↗

PubMed2000

Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area.

Dual-probe microdialysis (with HPLC and electrochemical detection) in freely moving rats and single-unit recording in anesthetized rats were used to study the extent to which impulse flow through the ventral tegmental area (VTA) contributes to elevations in nucleus accumbens (NAS) dopamine (DA) evoked by stimulation of the ventral subiculum (VS). During perfusion of artificial extracellular fluid into the VTA, injections of 0.74 microgram of the excitatory amino acid NMDA into the VS elevated accumbens DA to >150% of basal values. During intra-VTA perfusion of either 1 microM tetrodotoxin (which blocks impulse flow) or 1 mM kynurenic acid (which blocks excitatory glutamate receptors), injections of NMDA into the VS failed to elevate accumbens DA. Thus, increased impulse flow through VTA DA neurons, mediated by excitatory glutamate inputs to this region, appears critical for VS stimulation to elevate NAS DA. Increased impulse flow through VTA DA neurons was confirmed using single-unit recording in anesthetized rats. Intra-VS NMDA injections increased the firing rates of 45% (14 of 31), decreased the firing rates of 13% (4 of 31), and had no effect on 42% (13 of 31) of VTA DA neurons. Increases in firing rates were evident within 15 min of NMDA injections, a time at which VS NMDA injections elevate accumbens DA in awake animals. The results of the present experiments identify the VTA as a critical site through which outputs from the VS modulate NAS dopaminergic neurotransmission.

Animals↗

PubMed2000

Behavioral evidence of depolarization block of dopamine neurons after chronic treatment with haloperidol and clozapine.

Electrophysiological studies have shown that chronic treatment with haloperidol causes depolarization block (DB) of dopamine cells in anesthetized and paralyzed rats. It has been proposed that the emergence of DB underlies the therapeutic and side effects of this drug. However, the relevance of DB to the clinical actions of haloperidol has been questioned on the grounds that chronic drug-induced DB has not yet been demonstrated in freely moving animals. In this study, responding for rewarding electrical brain stimulation was used to assess the occurrence of DB in rats chronically treated with haloperidol or clozapine. The time course of the effects of acute haloperidol (7.8-500 microg/kg) and clozapine (5-40 mg/kg) and of withdrawal from chronic drug treatment on reward and performance measures were also characterized. Haloperidol and clozapine dose-dependently attenuated reward and performance, haloperidol producing a predominant suppression of performance, and clozapine preferentially attenuating reward. Chronic (21 d) treatment with haloperidol (500 microg/kg) caused responding to cease in the six rats tested, and repeated injection with apomorphine restored the behavior in all of them; such an effect of apomorphine was observed in only two of six rats treated acutely with the same dose of haloperidol. Chronic treatment with clozapine (20 mg/kg) increased reward thresholds, an effect that was reversed by apomorphine in chronically, but not acutely, treated rats. The times at which chronic haloperidol-treated rats resumed responding was positively correlated with indices of behavioral supersensitivity after withdrawal, suggesting that the effect of apomorphine was not caused by direct stimulation of upregulated postsynaptic receptors. These findings constitute the first behavioral evidence of DB in unanesthetized, freely moving animals treated chronically with antipsychotics. They also demonstrate that the neural substrates mediating reward and performance are functionally independent and differentially sensitive to haloperidol and clozapine.

Animals↗

PubMed1998

Electrophysiological evidence that a subset of midbrain dopamine neurons integrate the reward signal induced by electrical stimulation of the posterior mesencephalon.

This study was aimed at determining whether midbrain dopamine (DA) neurons are trans-synaptically activated by rewarding electrical stimulation applied near the midline in the posterior mesencephalon (PM), and in the affirmative, whether the increase in firing was proportional to the rewarding effectiveness of the stimulation. Experiments were performed on male Long-Evans rats trained to lever press to obtain 400 ms trains of cathodal rectangular pulses. Following the training period, curves relating the rates of responding to the stimulation frequencies were determined at two current intensities and reward thresholds were calculated for each animal. Each animal was then anesthetized with urethane (1.2 g/kg, i.p.) and firing rate of DA neurons were recorded before, during, and after each of 50 trains (1 train/3 s) of stimulation to the PM using stimulation parameters that either sustained near threshold responding (rewarding), or failed to sustain responding (non-rewarding), in the behavioral tests. A total of 24 DA cells were recorded from 13 behaviorally trained animals, and of these, 17 (71%) responded to rewarding stimulation by an increase in firing, five (21%) were unresponsive and two (8%) were inhibited. In 12 of the 17 cells that were activated, the increase in firing was proportional to the rewarding effectiveness of the stimulation rather than the total strength of the stimulation. These results provide evidence that a subset of midbrain DA neurons are trans-synaptically activated by rewarding PM stimulation and constitute a second, or subsequent, stage of the reward-relevant pathway that integrates the PM reward signal.

Action Potentials↗

PubMed1998

Activation of neurotensin receptors in the prefrontal cortex stimulates midbrain dopamine cell firing.

The effects of medial prefrontal cortex microinjections of 3 nmol/0.5 microl of neurotensin-(1-13), the inactive fragment neurotensin-(1-8), or vehicle on the firing rate of midbrain dopamine neurons were studied in anesthetized rats. Twelve of 19 cells tested with neurotensin-(1-13) showed an average 20-25% increase in firing rate between 10 and 20 min after the injection. This effect was not mimicked by neurotensin-(1-8) (9 cells), nor by a control injection (10 cells) suggesting that it is mediated by high-affinity neurotensin receptors. These results suggest that activation of neurotensin receptors in the medial prefrontal cortex can modulate neural activity of a subpopulation of midbrain dopamine neurons.

Animals↗

PubMed1997

Excitotoxic lesions of the prefrontal cortex reduce dopamine D1-like receptors in the ventral tegmental area.

Ventral mesencephalic dopamine D1-like receptors were quantified in brains of male rats ten days after unilateral microinjections of ibotenic acid (2 or 10 microg/microl) or its vehicle into the medial prefrontal cortex. The density of dopamine D1-like receptors was reduced by more than 40% in the ipsilateral ventral tegmental area (both doses) and by 15% (low dose) and 44% (high dose) in the contralateral side; no significant reduction was observed in the substantia nigra. These results suggest that a significant number of ventral tegmental D1-like receptors are localized on afferent terminals from the medial prefrontal cortex.

Animals↗

PubMed1997

Repeated activation of neurotensin receptors sensitizes to the stimulant effect of amphetamine.

Effects of repeated intracerebroventricular microinjections of 18 nmol/10 microl of neurotensin, [D-Tyr11]neurotensin, or saline were tested on motor activity in different groups of rats. One week after the fourth central injection, sensitivity to the behavioral stimulant effect of amphetamine (1 mg/kg, i.p.) was tested. As previously reported, neurotensin attenuated motor activity while [D-Tyr11]neurotensin when compared to saline produced an initial suppression followed by an excitation. Despite such different behavioral effects, both peptides produced sensitization to the stimulant effect of amphetamine. These results show that repeated activation of neurotensin receptors produces long-lasting changes in responsiveness to a psychostimulant drug.

Amphetamine↗

PubMed1996

Mesencephalic substrate of reward: axonal connections.

The behavioral version of the collision technique was used to study the existence of axonal linkage between reward-relevant sites in the ventral tegmental area (VTA) and posterior mesencephalon (PM) in six rats trained to self-administer trains of electrical brain stimulation. The combined use of fixed and moveable stimulation electrodes allowed us to carry out collision tests at a total of 46 different combinations of VTA-PM sites, and collision-like effects were observed at 24 of these. Stimulation of the VTA and the most caudal PM sites generally resulted in collision curves that were characterized by a single increase in paired-pulse effectiveness (E-values), whereas recovery in those collision curves obtained from stimulation of the VTA and more rostral PM sites was generally slower, and often characterized by a double rise. Despite little variability in interelectrode distances (1.0-3.8 mm), collision intervals varied widely, ranging from 1.5 to 7.3 msec. Recovery from refractoriness (initial 25%) was also estimated and ranged from 0.7 to 1.0 msec, resulting in conduction-time estimates of 0.7-6.3 msec. The lack of correspondence between interelectrode distances and conduction times suggests the presence of axonal branching. Results of this study constitute the first behavioral evidence of a reward-relevant axonal link between the VTA and the PM. In addition, the finding that in one animal the anterior electrode was located within the posterior portion of the lateral hypothalamus (LH) suggests that the reward-relevant axonal bundle linking the LH and VTA may extend as far back as the caudal regions of the PM.

Animals↗

PubMed1996

Estimates of the axonal refractory period of midbrain dopamine neurons: their relevance to brain stimulation reward.

Psychophysical studies have shown that the directly activated neurons subserving the rewarding effect produced by electrical stimulation of the medial forebrain bundle (MFB) have refractory periods (RPs) shorter than those of dopaminergic (DA) neurons: this suggests that the directly stimulated substrate for the rewarding effect does not include DA neurons. Comparison of RP estimates. however, is difficult since those of DA neurons were obtained with the standard electrophysiological technique that characterizes cell body/initial segment rather than the directly stimulated axonal segment. Using electrophysiological recording techniques in urethane anesthetized rats, we re-estimated and compared the RP of DA neurons that project to the MFB and the ventral striatum (VST) with two stimulation procedures: one that characterizes the axonal segment near the stimulation electrode and the standard one that characterizes the cell body/initial segment near the recording electrode. Results showed that DA axonal RPs range from 1.0 to 2.2 ms, whereas cell body/initial segment RPs range from 1.0 to 3.0 ms. The axonal RP was equal to or shorter (mean difference = 0.22 ms, n = 15) than the cell body/initial segment RP. Axonal RP estimates for MFB sites range from 1.3 to 2.1 ms. values that slightly overlap with the late recovery from refractoriness reported in psychophysical studies for reward-relevant neurons. Axonal RP estimates obtained for VST sites were very similar (mean = 1.66, LH and 1.62 ms, VST) suggesting that the excitability of DA axons does not differ along their path. These results further support the hypothesis that DA axons are unlikely to constitute a major component of the directly-stimulated reward-relevant axons in the MFB. They also suggest that the direct contribution of DA axons to reward produced by VST stimulation is more important than by the MFB.

Action Potentials↗

PubMed1996

Effect of pimozide on self-stimulation threshold under a continuous and fixed-interval schedule of reinforcement.

Rats implanted with a monopolar electrode in the medial mesencephalon and trained to press a lever to self-administer trains of stimulating pulses were tested under a continuous (CRF) and a fixed interval (FI-1s) schedule of reinforcement before and after systemic pimozide injection (0.35 mg/kg). As previously shown, this dose of pimozide caused reductions in maximal response rates and in the rewarding effectiveness of the stimulation. The magnitude of the attenuation in rewarding effectiveness was significantly greater under CRF than under FI conditions, an effect that can be attributed to the decrease in the number of earned rewards concomitant to a decrease in response rates. The present results show that the tighter control over reward density provided by the use of a FI schedule of reinforcement reduces the probability of artifactually measuring increases in reward thresholds following treatments that suppress response rates.

Animals↗

PubMed1995

Effects of granisetron, a 5-HT3 receptor antagonist, on morphine-induced potentiation of brain stimulation reward.

Using the curve-shift method, we studied the effects of four doses (0.003, 0.03, 0.3 and 3 mg/kg, s.c.) of granisetron (endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3- carboxamide hydrochloride), a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist, on the potentiation of brain stimulation reward by microinjection of 2.5 micrograms/0.25 microliters of morphine sulphate (7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol sulphate) into the ventral tegmental area. As previously reported, morphine produced a significant reduction in reward threshold without altering maximal rates of responding. Granisetron attenuated the potentiating effect of morphine at the highest dose and failed to alter reward threshold or maximal rates of responding when given alone, except at the lowest dose where a small and statistically significant increase in threshold was found. These results provide additional evidence that 5-HT3 receptor antagonists may reduce the rewarding effect of opiates and do not impair the ability to produce operant responses. The weak attenuation observed with granisetron alone suggests that 5-HT3 receptors are unlikely to constitute an important influence on the directly stimulated reward-relevant pathway(s).

Analysis of Variance↗

PubMed1995

Psychostimulant-like effect of central microinjection of neurotensin on brain stimulation reward.

The curve shift method and the brain stimulation reward paradigm were used to dissociate reward and performance changes and determine whether unilateral ICV microinjection of neurotensin (3, 10, and 30 micrograms/10 microliters) produces neuroleptic- or psychostimulant-like effect on a dopamine-dependent behavior. At the highest dose tested, neurotensin potentiated brain stimulation reward, producing a significant time-dependent decrease in frequency threshold. Neurotensin also suppressed maximal rate of responding at every dose tested, suggesting that it was more effective at attenuating performance capability. These results suggest that a centrally acting neurotensin receptor agonist may specifically stimulate dopamine-dependent behaviors, producing psychostimulant-like effect that can be attenuated or masked by a suppression of performance capability.

Animals↗

PubMed1994

Thermogenesis in brown adipose tissue is activated by electrical stimulation of the rat dorsal raphe nucleus.

Brainstem mechanisms involved in the central control of thermogenesis in brown adipose tissue (BAT) were investigated, in urethane-anaesthetized rats, by observing changes in the temperature of interscapular BAT following electrical stimulation of sites in the dorsal raphe nucleus (DRN). Large increases in temperature could be produced by single 30 s stimulation trains. The magnitude of the temperature increase grew as a function of both current and frequency. Non-linear temporal summation was observed when near-threshold trains were delivered in close succession. These results are consistent with the view that ascending projections from the DRN relay thermal information to the basal forebrain and hypothalamus.

Adipose Tissue, Brown↗

PubMed1993

Mesencephalic microinjections of neurotensin-(1-13) and its C-terminal fragment, neurotensin-(8-13), potentiate brain stimulation reward.

Using the curve shift method, we assessed the effects of ventromedial mesencephalic tegmental (VMT) microinjections of an equimolar concentration of neurotensin-(1-13) (NT-(1-13)) and of its C-terminal fragment, neurotensin-(8-13) (NT-(8-13)), on operant responding for rewarding electrical stimulation of the caudal mesencephalic central gray. The effects of NT-(1-13) and NT-(8-13) on brain stimulation reward (BSR) were also compared to those of systemically administered quinpirole (0.1 and 0.2 mg/kg, s.c.), a direct dopamine agonist, and GBR-12909 (10 and 20 mg/kg, i.p.), a selective dopamine uptake blocker. At the concentration injected, NT-(8-13) was as effective as NT-(1-13) at facilitating BSR, producing significant leftward shifts of the function relating the rate of responding to the stimulation frequency (R/F function); neither form of the peptide was effective when injected in regions dorsal to the VMT. Similarly, GBR-12909 produced a parallel leftward shift of the R/F function, but, unlike NT-(1-13), also significantly increased the asymptotic rates of responding. In contrast, the high dose of quinpirole produced non-parallel leftward shifts of the R/F function and suppressed the asymptote. The similarity between the effects of neurotensin and GBR-12909 on one hand, and the differences between those of neurotensin and quinpirole on the other, suggest that activation VMT neurotensin receptors potentiate BSR by enhancing increases in dopamine neurotransmission that are contingent upon operant responding or rewarding brain stimulation, or both.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Opposite effects of mesencephalic microinjections of cholecystokinin octapeptide and neurotensin-(1-13) on brain stimulation reward.

Changes in operant responding for brain stimulation reward were studied before and after a microinjection of 1 nmol of sulphated cholecystokinin octapeptide, neurotensin or saline into the ventral tegmental area. Neurotensin produced a significant and long lasting decrease in the stimulation frequency required to produce a half-maximal rate of responding; cholecystokinin had the opposite effect, attenuating the rewarding efficacy the stimulation during the first 30 min post-injection. It is suggested that the opposite effects of the peptides on reward are due to their differential modulatory effects on a subpopulation of mesencephalic dopamine neurones.

Animals↗

PubMed1992

Acute depolarization block of A10 dopamine neurons: interactions of morphine with dopamine antagonists.

Extracellular single-unit recording techniques were used to determine the effects of morphine, administered either systematically (intravenous) or locally (microiontophoresis), on ventral tegmental area (A10) dopamine (DA) neuronal activity in animals pretreated with D1 (SCH 23390) or D2 (pimozide) DA receptor antagonists. In rats pretreated with the D2 antagonist pimozide, A10 DA neurons readily entered a state of apparent depolarization block in response to either i.v. or iontophoretically applied morphine. Whether the inactivation of DA neurons was induced by systemic or local morphine, it was reversed in 22 of 27 cases by iontophoretic administration of the inhibitory amino acid transmitter gamma-aminobutyric acid (GABA), suggesting depolarization block as the underlying mechanism. Pretreatment of rats with the D1 antagonist SCH 23390 did not significantly alter the tendency of A10 DA neurons to enter apparent depolarization block in response to morphine. These data support recent behavioral evidence suggesting that the combination of systemic pimozide and ventral tegmental area morphine can result in depolarization inactivation of the mesoaccumbens DA reward system.

Analysis of Variance↗

PubMed1992

Facilitation of brain stimulation reward by mesencephalic injections of neurotensin-(1-13).

The effects on brain stimulation reward of neurotensin-(1-13) microinjected at different concentrations (2.5, 5, 10 and 20 micrograms/0.5 microliters) into the ventral mesencephalic region containing mesocorticolimbic dopamine neurons were tested in 12 male rats. Neurotensin lowered the stimulation frequency required to sustain threshold levels of responding for brain stimulation reward, suggesting that this neuropeptide is involved in modulating the activity of dopamine neurons that mediate behaviors motivated by positive reinforces. The magnitude of the facilitatory effect of neurotensin on brain stimulation reward was dependent on the concentration injected and to a significant extent also on whether the peptide was administered in an ascending or a descending order of concentration. The different effects of neurotensin depending on the order of administration may suggest long-lasting effects on the responsiveness of neurotensin receptors in this region after injection of high concentrations of the peptide. Subsequent injection of morphine (2.5-5 micrograms/0.5 microliter) into the same site produced a weaker facilitation of brain stimulation reward than expected, suggesting that local damage after multiple central injections or prior injections of neurotensin itself reduced the responsiveness of dopamine neurons to opiates. Taken together, the results are consistent with data indicating that activation of neurotensin receptors in the ventral mesencephalon stimulates dopamine cell firing and axonal dopamine release in limbic terminal fields and suggest that endogenous neurotensin is involved in the control of behavior motivated by positive reinforcement.

Animals↗

PubMed1990

GBR 12909 reverses the SCH 23390 inhibition of rewarding effects of brain stimulation.

Curve-shift was used to test the effect of SCH 23390, a dopamine D1 receptor antagonist, and GBR-12909, a selective dopamine uptake blocker, on self-stimulation behavior. GBR 12909 (8 mg/kg) produced a significant decrease in self-stimulation threshold when administered alone, and reversed the increase in threshold produced by SCH 23390 (0.08 mg/kg). The reversal of the SCH 23390 effect by GBR 12909 suggests that the inhibition of self-stimulation produced by SCH 23390 is due to blockade of dopamine receptors.

Animals↗