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Intracranial self-stimulation in rats as a function of various stimulus parameters. VI. Influence of fentanyl, piritramide, and morphine on medial forebrain bundle stimulation with monopolar electrodes.

The effects of different subcutaneous doses of fentanyl (0.02, 0.04, 0.08, and 0.16 mg/kg), piritramide (0.63, 2.50, 10.0 and 40.0 mg/kg), and morphine (2.50, 5.00, 10.0 and 20.0 mg/kg) on self-stimulation in rats were studied. Different stimulus parameter combinations (SPC) inducing low, high or intermediate control response rates (CRR) were applied during the same experimental sessions. The three narcotic analgesics induced response depression (RD) and response stimulation (RS). RS was mostly observed at low dose levels; RD was dose-related. SPC's inducing low CRR were more sensitive than those inducing high CRR. Fentanyl was more potent than piritramide and than morphine. The RD is related to motor incapacitation, as the doses needed to effectively reduce self-stimulation also induced obvious catatonia. The RS probably is a more specific effect reflecting sensitization of structures involved in reinforcement of behavior.

Analgesics, Opioid

Effect of clonidine on the noradrenergic cyclic AMP generating system in the limbic forebrain and on medial forebrain bundle self-stimulation behavior.

The present results show that clonidine does not mimic the agonist action of norepinephrine (NE) on the noradrenergic cyclic AMP generating system of the limbic forebrain, but antagonizes the stimulatory effect of NE while not influencing the action of isoprenaline. In self-stimulation behavior, clonidine decreases responding and blocks the facilitation caused by d-amphetamine.

Adenosine Monophosphate

Strength-duration analysis of the organization of reinforcement pathways in the medial forebrain bundle of rats.

Strength-duration curves were determined for electrical self-stimulation of the brain in rats implanted with lateral hypothalamic electrodes. The rats self-stimulated in different behavioral situations which required them to make different responses, and the parameters of the strength-duration curves determined in each situation were compared. The comparisons suggested that two distinct groups of neurons were involved in the mediation of brain stimulation reinforcement of the bar pressing response, and that one of these groups was primarily involved in mediating the reinforcement of an alley running response, while the other group primarily mediated the reinforcement of a responses suggested that the nature of the response a rat is response a rat is required to perform determines the exact combination of neurons from the two groups which participate in mediating the brain stimulation reinforcement of the task. The possible functional significance of these two neuron groups was discussed.

Animals

Effect of substance P on medial forebrain bundle self-stimulation in rats following intracerebral administration.

The effect of Substance P infused intracerebrally via chronically implanted electrode-cannulae on self-stimulation induced from the same site was studied in rats. Substance P caused a significant depression of self-stimulation at 60 and 120 microgram/rat. Morphine infused into this site also caused significant depression of self-stimulation, but the doses were considerably lower than those of Substance P (5 and 10 microgram/rat). Pretreatment with naloxone, a narcotic antagonist, significantly antagonized the effects of Substance P on self-stimulation. It is proposed that Substance P modulates self-stimulation by the release of an endogenous morphine-like substance, but the possibility of a direct effect of Substance P was not ruled out.

Animals

Tolerance to amphetamine's facilitation of self-stimulation responding: anatomical specificity.

Further work on the phenomenon reported by Leith and Barrett, wherein tolerance was shown to develop to the well-known D-amphetamine-induced facilitation of self-stimulation, clearly indicates that the development of such tolerance is dependent on the location of the stimulating electrode. Thirty-seven Fisher or Harlan rats were trained to bar press for hypothalamic stimulation (60 Hz, AC). Following several sessions during which small doses of D-amphetamine were administered to demonstrate facilitation, the subjects were placed on a 4-day D-amphetamine regimen. During this time they were given three daily injections of continuously increasing doses of D-amphetamine (total 78 mg/kg). Subsequent tolerance was shown for electrodes stimulating dorsal or medial hypothalamic structures (H2 field of Forel, dorsal medial forebrain bundle, medial hypothalamic nuclei), but did not develop with ventral or lateral hypothalamic stimulation sites (fornix, ventral medial forebrain bundle).

Animals

Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study.

The ascending projections of the locus coeruleus were studied using an autoradiographic method. The major projection of locus coeruleus neurons ascends in a dorsal pathway traversing the midbrain tegmentum in a position ventrolateral to the periaqueductal gray. At the caudal diencephalon the locus coeruleus axons descend to enter the medial forebrain bundle at a caudal tuberal hypothalamic level. They are jointed in the medial forebrain bundle by a much smaller locus coeruleus projection which takes a ventral course through the midbrain tegmentum and enters the medial forebrain bundle via the mammillary peduncle and ventral tegmental area. Terminal projections are evident in the midbrain to the periaqueductal gray, tegmentum and raphe nuclei. There are widespread projections to the dorsal thalamus. The heaviest of these are to the intralaminar nuclei, the anteroventral and anteromedial nuclei, the dorsal lateral geniculate and the paraventricular nucleus. In the hypothalamus the largest projections are to the lateral hypothalamic area, periventricular nucleus, supraoptic nucleus and paraventricular nucleus. As the locus coeruleus projection ascends in the medial forebrain bundle, fibers leave it to traverse the lateral hypothalamus and zona incerta and enter the internal capsule, the ventral amygdaloid bundle and ansa peduncularis. These appear to terminate in the amygdaloid complex and, via the external capsule, in the lateral and dorsal neocortex. At the level of the septum 4 projections are evident. One group of fibers enters the stria medullaris to terminate in the paraventricular nucleus and habenular nuclei. A second group joins the stria terminalis to terminate in the anygdaloid complex. The third group turns into the diagonal band and medial septum; some fibers terminate in the septal nuclei and others continue into the fornix to termimate in hippocampus. A large component continues around the corpus callosum into the cingulum to terminate in the cingulate and adjacent neocortex, the subiculum and hippocampus. The remaining fibers continue rostrally in the medial forebrain bundle to terminate in olfactory forebrain and frontal neocortex. Commissural projections arise at 4 locations. The first decussation occurs in the dorsal tegmentum just below the central gray rostral to the locus coeruleus. The crossing fibers enter the contralateral dorsal bundle. A second group of fibers leaves the ipsilateral dorsal pathway, crosses in the posterior commissure and enters the contralateral dorsal pathway at the level. The third commissural projection arises more rostrally and crosses in the dorsal supraoptic commissure to enter the contralateral medial forebrain bundle. The fourth commissural projection is through the anterior commissure. The termination of the contralateral projection appears similar to that of the ipsilateral projection.

Afferent Pathways

Hunger induced changes in the noradrenaline and dopamine contents in various nuclei of the limbic system in rats.

Teh effect of 48 hr food deprivation on noradrenaline (NA) and dopamine (DA) content in the dorsomedial, ventromedial and arcuate hypothalamic nuclei, in the anterior and posterior part of medial forebrain bundle, in the medial preoptic region, nucleus of diagonal band (septum), and in the central, medial and basal nuclei of the amygdaloid complex was investigated by radioenzymatic assay. It was found that starvation resulted in decreased NA and DA levels in arcuate and ventromedial nuclei, and increased DA content in the posterior medial forebrain bundle. A statistically insignificant increase of DA in the central amygdaloid nucl. was also observed.

Amygdala

Total and partial hypothalamic deafferentations for topographical identification of catecholaminergic innervations of certain preoptic and hypothalamic nuclei.

After total deafferentation of the medial hypothalamus in the rat, noradrenaline concentration in the nucleus arcuatus and the eminentia mediana diminished to one-third. The same decrease of noradrenaline concentration resulted also from partial (anterolateral) deafferentation. Rostral and caudal cuts from the medial hypothalamus did not induce any change in the noradrenaline concentration of the two above-mentioned areas. This indicates that noradrenaline containing axons enter the medial basal hypothalamus laterally from the medial forebrain bundle. Total or partial deafferentation of themedial hypothalamus did not affect noradrenaline or dopamine concentrations in the nucleus preopticus medialis, the nucleus interstitialis striae terminalis, the nucleus hypothalamicus anterior and nucleus supraopticus. The catecholaminergic fibres supplying these regions do not pass the medial hypothalamus, but probably ascend laterally from it, in the medial forebrain bundle. The noradrenaline innervation of the nucleus dorsomedialis takes its origin in the ventral noradrenaline bundle and the fibres from the medial forebrain bundle ascend into the nucleus from the lateral side. After total or lateral deafferentation of the medial hypothalamus, that ransects the fibres running to the nucleus laterally, noradrenaline concentration decreases, apart from the nucleus located within or outside the deafferented island. In this case anterior or posterior deafferentation of the hypothalamus is ineffective. Total deafferentation did not change dopamine concentration in the nuclei of the medial basal hypothalamus, thereby furnishing evidence for its intrahypothalamic origin from the A12 cell group. However, after total deafferentation, some slight decrease of dopamine concentration could be observed in the median eminence. This suggests that the dopamine concentration in the median eminence does not originate exclusively from thenucleus arcuatus but to some extent originates from extrahypothalamic sites. After posterior deafferentation, which destroys the fibres of the incertohypothalamic dopamine system, dopamine concentration in the nucleus dorsomedialis decreases. After total deafferentation of the medial hypothalamus, which isolates the nucleus from the ventral nuclei (and so also from the A12 cell group) of the medial hypothalamus, the dopamine concentration in the nucleus dorsomedialis did not change.

Animals

[Role of the median forebrain bundle in organizing the electrical activity of the neocortex].

Bilateral coagulation of the forebrain medial bundle in the lateral hypothalamus enhances the formation of spontaneous spindles and facilitates the recruiting response in the neocortex. This combines with a defect of desynchronizing influences of the posterior hypothalamus and the concurrent dominance of synchronizing effects of the preoptic area (PA). PA stimulation enhances the slow wave and spindle activity in the ECoG of the intact brain. After disruption of PA connections with the bulbar synchronizing apparatus the stimulation effect is manifested only in enhanced spindle activity. It is assumed that in addition to hypnogenic influences which PA shares with the parasolitary apparatus, it maintains a definite level of cortical reactivity after the onset of sleep. Elimination of the orbito-frontal cortex, as well as PA coagulation, does not prevent the appearance of spindles in the ECoG of the preparation with an intersected medial bundle, only limiting them to some extent.

Animals

An autoradiographic study of the efferent connections of the lateral hypothalamic area in the rat.

The efferent connections of the lateral hypothalamic area (LHA) have been analyzed in a series of 30 rat brains with injections of 3H-amino acids into different parts of the area and the surrounding regions. Our findings indicate that all parts of the LHA contribute ascending and descending fibers to the medial forebrain bundle, and also project medially to certain of the adjoining hypothalamic nuclei. All levels of the LHA appear to send some fibers to a continuous group of structures that extends from the medial septal-diagonal band complex rostrally, through the lateral preoptic and lateral hypothalamic areas to the mammillary complex and the ventral tegmental area caudally. In addition, it is evident that cells at different levels within the LHA may have differential projections. Thus, the anterior and lateral parts of the LHA also appear to project substantially to the anterior hypothalamic area, the ventromedial and dorsomedial hypothalamic nuclei, the parataenial and paraventricular nuclei of the thalamus, and the medial part of the lateral habenular nucleus. Similarly, cells in the tuberal and posterior parts of the LHA project to the central gray, the longest projections from the posterior region reaching as far caudally as the central tegmental field, the parabrachial nucleus, the locus coeruleus, and the superior central and dorsal nuclei of the raphe. Viewed as a whole, the LHA is therefore well-suited to integrate inputs from the limbic system and brainstem and to relay them on the one hand to the medial zone of the hypothalamus and on the other to virtually every structure closely associated with the medial forebrain bundle and to the nuclei of origin of the major ascending monoaminergic systems.

Animals

Identification of pathways mediating cardiovascular responses elicited by stimulation of the septum in the rat.

1. Experiments were done in rats anaesthetized with sodium pentobarbitone to localize pathways mediating the cardiovascular responses elicited by electrical stimulation of the septum. The major efferent projections from the septum were first identified anatomically by the Fink-Heimer II technique and these pathways were subsequently lesioned in acute experiments to establish their role in the mediation of the cardiovascular responses elicited by septal stimulation. 2. Electrical stimulation of histologically localized sites in the lateral septum elicited hypotension and bradycardia whereas stimulation of sites in the medial septum elicited hypertension and bradycardia. 3. Selective lesions of cardiovascular responsive sites in either the lateral or medial septum produced a pattern of degeneration essentially similar to that of previous anatomical studies, i.e. the main efferent projections were localized to the fornix, stria medullaris and the medial forebrain bundle. 4. Stimulation of the fornix did not elicit cardiovascular changes and lesions of this pathway did not alter cardiovascular responses to septal stimulation. 5. Stimulation of the stria medullaris elicited hypotension and bradycardia whereas stimulation of the medial forebrain bundle elicited hypertension and bradycardia. Ipsilateral lesions of the stria medullaris, signicicantly attenuated the hypotension and bradycardia elicited by stimulation of the lateral septum but did not affect the responses to stimulation of the medial septum. Bilateral lesions of the medial forebrain bundle in the region of the lateral hypothalamus abolished the hypertension but did not affect the bradycardia elicited by medial septum stimulation. Cardiovascular, reponses elicited by stimulation of the lateral septum were not affected by medial forebrain bundle lesions. 6. It is suggested that the cardiovascular responses elicited by stimulation of the lateral septum are mediated via the stria medullaris and that the hypertension elicited by stimulation of the medial septum is mediated via the medial forebrain bundle. On the other hand, the bradycardia elicited by stimulation of the medial septum is probably mediated by a pathway presently unknown.

Animals

[Effect of the orbital-frontal cortex on several autonomic functions].

It is not only the cortex of orbito-insular complex ("vagal" zone) but also the proreal cortex (frontal zone) which take part in regulation of respiration, blood pressure, rhythmical heart activity. Cortico-fugal impulses spread along two tracts from the proreal gyrus: to the trunk vegetative centers directly and indirectly -- through the orbital gyrus. The experiments with combined destruction of main efferent tracts of the orbito--frontal cortex showed the forebrain medial bundle to be the principal morphological tract of the orbito-frontal cortex projecting to the trunk vegetative centers.

Animals

Changes in morphine self-administration after tel-diencephalic lesions in rats.

Rats were trained to bar-press for intravenous infusions of morphine sulfate during 1-h daily test sessions. Rates of morphine self-administration were enhanced by lesions of the frontal cortex and hippocampus and transiently reduced by lesions of the medial forebrain bundle and medial thalamus. Dose-response studies indicated that sensitivity to morphine's rewarding property was decreased by frontal cortical and hippocampal lesions. Lesions of the posterior cortex, the tuberculum olfactorium, and the nucleus accumbens had no effect on self-administration behavior. The results are discussed in relation to previous findings with caudate and brainstem lesions. A neuroanatomical substrate for morphine reinforcement is suggested.

Animals