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)     

Behaviorally derived measures of conduction velocity in the substrate for rewarding medial forebrain bundle stimulation

The results of collision and refractory period tests were used to compute conduction velocity estimates for reward-relevant neurons activated by electrodes aimed approximately 3 mm apart along the trajectory of the medial forebrain bundle (MFB). Collision tests consisted of delivering pairs of pulses in alternating fashion to the lateral hypothalamus and ventral tegmental area. As the interval between pulses was increased the behavioral effectiveness of double-pulse stimulation abruptly increased and then levelled off at longer pulse-pair intervals. In 6 subjects the C-T interval at which the abrupt rise was observed ranged from 1.0 to 3.0 ms. Refractory periods were estimated using an analogous paradigm but with both pulses applied through the same electrode. Recovery was first evident at pulse-pair intervals greater than 0.4-0.6 ms. Conduction velocity was determined for each subject by dividing the interelectrode distance by the difference between the collision interval and the refractory period; a range of 1.0-4.5 m/s was obtained, values that are inconsistent with the reported conduction velocities for catecholaminergic fibers. It is proposed that the substrate for brain-stimulation reward in the MFB consists of small, myelinated, non-catecholaminergic fibers.     

Electrolytic lesions of the cortical and adjacent nuclei in the amygdala differentially influence thresholds for rewarding medial forebrain bundle stimulation.

After electrolytic lesions to the cortical and adjacent amygdaloid subnuclei, thresholds for rewarding medial forebrain bundle (MFB) stimulation were tracked in 19 rats with bilateral implants and 8 with single implants. Results were categorized into 3 groups depending on the magnitude of the lesion effect on ipsilateral frequency thresholds: substantial (> 60%), small (> 26%), or none (     

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.     

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.     

Increased expression of NGFI-A mRNA in the rat striatum following burst stimulation of the medial forebrain bundle

Using in situ hybridization, we examined the mRNA expression for several immediate early genes in dopamine-innervated brain areas following electrical burst vs. regular stimulation of the medial forebrain bundle in anaesthetized rats. Two hours after 5 Hz burst stimulation, the expression of the nerve growth factor-inducible clone A (NGFI-A) mRNA was increased in the medial part of the striatum. This increase was prevented by pretreatment with the dopamine-D1 receptor antagonist, SCH23390 (0.1 mg/kg i.p.). After 8 Hz burst stimulation, NGFI-A mRNA expression was increased in the medial, central and lateral parts of the striatum. Induction occurred predominantly in cells expressing mRNAs for the dopamine-D1 receptor, substance P and dopamine and cAMP-regulated phosphoprotein (DARP-32). Regular stimulation had no effect on NGFI-A mRNA expression. The induction of NGFI-A was related to the levels of dopamine released by burst or regular stimulation as demonstrated with in vivo amperometry. Two hours after stimulation, the expression of none of the other genes studied was altered. One hour after 8 Hz burst stimulation, the expression of NGFI-A, NGFI-B and jun-B mRNAs was increased in the striatum and that of NGFI-A, NGFI-B, c-fos, fos-B and jun-B mRNAs was variably increased in the nucleus accumbens and lateral septum. These results provide additional support for the physiological importance of burst firing activity in midbrain dopamine neurons for the activation of their target cells. They demonstrate a spatial and temporal specificity as regards the brain region, the gene activated, the receptor involved and the phenotype of the cells affected.     

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)     

Effects of knife-cut lesions of the medial forebrain bundle in self-stimulating rats.

Unilateral frontal-plane knife-cut lesions were made in the anterior medial forebrain bundle ipsilateral to a lateral hypothalamic self-stimulation electrode. Behavioral effects of the knife cut on self-stimulation reward and operant performance capacity were measured via the reward summation function method. Knife cuts placed at the level of the anterior commissure were ineffective in altering reward or motor/performance capacity, whereas knife cuts just posterior in the caudal lateral preoptic area degraded reward and sometimes impaired motor/performance capacity. In a second experiment, knife cuts placed posterior to the ventral tegmental area were ineffective unless they intruded on the ventral tegmental area itself. Several small knife cuts placed just anterior to the ventral tegmental were effective in reducing self-stimulation reward. The results are discussed in terms of the anatomical substrate of lateral hypothalamic self-stimulation reward and as a first step in a larger mapping study. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulation of the medial preoptic area facilitates sexual behavior but does not reverse sexual satiation.

The aim of the present study was to establish whether electrical and/or drug stimulation of the medial preoptic area/anterior hypothalamus (mPOA/AH) surmounts the sexual behavior inhibition that results from copulation to exhaustion. Thus, intermittent electrical stimulation of the mPOA/AH (alone or combined with the systemic injection of yohimbine or apomorphine, at doses that were subthreshold for reversing sexual exhaustion) or intrapreoptic treatments to block GABAergic transmission were applied to sexually satiated rats. The results suggest that the mPOA/AH is not responsible for male sexual behavior inhibition or for the pharmacologically induced sexual behavior expression in satiated rats. Data are discussed in terms of the roles ascribed to the mPOA/AH, both in the control of sexual behavior expression and in the regulation of the postejaculatory interval. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transforming growth factor-alpha expands progenitor cells of the basal forebrain, but does not promote cholinergic differentiation

Specific transport activities package classical neurotransmitters into secretory vesicles for release by regulated exocytosis, but the proteins responsible for the vesicular transport of neurotransmitters are still being identified. One family of proteins includes vesicular transporters for monoamines and acetylcholine. Genetic manipulation in cells and in mice now shows that changes in the expression of these proteins can alter the amount of neurotransmitter stored per synaptic vesicle, the amount released and behavior. Although the mechanisms responsible for regulating these transporters in vivo remains unknown, recent work has demonstrated the potential for regulation by changes in intrinsic activity and in location. In addition, a recently identified vesicular transporter for GABA defines a novel family of proteins that mediates the packaging of amino acid neurotransmitters.     

Effects of concomitant motor reactions on the measurement of rewarding efficacy of brain stimulation.

We describe an experiment in which the presence and severity of motoric reactions were controlled experimentally by simultaneous stimulation through a second electrode, located in a motoric brain region. Rats were implanted with one hypothalamic (LH) electrode (which elicited self-stimulation) and one reticular (RF) electrode (which elicited head and body movements). The rate-frequency function for each LH electrode was obtained under a single-pulse condition (LH electrode alone) and under a paired-pulse condition repeated three times, in which each LH pulse was accompanied by three different intensities of an RF pulse. Despite its severe effect on the slope and the asymptotic rate of R-F function, the interfering reaction failed to shift the R-F function to any significant degree. We concluded that these interfering reactions do not alter the estimates of neuronal density obtained through application of the curve-shift paradigm. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of lesions in the medial forebrain bundle on three measures of pain sensitivity and noise-elicited startle.

Subjected 137 male Holtzman albino rats to bilateral lesions of the medial forebrain bundle (MFB) or to surgical control procedures. Lesions produced equivalent decreases in paw-lick latency to heat and in jump and high-magnitude-response thresholds to footshock. Flinch and detection thresholds to footshock were also significantly decreased, though the lesion did not alter the magnitude or habituation of noise-elicited startle. Injection of 75 mg/kg serotonin into lesioned Ss returned the high-magnitude-response threshold to normal values but did not affect detection threshold. It is concluded that the increased sensitivity to painful stimuli resulted from the decrease in telencephalic content of serotonin following MFB lesions. Previous exposure of lesioned Ss to footshock resulted in a potentiation of the startle response to noise, further suggesting that the lesion had increased the aversiveness of footshock. (27 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of rostral medial forebrain bundle and olfactory tubercle lesions upon sexual behavior of male rats.

Examined the effect on sexual behavior of 57 male Sprague-Dawley rats of reduced olfactory system input to the preoptic area and medial forebrain bundle (MFB). Bilateral electrolytic lesions in the MFB just caudal to the preoptic area virtually abolished mating behavior. Electrolytic lesions or sham lesions placed bilaterally in the olfactory tubercle produced decrements in the mating behavior. There was no evidence of gonadotropic dysfunction in any of the groups, nor were there significant differences in their mean body weights at sacrifice. (22 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Altered sensitivity to footshock after selective serotonin depletion: Comparison of electrolytic lesions and neurotoxin injections in the medial forebrain bundle of the rat.

Compared the changes in 183 male albino rats' jump threshold with changes in monoamine content of the telencephalon after damage to the lateral hypothalamus produced either by electrolytic lesions or by 6-hydroxydopamine (6-OHDA) and 5,7-dihydroxytryptamine (DHT). Electrolytic lesions produced significant decreases in jump threshold and in telencephalic content of serotonin, norepinephrine, and dopamine. Infusions of DHT, with or without pretreatment with desipramine, always reduced both jump thresholds and serotonin content, even when there was no effect on norepinephrine or dopamine. In contrast, 6-OHDA had no effect on jump thresholds or serotonin content, even though both norepinephrine and dopamine were greatly reduced. Results suggest that the increased sensitivity to footshock was solely due to the interruption of ascending serotonergic pathways within the lateral hypothalamus and was not a result of damage either to norepinephrine and dopamine pathways or to some other neural system. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Additive wake-promoting actions of medial basal forebrain noradrenergic α1- and β-receptor stimulation.

The locus coeruleus-noradrenergic system exerts an activating influence on forebrain neuronal and behavioral activity states, in part through the actions of noradrenergic β-receptors in the medial septal (MS) and medial preoptic (MPOA) areas. MPOA α1-receptors exert similar wake-promoting actions. The current study examines the influence of α1-receptors located within MS on sleep-wake state. In addition, the extent to which α1- and β-receptors located within MS and MPOA interact in the modulation of behavioral state was investigated by examining the effects of individual or combined infusion of α1- and β-agonists into these regions. Results show that al-receptors located within MS exert wake-promoting actions. Within both MS and MPOA, additive wake-promoting actions were observed with α1- and β-receptor stimulation, the sum of which contributes to the overall arousal state of the animal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic exposure to morphine does not alter the neural tissues subserving its acute rewarding properties: Apparent tolerance is overshadowing.

Drug-naive, but not morphine-dependent, rats preferred places paired with morphine (2 mg/kg) over unfamiliar neutral places. Both drug-naive and morphine-dependent rats preferred places paired with higher doses of morphine (20 mg/kg) over unfamiliar places. Lesions of the tegmental pedunculopontine nucleus (TPP) blocked the conditioned place preferences produced by both 2 and 20 mg/kg morphine in drug-naive rats but not the preferences produced by 20 mg/kg morphine in dependent rats. When morphine-dependent animals received withdrawal-alleviating doses of morphine (20 mg/kg) 3.5 hrs before pairing one environment with 2 mg/kg morphine, they showed morphine-conditioned place preferences that were abolished by TPP lesions. The apparent behavioral tolerance to the TPP-mediated rewarding effects may have resulted from overshadowing by separate withdrawal-related motivational mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tactile evaluation of the response to double burst stimulation decreases, but does not eliminate, the problem of postoperative residual paralysis

BACKGROUND: Routine perioperative monitoring with accelero-myography might prevent residual block, whereas routine tactile evaluation of the response to train-of-four (TOF) nerve stimulation does not. The purpose of this prospective, randomised and blinded study was to evaluate the effect of manual evaluation of the response to double burst stimulation (DBS3.3) upon the incidence of residual block. METHODS: Sixty adult patients scheduled for elective abdominal surgery were included in the study. Pancuronium 0.08 to 0.1 mg kg-1 was given for relaxation and tracheal intubation. For maintenance of neuromuscular block, pancuronium 1-2 mg was administered. The patients were randomly allocated into two groups. In group DBS (double burst stimulation) the degree of block during anaesthesia was assessed by manual evaluation of the response to TOF nerve stimulation. During reversal, when no fade was detectable in the TOF response, the stimulation pattern was changed to DBS3.3. The trachea was extubated when the anaesthetist judged the neuromuscular function to have recovered adequately and no fade in the DBS3.3 response could be felt. In group CC (clinical criteria) patients were managed without the use of a nerve stimulator, and the level of neuromuscular block and reversal were evaluated solely on the basis of clinical criteria. In both groups, the TOF ratio was measured by mechanomyography immediately after tracheal extubation. Also, the ability to sustain head lift for 5 s, to protrude the tongue, to open the eyes, and to lift one arm to the opposite shoulder were tested. RESULTS: The TOF ratio, as measured immediately after tracheal extubation, was significantly lower in group CC than in group DBS (means: 0.68 and 0.78, respectively), and the incidence of residual neuromuscular block defined as a TOF ratio < 0.7 was significantly higher in group CC than in group DBS (57 and 24%, respectively). The time from the first TOF measurement until the TOF ratio reached 0.8 was significantly longer in group CC than in group DBs (means: 11.5 and 6.2 min, respectively). No significant differences between the two groups of patients were found in duration of anaesthesia, in times from end of surgery to injection of neostigmine, tracheal extubation or TOF ratio 0.8, in dose of pancuronium, or in any other postoperative variable. CONCLUSION: Routine perioperative manual evaluation of the responses to TOF and DBS3.3 decreased the incidence and the degree of residual block following the use of pancuronium. It did not, however, exclude clinically significant residual paralysis, nor did it influence the amount of pancuronium used during the operation, the duration of anaesthesia or the time from end of surgery to tracheal extubation or to sufficient recovery of neuromuscular function (TOF = 0.8).     

Subjective reward magnitude of medial forebrain stimulation as a function of train duration and pulse frequency.

The growth of the subjective reward magnitude of medial forebrain bundle stimulation in the rat (Sprague-Dawley) as a function of train duration and pulse frequency was measured in 2 ways: (1) a titration method, which used differences in rate of reward on 2 levers to compensate for differences in the magnitude of the rewards; and (2) a direct method, in which the ratio of the reward magnitudes at the 2 levers was assumed to be given by the ratio of times spent on each lever. The results of the 2 methods agree. Reward magnitude grows as approximately a power function of train duration up to train durations of about 1 sec, then declines somewhat over the interval from 2–20 sec. The exponent of growth varies from 0.4 to 2.3. With stronger stimulation (higher pulse frequency), peak reward magnitude is bigger, but the saturating train duration is approximately the same. (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)     

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)