Anatomical dissociation of the substrates of medial forebrain bundle self-stimulation and exploration.

The purpose of this research was to determine whether brain stimulation reward and exploration are induced by activation of the same set of neurons along the medial forebrain bundle. The behavioral version of the collision test was utilized with electrodes in the lateral hypothalamus (LH) and the ventral tegmental area (VTA). A collision effect obtained between LH and VTA in one behavior at the exclusion of the other was treated as evidence of the involvement of two different sets of fibers. In 4 rats, a collision effect was observed only in self-stimulation, whereas in 1 rat, a collision was obtained in exploration at the exclusion of self-stimulation. Three animals showed no collision in either behavior. These data suggest that coexistence of self-stimulation and exploration following medial forebrain bundle stimulation can be explained by current spread on two different sets of fibers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Microbial degradation of tetraethyl lead in soil monitored by microcalorimetry

Fos immunohistochemistry was used to stain neurons in the caudal diencephalon, midbrain and hindbrain driven by rewarding stimulation of the lateral hypothalamus (LH). Increases in Fos-like immunoreactivity were most pronounced ipsilateral to the site of stimulation and tended to be confined within discrete structures such as the posterior LH, arcuate nucleus, ventral tegmental area (VTA), central gray, dorsal raphé, pedunculopontine area (PPTg), parabrachial nucleus, and locus coeruleus. At least two of these structures, the VTA and PPTg, have been implicated in medial forebrain bundle self-stimulation.     

Conditioned suppression of medial forebrain bundle and septal intracranial self-stimulation in the rat: Evidence for a fear-relief mechanism of the septum.

In 3 experiments, a conditioned emotional response (CER) paradigm was presented to 2 groups of male albino Sprague-Dawley rats (N?=?20) during intracranial self-stimulation (ICSS). One group barpressed for medial forebrain bundle (MFB) stimulation reward; the other group barpressed for septal stimulation reward. The MFB ICSS was found to be suppressed by the CER procedure, but this procedure failed to suppress septal ICSS. The difference between the 2 sites was found only when both MFB and septal ICSS current intensities were available at their optimal levels. When ICSS current intensities were lowered to either threshold or medium level, both groups exhibited the CER suppression effect. Ss were also tested for a possible analgesic effect produced by the ICSS. MFB stimulation was found to produce some degree of analgesia, but septal stimulation failed to produce any analgesic effect. Thus, the possibility that the attenuation of the CER suppression effect in the septal group was due to analgesia was excluded. The difference in MFB and septal ICSS behavior during the presentation of the aversive stimulus suggests a possible qualitative distinction between the reward functions of the 2 sites, and a possible fear-reduction property of the septal area. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Dopamine release in the nucleus accumbens by hypothalamic stimulation-escape behavior

It is known that lateral hypothalamic stimulation or self-stimulation can release dopamine in the nucleus accumbens (NAc). The present experiment illustrates that an aversively motivated behavior can also do this. Rats were prepared with microdialysis probes in the NAc and electrodes in the lateral hypothalamus (LH) or medial hypothalamus (MH). Automatic stimulation of the LH increased extracellular dopamine in the NAc 30% as reported earlier. The animals would perform both self-stimulation to turn the current on and stimulation-escape to turn it off, suggesting a combination of reward and aversion. Escape responding increased extracellular dopamine (DA) 100%, even though there was less total stimulation. Automatic stimulation of the MH did the opposite of the LH by decreasing accumbens dopamine (-20%), and the animals would only perform stimulation-escape, indicative of pure aversion. But again, extracellular DA in the NAc increased 100% during escape responding. Thus DA can be released during negative reinforcement when an animal's behavior is reinforced by escape from lateral or medial hypothalamic stimulation. This suggests that DA release was correlated with stimulation-escape behavior, rather than the aversiveness of automatic stimulation.     

Integration of free pulses in electrical self-stimulation of the rat brain.

Frequency thresholds for electrical self-stimulation of the medial forebrain bundle were estimated in rats while low frequencies of pulses were applied continuously. When continuous pulses were delivered to the same electrode that received the 0.5-sec trains of response-initiated stimulation, thresholds decreased by the free-pulse frequency (Experiment 1), consistently across current (Experiment 2). Estimates of the reward added by concurrent, response-contingent stimulation of the opposite electrode of a bilateral pair predicted the drop in threshold caused by the noncontingent pulses applied to the opposite hemisphere (Experiment 3), again, robustly across test current (Experiment 4). Continuous pulses restricted to times between self-initiated trains lost their effect (Experiment 5). The perception of reward was invariant despite changes in the overall activity of the self-stimulation substrate. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence for a role of dopamine in self-stimulation of the nucleus accumbens of the rat.

Investigated the effects of centrally administered spiroperidol, a dopamine receptor blocking agent, on self-stimulation of the nucleus accumbens and medial prefrontal cortex in the rat. Spiroperidol in a volume of 1 μl was microinjected into the region of the stimulating electrodes. Self-stimulation of the nucleus accumbens was significantly attenuated by .75, 1.0, and 2.0 μg spiroperidol. Control microinjections of the drug vehicle had no effect. Spiroperidol microinjected into the nucleus accumbens contralateral to the stimulating electrode, as a control for possible motor or nonspecific effects, did not attenuate self-stimulation. Microinjections of spiroperidol into the region of the stimulating electrodes in the prefrontal cortex had no consistent effect on self-stimulation with the two lower doses, but did result in attenuation at the 2.0 μg dose. Self-stimulation of the nucleus accumbens was not changed by microinjections of spiroperidol into the ipsilateral or contralateral prefrontal cortex. Similarly, self-stimulation of the prefrontal cortex was not altered by microinjections of spiroperidol into the nucleus accumbens. By controlling for nonspecific effects of spiroperidol, the results provide further evidence that dopaminergic neurons contribute to self-stimulation of the nucleus accumbens. (French summary) (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of dopamine in maintaining intracranial self-stimulation in the ventral tegmentum, nucleus accumbens, and medial prefrontal cortex.

Male albino Wistar rats were prepared with 2 chronic bipolar electrodes implanted ipsilaterally in the ventral tegmentum and either the nucleus accumbens or the medial prefrontal cortex. Once stable intracranial self-stimulation was elicited from both midbrain and forebrain electrodes, 6-hydroxydopamine lesions were placed into the ascending dopaminergic pathways between the rewarding electrode placements at the level of the lateral hypothalamus. Data suggest that dopamine plays an important role in self-stimulation in the ventral tegmentum and contributes to this behavior in the prefrontal cortex. Findings also show that nondopaminergic systems contribute to the phenomenon of brain-stimulation reward. (French summary) (28 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased ipsilateral expression of Fos following lateral hypothalamic self-stimulation

Immunohistochemical labeling of Fos protein was used to visualize neurons activated by rewarding stimulation of the lateral hypothalamic level of the medial forebrain bundle (MFB). Following training and stabilization of performance, seven rats were allowed to self-stimulate for 1 h prior to anesthesia and perfusion. Brains were then processed for immunohistochemistry. Two control subjects were trained and tested in an identical manner except that the stimulator was disconnected during the final 1 h test. Among the structures showing a greater density of labeled neurons on the stimulated side of the brains of the experimental subjects were the septum, lateral preoptic area (LPO), medial preoptic area, bed nucleus of the stria terminalis, substantia innominata (SI), and the lateral hypothalamus (LH). Several of these structures, the LPO, SI, and LH, have been implicated in MFB self-stimulation by the results of psychophysical, electrophysiological, and lesion studies.     

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)     

Prolonged rewarding stimulation of the rat medial forebrain bundle: Neurochemical and behavioral consequences.

Extracellular dopamine levels were measured in the rat nucleus accumbens by means of in vivo microdialysis. Delivery of rewarding medial forebrain bundle stimulation at a low rate (5 trains/min) produced a sustained elevation of dopamine levels, regardless of whether train onset was predictable. When the rate of train delivery was increased to 40 trains/min, dopamine levels rose rapidly during the first 40 min but then declined toward the baseline range. The rewarding impact of the stimulation was reduced following prior delivery of stimulation at the high, but not the low, rate. These results support the idea that dopamine tone plays an enabling role in brain stimulation reward and is elevated similarly by predictable and unpredictable stimulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Voltammetry of extracellular dopamine in rat striatum during ICSS-like electrical stimulation of the medial forebrain bundle

Fast-scan cyclic voltammetry in the striatum of anesthetized rats has been used to monitor extracellular dopamine during forced electrical stimulation of the media forebrain bundle using parameters that mimic intracranial self-stimulation. The temporal resolution provided by microelectrodes positioned very near sites of dopamine release allows resolution of the response to individual 500-ms stimulation trains separated by 500-ms intervals. Uptake inhibition by Nomifensine alters the resolution obtained at short times after initiation of stimulation.     

A neuroanatomical investigation of enhanced cutaneous and gustatory responsivity associated with septal forebrain injury.

Observed enhanced reactivity to cutaneous stimulation (handling and footshock) in 14 male Sprague-Dawley rats sustaining either large septal lesions or medial forebrain bundle ablations at the level of the septum. Cutaneously elicited hyperreactivity was not noted in 7 unoperated controls or 28 Ss with smaller septal lesions placed in the anterior, posterior, or dorsal septum or with lesions in the stria terminalis. All septal ablations but neither the medial forebrain bundle nor the stria terminalis lesions produced a gustatory hyperreactivity in the form of altered intakes of quinine and saccharin solutions. The gustatory hyperreactivity to quinine was clearly maximal in Ss with posterior ventral septal injury. Significantly, this lesion always extended into the medial preoptic nucleus. These results point to different neuroanatomical mechanisms in the septum underlying cutaneous- vs. gustatory-elicited behavior. (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.     

Ontogenic expression of natriuretic peptide mRNAs in postnatal rat brain: implications for development?

The central natriuretic peptide system is composed of at least three structurally homologous and uniquely distributed peptides and receptors which are thought to be involved in the central regulation of cardiovascular and autonomic function and more recently been shown to affect cellular growth and proliferation, processes pertinent to mammalian development. As such, following our initial mapping of preproatrial natriuretic peptide (ppANP) mRNA in adult brain [M.C. Ryan, A.L. Gundlach, Anatomical localization of preproatrial natriuretic peptide mRNA in the rat brain by in situ hybridization histochemistry: in olfactory regions, J. Comp. Neurol., 356 (1995) 168-182], it was of interest to determine the ontogenic expression of natriuretic peptide mRNAs in the developing rat brain. Using in situ hybridization histochemistry of specific [35S]- or [33P]-labeled oligonucleotides, ppANP and preproC-type natriuretic peptide (ppCNP) mRNAs were detected in the developing rat brain from postnatal day 4 to day 60 (adult). PpANP mRNA was observed in many hindbrain, but only some forebrain, regions at postnatal day 4. Regional differences in the temporal expression of ppANP mRNA were apparent with ppANP mRNA detected in the medial preoptic area, mammillary nuclei and medial habenular nucleus at postnatal day 4 and in other areas including the arcuate and dorsomedial hypothalamic nuclei and in olfactory and limbic regions at postnatal day 10. A number of regions also exhibited transient expression of ppANP mRNA such as the bed nucleus of the stria terminalis and the medial cerebellar nucleus. In contrast, ppCNP mRNA was detected at relatively high levels in several regions on postnatal day 4 including olfactory nuclei, the hippocampus and particularly the pontine nucleus. The level of expression appeared to increase markedly in most regions including forebrain olfactory and hippocampal areas and in brainstem regions including the pontine nucleus, the parvocellular and lateral reticular and spinal trigeminal nuclei by postnatal days 10 and 13, but decreased from this peak to equivalent to adult levels by postnatal day 28. The differential and transient expression of the natriuretic peptides during postnatal development, together with previous reports of the ontogenic regulation of natriuretic peptide receptor expression and binding patterns, further suggests their involvement in developmental processes in the rat CNS and provides information relevant to the likely functional development of natriuretic peptide-utilizing pathways.     

Medial forebrain bundle stimulation in rats activates glycogen phosphorylase in layers 4, 5b and 6 of ipsilateral granular neocortex

Functional activation in human brain produces an increase in glycolytic metabolism. Animal studies suggest activation-induced glycolysis is coupled to brain glycogenolysis. Medial forebrain bundle (MFB) stimulation activates the release of neurotransmitters which promote neocortical glycogenolysis in vitro. In the present study, active glycogen phosphorylase (GP), an index of glycogenolysis, is assessed histochemically in rat brain after 15 min of MFB self-stimulation. Active GP increased significantly in layers 4, 5b and 6 of granular neocortex ipsilateral to MFB self-stimulation. Restriction of increased glycogenolysis to granular neocortex suggests an important functional interaction between sensory neocortical processing and ascending MFB systems.     

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)     

Behaviorally measured refractory periods are lengthened by reducing electrode tip exposure or raising current.

Measured the effects of current and tip surface area on stimulation parameters required to produce a constant rate of self-stimulation of lateral hypothalamic sites or of circling when stimulating medial brain stem sites. Data from 20 male Wistar rats show that thresholds for circling decreased when tip surface area was decreased to 0.01 mm–2. Refractory period curves for both circling and self-stimulation were shifted to slightly longer intrapair intervals when tip surface area was decreased or current was increased. This suggests that long refractory period axons make larger contributions when current density is increased. Chronaxies were not lengthened by small tip exposures but were reduced when electrodes were placed far lateral to the circling substrate. Threshold differences between axons stimulated by different tip exposures and currents are discussed. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Suppression of VMH-lesion-induced reactivity and aggressiveness in the rat by stimulation of lateral septum, but not medial septum or cingulate cortex.

32 male hooded rats made vicious with bilateral ventromedial hypothalamic lesions had bipolar electrodes implanted unilaterally in the lateral septum, medial septum, or cingulate cortex. Four days later, the Ss' reactivity and aggressiveness were evaluated 5 min before, during, and 5 min after stimulation at 20 muA (60 Hz, sine wave). Lateral septal stimulation suppressed reactivity and aggressiveness by almost 80% compared with pre- and poststimulation levels. Stimulation of neither the cingulate cortex nor the medial septum produced a change reliably different from that seen in unstimulated control Ss. Further tests with stimulation of the lateral septum at the 20 muA level showed that neither rewarding self-stimulation nor disruption of ongoing water drinking was produced. These results are congruent with evidence from lesion studies that the lateral septum normally acts to suppress reactivity and aggressiveness in the rat; they do not support previous suggestions that the medial septum is involved in the modulation of these behaviors. (30 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)