Self-stimulation of the habenular complex in the rat.

65 male hooded Long-Evans rats learned to barpress for rewarding electrical stimulation of the medial or lateral habenular nucleus or the fasciculus retroflexus, but not the surrounding thalamic nuclei. Response rates were moderate and steady and were not influenced by food or water deprivation. Habenular self-stimulation was significantly facilitated by placing lesions in the ipsilateral anterior part of the medial forebrain bundle (MFB). Similarly, MFB self-stimulation was enhanced by ipsilateral habenular lesions. Lesions centered in the region of median raphe nucleus suppressed habenular self-stimulation for more than 4 wks. Self-stimulation of median raphe was not affected by habenular lesions. Results show that habenular stimulation can produce a rewarding effect by exciting neurons in the region of the raphe nuclei but apparently without requiring the participation of the well-known MFB reward system. (44 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amphetamine-induced disruption of latent inhibition depends on the nature of the stimulus

It is well documented that latent inhibition (LI), i.e. slower conditioning to a stimulus that had been repeatedly pre-exposed without consequences, compared to a non-pre-exposed stimulus, is prevented by amphetamine. Recently, we found that the effects of amphetamine on LI, as assessed in an off-baseline conditioned emotional response (CER) procedure, depend on the nature of the pre-exposed stimulus, irrespective of reinforcer intensity. Because these results contrast with a recent finding that a reduction in reinforcer intensity reversed amphetamine-induced attenuation of LI in an on-baseline CER procedure, the present study investigated the effects of amphetamine on LI as a function of the nature of the pre-exposed stimuli and shock intensity, using an on-baseline CER procedure. The effects of amphetamine on post-shock suppression of drinking as well as on activity, were monitored throughout the stages of the CER procedure. Experiment 1 used a 5 s steady light as the pre-exposed and conditioned stimulus, and two shock intensities in conditioning, and Experiment 2 used a 10 s flashing light and two shock intensities. Amphetamine disrupted LI with a steady light at both low and high shock intensities, but failed to disrupt LI with a flashing light at both shock intensities. In addition, the drug disrupted LI in Experiment 3, which increased the duration of the steady light to 10 s and used only low shock intensity, but failed to affect LI in Experiment 4 which used the flashing light on the background of darkness or of light, and only high shock intensity. The effects of amphetamine on LI were not related to its effects on behavioural suppression after footshock, or on activity.     

Destruction of the medial forebrain bundle caudal to the site of stimulation reduces rewarding efficacy but destruction rostrally does not.

Rats with an electrode in the medial forebrain bundle (MFB) in or near the ventral tegmental area and another at the level of the rostral hypothalamus sustained large electrolytic lesions at either the rostral or the caudal electrode. The rewarding efficacy of stimulation through the other electrode was determined before and after the lesion. Massive damage to the MFB in the rostral lateral hypothalamus (LH) generally had little effect on the rewarding efficacy of more caudal stimulation, whereas large lesions in the caudal MFB generally reduced the rewarding efficacy of LH stimulation by 35–60%. Similar reductions were produced by knife cuts in the caudal MFB. These results appear to be inconsistent with the hypothesis that the reward fibers consist either of descending or ascending fibers coursing in or near the MFB. It is suggested that the reward fibers are collaterals from neurons with both their somata and their behaviorally significant terminals located primarily in the midbrain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Brain stimulation reward following chronic lead exposure in rats.

Adult male rats were exposed to drinking water containing either 500 parts per million (ppm) lead acetate or an equal concentration of sodium acetate for 80 days. Bipolar electrodes were then implanted into the medial forebrain bundle (MFB), and rats were allowed to recover for 7 days. On Day 8 postsurgery, control and lead-treated rats were placed in an operant chamber and shaped to press a lever to receive 200-msec trains of current. Data from a range of current intensities and frequencies were recorded to obtain threshold values for each rat, defined as the stimulation needed to support half-maximal lever responding. Results indicated that chronic lead exposure attenuated the reinforcing effect of brain stimulation. Because of the large number of reward systems mediated by the MFB nucleus accumbens pathway, these data suggest that a variety of motivational phenomena may be affected by contaminant exposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activation and expression of endogenous pain control mechanisms in rats given repeated nociceptive tests under the influence of naloxone.

In six experiments, it was found that animals administered the opiate receptor blocker naloxone prior to either hot-plate or tail-flick nociceptive tests developed reduced sensitivity to pain relative to animals tested under saline. The naloxone-induced analgesia was most pronounced following administration of 10 mg/kg naloxone, with weaker effects occurring at 0.5 and 2 mg/kg. The effect manifested itself in tests using mild (48.5° hot-plate tests), but not more severe (52° or 56° hot-plate tests), intensities of nociceptive stimulation. The analgesia observed in animals tested under naloxone arose in part from the attenuation of the habituation of stress-induced analgesia produced by the novelty of the test apparatus, and in part from exposure to nociceptive stimulation. It appears to be mediated by a nonopiate mechanism; naloxone enhanced the analgesia produced by exposure to brief, continuous shock, but blocked the analgesia elicited by prolonged, intermittent shock (see Lewis, Cannon, & Liebeskind, 1980). We also found that administration of naloxone prior to nociceptive testing enhanced the development of conditioned autoanalgesia (as assessed by nociceptive tests conducted under saline), and that the enhanced conditioned autoanalgesia summated with the analgesic effect of morphine. The results are discussed in terms of the activation and expression of both opiate and nonopiate pain suppression mechanisms; their implications for models of situation specific morphine analgesic tolerance are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Assessment of the neural substrate for intracranial self-stimulation by the postreinforcement pause technique.

The poststimulation excitability of neurons mediating intracranial self-stimulation (ICSS) was evaluated by the paired-pulse method. Stimulus effectiveness was assessed by the postreinforcement pause (PRP) and by frequency threshold (FT) determinations in 7 rats performing ICSS in the medial forebrain bundle (MFB) and in the ventral tegmental area (VTA). Stimulus effectiveness values were minimal at conditioning-test (C-T) pulse intervals of 0.6 and 0.8 ms for MFB and VTA animals, respectively, because of neuronal refractoriness. Local potential summation could account for the increase in effectiveness at very short C-T intervals, and an additional peak of enhanced effectiveness at a C-T interval of 2.0 ms, perhaps reflecting synaptic events, was observed only in VTA animals with the PRP method. Important advantages of the PRP method were that the C-T interval was the only stimulus parameter that was varied, and the behavioral output of the animal remained relatively constant. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lesions of pontomesencephalic cholinergic nuclei do not substantially disrupt the reward value of medial forebrain bundle stimulation

This study examines the effects of lesioning the pedunculopontine tegmentum (PPTg) and laterodorsal tegmentum (LDTg) on the reward effectiveness of medial forebrain bundle (MFB) stimulation. Although the focus is on the effects of unilateral lesions made ipsilateral to stimulation sites in the hypothalamic and ventral tegmental MFB, the effects of contralateral lesions of both targets are also investigated. Reward effectiveness was assessed using the rate-frequency curve shift paradigm. In nine rats with unilateral PPTg lesions and five rats with unilateral LDTg lesions, the frequency required to maintain half-maximal response rats was generally not changed by more than 0.1 log units relative to prelesion baseline mean. In three rats with contralateral PPTg lesions and four rats with contralateral LDTg lesions, required frequency was also not substantially changed. The results are interpreted in terms of a previously proposed hypothesis regarding the role in MFB self-stimulation of ascending cholinergic input from the pontomesencephalon to ventral tegmental dopaminergic neurons.     

Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians

A possible future clinical application of NMDA receptor antagonists is the control of the development of opiate analgesic tolerance. Therefore, the ability of NMDA receptor antagonists to modify the acute analgesic effects of opiates becomes increasingly important. The present study sought to evaluate the analgesic potency of combined administration of morphine (5-20 mg/kg) and a competitive NMDA receptor antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; 0.3-5.6 mg/kg) in the tail-flick and tail-pinch tests with rats. It was found that D-CPPene significantly increased the duration of morphine analgesia, but there was hardly any evidence for potentiation of morphine analgesia shortly after morphine administration. This effect could only in part be attributed to the D-CPPene-induced disruption of the development of 'learned hyperresponsiveness' (i.e., acquisition of decreased latencies to escape from repeated exposures to noxious stimulation). In addition, the plasma concentration of morphine was not affected by concurrent treatment with D-CPPene.     

Pain-reducing properties of rewarding electrical brain stimulation in the rat.

In 4 experiments with 13 male Charles River rats, electrodes implanted along the medial forebrain bundle were screened for self-stimulation and stimulation-induced analgesia. Analgesia was defined by changes in unconditioned or escape responses to footshock. Almost all electrodes produced both self-stimulation and analgesia or neither. Thresholds for the 2 effects were highly correlated. Brain stimulation produced an analgesic aftereffect comparable in duration with the poststimulation enhancement of performance in self-stimulation (the priming effect). The refractory period of neurons underlying analgesia, assessed by behavioral means, was similar to that previously found for the priming effect in self-stimulation (.8-1.2 msec). Results suggest a common neural system mediating electrical analgesia and the priming effect of self-stimulation. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lipopolysaccharide, central in vivo biogenic amine variations, and anhedonia

Systemic administration of lipopolysaccharide (LPS), a non-specific activator of proinflammatory cytokine release from macrophages, provokes sickness characterized by anorexia, soporific effects, and disturbances of locomotor activity and exploration. In addition, endotoxin treatment may provoke an anhedonic response. Assessment of anhedonia in appetitive paradigms, however, is compromised by the anorexia provoked by the treatment. The present investigation assessed the anhedonic effects of LPS on rewarding lateral hypothalamic brain stimulation. Using a simultaneous discrimination, current titration procedure in the assessment of intracranial self-stimulation (ICSS), it was found that acute systemic administration of LPS (50 microg, 100 microg or 200 microg) reduced ICSS during the ascending sequence of current presentations, but had little effect on responding to a series of descending currents. In a parallel experiment, peripheral administration of LPS (100 microg) increased in vivo dopamine (DA) efflux from the nucleus accumbens, a region thought to be involved in goal-directed responding to positively reinforcing stimuli. It is suggested that LPS alters ICSS in a manner different than that observed following stressor exposure or peripheral IL-2 treatment. Furthermore, LPS may engender an anhedonic effect (possibly secondary to sickness), and the decline of responding reflects the relation between the cost of responding given in the face of sickness and the reward received for responding.     

The role of corticosteroids in analgesic effect caused by stimulation of the periaqueductal gray matter of the midbrain in rats

The effects of stimulation of periaqueductal gray matter on pain threshold and blood corticosterone level were studied in anesthetized rats. The stimulation resulted in a alteration of analgesia and corticosterone level. Stimuli-induced analgesia was decreased by adrenalectomy. Corticosterone implantation (50 micrograms) in periaqueductal gray matter resulted in the increase of analgesia. Pretreatment with naloxone (1 mg/kg) failed to modify the effect of stimulation of periaqueductal gray matter on analgesia and corticosterone level. Our results indicate the involvement of corticosterone in the analgesia induced the stimulation of periaqueductal gray matter.     

Associative factors in tolerance to analgesia produced by electrical stimulation in the brainstem.

Tolerance to the analgesic effects of electrical stimulation of the periaqueductal gray was confirmed, and it was demonstrated that this effect was mediated by environmental conditional stimuli (CSs). First, tolerance was extinguished after repeated presentation of CSs in the absence of brain stimulation. Second, environment-specific tolerance was demonstrated. Analgesia was reinstated after brain stimulation in a different test environment. Omission of brain stimulation in the stimulation environment failed to reveal a hyperalgesic response in tolerant Ss. Brainstimulation analgesia should be beneficial for analyzing neural mechanisms underlying conditioned tolerance to analgesia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Does the MFB convey functionally different reward signals?

Pulse frequencies that sustain the same % of the maximum self-stimulation rate (equipotent frequencies) are equipreferred by rats because they elicit identical reward signals. However, when two equipotent frequencies are delivered through different electrodes, lack of equipreference can be expected if the resulting neural signals belong to different rewarding processes and if these signals are differentially ranked on the animal's decisional scale. We used this rationale to test the possibility that the MFB conveys functionally different signals. Rats were implanted with an electrode near the anterior MFB (aMFB) and another near the posterior MFB (pMFB). The rate of self-stimulation, as a function of the pulse frequency, was first obtained for each electrode, separately. Rats were then allowed to press for aMFB or pMFB stimulation in a double-lever box. One of the levers delivered a fixed aMFB frequency whereas the other delivered a variable pMFB frequency. In the following session, this situation was reversed. The time spent bar-pressing for each stimulus was plotted as a function of the variable frequency. Equipreference for equipotent stimuli (i.e. for frequencies that supported the same % of the maximum rate in the single-lever box) was noted for 6 out of 11 electrode pairs. However, in 3 cases, the subjects preferred the pMFB stimulus over an aMFB equipotent stimulus and in two other cases they preferred the aMFB stimulus. The data from these five subjects suggest the presence of functional heterogeneity within the MFB reward pathway, a view already supported by a variety of other studies.     

Kindling antagonism: mapping of susceptible sites

Previous research has shown that concurrent alternating stimulation of paired limbic sites culminates in kindling of generalized seizures from 1 (dominant) site, whereas the other (suppressed) site supports only focal or partial seizures. This phenomenon has been referred to as kindling antagonism, and it has been proposed that antagonism reflects an arrest of kindling, which is therefore viewed as a non-continuous stepwise process. We have attempted to replicate these important observations in adult rats stimulated in various combinations of forebrain sites. Kindling antagonism was displayed by rats stimulated in the amygdala and the septal area, in the bilateral amygdala, the septal area and the splenium of the corpus callosum, and the amygdala and the cingulate cortex. We also found that antagonism between the amygdala and septal area as well as electrographic and behavioral correlates of alternating stimulation were sensitive to the hemispheric relation of the electrodes and to the order in which the sites received initial stimulations. That is, rats that carried ipsilateral amygdaloid and septal electrodes were less likely to display antagonism when the amygdala was the first site stimulated. On the other hand, we failed to obtain antagonism from rats stimulated in other limbic pairs (e.g. entorhinal cortex and septal areas.     

Conditioned facilitation of brain reward function after repeated cocaine administration.

Cocaine lowers brain reward thresholds, reflecting increased brain reward function. The authors investigated whether, similar to acute cocaine administration, cocaine-predictive conditioned stimuli would lower intracranial self-stimulation (ICSS) thresholds. Rats received a saline injection for 5 days, a cocaine injection (10 mg/kg) for 20 consecutive days, then saline for 5 additional days. Thresholds were measured immediately before and 10 min after each injection. The initial 5 saline injections had no effect on thresholds, whereas cocaine significantly lowered thresholds for 20 days. There was no tolerance or sensitization to this effect of cocaine over days. During the last 5 days when cocaine administration was substituted with saline, rats demonstrated a conditioned lowering of thresholds during the 2nd daily ICSS session. These data demonstrate that cocaine-predictive conditioned stimuli induce a conditioned facilitation of brain reward function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deficient passive and one-way active avoidance acquisition following medial forebrain bundle lesions in rats.

In 3 experiments with 93 Long-Evans male hooded rats, cathodal electrolytic lesions of the medial forebrain bundle (MFB) at posterior hypothalamic levels produced a mild, transient hypodipsia and lowered jump thresholds to footshock. Lesions produced marked deficits in passive avoidance performance in a paradigm that paired discrete, linearly incrementing footshock intensities with contact of a water spout following 48 hrs of water deprivation. Injections of levo-dextro-5-hydroxytryptophan (75 mg g, ip), the immediate metabolic precursor of serotonin, had no effect on the passive avoidance performance of either experimental or operated control Ss. Lesions of the MFB also resulted in deficient acquisition in a 1-trial step-through passive avoidance paradigm not using motivation to drink and caused a severe acquisition deficit in a 1-way active avoidance task. Lesions of the septal nuclei produced lowered jump thresholds but did not affect acquisition in the 1st passive avoidance task. Results are interpreted as indicating a lesion-induced deficiency in fear learning, independent of the serotonergic functions of the MFB. (45 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parasympathetic neuropathy associated with left ventricular diastolic dysfunction in patients with insulin-dependent diabetes mellitus

BACKGROUND: As extracorporeal shock wave lithotripsy (ESWL) is frequently carried out on an outpatient basis, it is crucial to choose an adequate analgesic with less adverse effect. This study evaluated the use of three different intravenous agents: fentanyl, tramadol HCl and tenoxicam in ESWL. METHODS: One hundred and twenty patients undergoing lithotripsy were randomly assigned to receive either intravenous fentanyl 1 microgram/kg, tramadol HCl 1.5 mg/kg or tenoxicam 0.3 mg/kg before lithotripsy. Pain intensity was recorded using verbal rating pain scales (VRPS). Cases without adequate analgesia (VRPS > 4) or could not tolerate the pain, additional bolus of fentanyl 25 micrograms were given until adequate analgesia was achieved. Side effects were recorded as well. RESULTS: No significant differences were found among groups in demographic data, VRPS, number of total shock waves, cases with supplementary fentanyl, mean dose of supplementary fentanyl or the incidence of dizziness. However, the incidence of nausea or vomiting was significantly higher in fentanyl and tramadol groups comparing with tenoxicam group (15.0% and 25.0% vs. 0.0%). Oxygen saturation in fentanyl group was also significantly lower than the other two groups (p < 0.01). In addition, VRPS had a significant correlation with voltage intensities (p < 0.05). CONCLUSIONS: Lithotripsy can be satisfactorily performed by employing fentanyl, tramadol or tenoxicam for analgesia; tenoxicam apparently offers a better analgesic quality with less side effect. Furthermore, the need for stronger analgesia during larger voltage intensity should be tailored to the needs of the individuals.     

The effect of the reduction of colloid oncotic pressure, with and without reduction of osmolality, on post-traumatic cerebral edema

The fact that centrally acting analgesics have abuse potential commensurate with their analgesic activity raises the question of whether these effects are related. The abuse potential of drugs depends on their ability to produce reinforcing effects, which are mediated by a neural system that includes the ventral tegmental dopamine cells and their connections with the ventral striatum. Morphine and amphetamine are both powerful analgesics and have high abuse potential. Their analgesic and reinforcing effects are mediated by similar receptors, similar sites of action, and overlapping neural substrates. These coincidences suggest that reinforcers may produce analgesia by transforming the aversive affective state evoked by pain into a more positive affective state. The implications of this hypothesis and its relation to other known mechanisms of analgesia are discussed. The hypothesis predicts that drugs with reinforcing effects should produce analgesia. A survey of drugs acting through 21 classes of receptors reveals that in 13 classes there is evidence for both analgesic and reinforcing effects that are approximately equipotent. The GABA(A) agonists were found to be the only drugs with confirmed abuse potential that lack analgesic activity. The interpretation of this and several other anomalous cases is discussed.     

Latent inhibition and overshadowing in conditioned emotional response conditioning with rats.

Tested whether unreinforced preexposure to one element of a compound CS would prevent that element from overshadowing the other element, using 64 male hooded COBS rats. Groups of Ss were given 20 preexposure trials to a light prior to conditioned emotional response (CER) conditioning or were given no pre-exposure. In CER conditioning, Ss received either a noise plus light or a noise followed by shock. In Ss given no pre-exposure, the presence of the light significantly attenuated conditioned suppression to the noise CS. However, in the pre-exposed compound-cue group no reduction in suppression to the noise CS was observed after 4 CER trials. After 8 CER trials, suppression to the noise CS was significantly attenuated. Latent inhibition temporarily reduced the extent to which the light CS overshadowed the noise CS. Overshadowing of the noise in the pre-exposed compound-cue group after 8 CER trials was not accompanied by any increase in suppression to the light CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anti asialoglycoprotein receptor antibodies and soluble interleukin-2 receptor levels as marker for inflammation in autoimmune hepatitis

Previous results using an amphibian model showed that systemic and spinal administration of opioids selective for mu, delta and kappa-opioid receptors produce analgesia. It is not known whether non-mammalian vertebrates also contain supraspinal sites mediating opioid analgesia. Thus, opioid agonists selective for mu (morphine; fentanyl), delta (DADLE, [D-Ala2, D-Leu5]-enkephalin; DPDPE, [D-Pen2, D-Pen5]-enkephalin) and kappa (U50488, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate; CI977, (5R)-(544alpha,744alpha,845beta)-N-methyl-N-[7-(1-p yrr olidinyl)-1-oxaspiro[4,5]dec-8yl]-4-benzofuranaceta mide++ + monohydrochloride) opioid receptors were tested for analgesia following i.c.v. administration in the Northern grass frog, Rana pipiens. Morphine, administered at 0.3, 1, 3 and 10 nmol/frog, produced a dose-dependent and long-lasting analgesic effect. Concurrent naltrexone (10 nmol) significantly blocked analgesia produced by i.c.v. morphine (10 nmol). ED50 values for the six opioids ranged from 2.0 for morphine to 63.9 nmol for U50488. The rank order of analgesic potency was morphine > DADLE > DPDPE > CI977 > fentanyl > U50488. These results show that supraspinal sites mediate opioid analgesia in amphibians and suggest that mechanisms of supraspinal opioid analgesia may be common to all vertebrates.