F. Mora

Glutamic Acid as a Putative Transmitter of the Interhemispheric Corticocortical Connections in the Rat

Abstract The effect of hemidecortication on the endogenous levels of amino acids in medial, sulcal, and dorsal frontal cortex as well as in parietal, temporal, and occipital cortex of the rat was investigated. Under aseptic conditions, the right cerebral cortex was aspirated by suction. Then, 21 days later, the content of glutamic acid, aspartic acid, γ‐aminobutyric acid, glycine, serine, threonine, and alanine was analyzed in six areas of the intact contralateral cortex using GLC. The results demonstrated a specific decrease in the endogenous levels of glutamic acid in both parietal and temporal cortex after hemidecortication of the contralateral side. This finding suggests that glutamic acid may serve as a neurotransmitter for some of the interhemispheric corticoparietal and corticotemporal fibers. In a follow‐up experiment, the effect of a frontal lesion on the endogenous levels of the same amino acids in the striatum was also examined. In this case, the glutamic acid content exhibited a decrease of 31 % relative to the control value. This observation confirms the earlier finding of a glutamate‐containing pathway from the frontal cortex to the striatum.

Effects of agonists and antagonists of D1 and D2 dopamine receptors on self-stimulation of the medial prefrontal cortex in the rat.

The possible participation of D1 versus D2 dopamine receptors in mediating dopaminergic neurotransmission of self-stimulation (SS) in the medial prefrontal cortex (MPC) of the rat was studied neuropharmacologically. Intracerebral as well as intraperitoneal injections of agonists and antagonists of dopamine receptors were used in this study. In all experiments performed with systemic injections, spontaneous motor activity (SM) was measured parallel to self-stimulation behavior as control for non specific effects of the drugs. Intracranial injections were done unilaterally serving SS of the contralateral side (not injected or injected with 0.9% NaCl) as control in the same animals. Spiroperidol and pimozide were used as D1-D2 dopamine antagonists, while sulpiride was used as a specific D2 antagonist. Apomorphine was used as D1-D2 agonist, while bromocriptine and lergotrile were used at doses in which these ergot drugs are considered predominantly D2 agonists. Sulpiride, intraperitoneally or intracerebrally injected at the same locus at which the stimulating electrode was located produced no effect on SS. On the contrary, the D1-D2 antagonists, spiroperidol and pimozide intraperitoneally or intracerebrally injected produced a dose-dependent decrease on SS. On the basis of these data it is suggested, that the dopamine neurotransmission involved in SS of the MPC is mediated via D1 dopamine receptors. This suggestion is further emphasized by the results obtained with the agonists, apomorphine, bromocriptine and lergotrile. Apomorphine produced a dose-related decrease on SS and a decrease at lower doses and an increase at higher doses on SM. Bromocriptine and lergotrile had, on the contrary, no effect on SS and a dose-related decrease on SM.

Neurotransmitters, pathways and circuits as the neural substrates of self-stimulation of the prefrontal cortex: Facts and speculations

Through a multidisciplinary approach considerable progress has been made in understanding the neural substrates of self-stimulation (SS) of the medial prefrontal cortex (MPC). Thus, neuroanatomical studies have revealed that intrinsic neurones in the MPC seem to be the central elements responsible for initiating and maintaining this phenomenon in this area of the brain. Complementary to this central finding are the electrophysiological and neurohistological data reviewed here, showing that neurones in the MPC are directly activated and have monosynaptic feed-back connections with neurones located in areas which also support SS. These findings have given rise to the hypothesis that several single feed-back pathways or single circuits exist between points of SS in the MPC and points of SS in other areas of the brain. This hypothesis implies that SS in a particular area would depend not only on the intrinsic local activity induced by the electrical stimulation but on the functional and specific activity of other nuclei in the brain. The fact that lesions of single circuits, which are apparently involved in SS of the MPC such as the medial prefrontal cortex-ventrotegmental area-medial prefrontal cortex and medial prefrontal cortex-n. dorsomedialis of the thalamus-medial prefrontal cortex, do not produce a permanent decrease of SS, together with the finding that transynaptic connections seem to exist between MPC and other areas of the brain, suggests further that a complex rather than several single independent circuits could be at the neural basis of SS of the MPC. If that were the case, then SS of the MPC would not only depend upon local and single feed-back activity but upon specific functional feed-back activity among the nuclei, which in turn have single feed-back connections with the MPC (see the concept of complex circuit outlined in the section of Behavioural studies). On the basis of this hypothesis no permanent changes should be expected after lesions of single pathways since physiological and even anatomical compensation could be reached through the rest of the undamaged circuit. That terminals containing specific neurotransmitters exist in layers of the PC where electrodes for SS are located has been reviewed in this paper. Some of these neurotransmitters have been suggested to be part of the local substrates activated by SS.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent pathways to points of self-stimulation in the medial prefrontal cortex of the rat as revealed by the horseradish peroxidase technique.

Afferent projections to points of self-stimulation (SS) in the medial prefrontal cortex (MPC) of the rat were studied using the horseradish peroxidase (HRP) technique. Intracranial microinjections of HRP (30%) were delivered at the same stereotaxic points at which the electrodes eliciting SS were located. Retrogradely transported HRP labeled neurons in different thalamic, hypothalamic, mesencephalic and pontine areas. In the thalamus, labeled neurons were found in the dorsomedial, anteromedial, anteroventral, ventral, ventromedial, posteromedial, paratenial, parafascicular nuclei and n. reuniens. Labeled neurons in mesencephalic areas were found in the n. interpeduncularis, ventral tegmental area (AVT) and substantia nigra (SN). In the pons, labeled neurons were found in the locus coeruleus and in the periaqueductal gray. Other nuclei in which labeled neurons were also found were: lateral hypothalamus (LH), periventricular gray and zona incerta (ZI). Theoretically it is possible that all these afferent areas contribute to SS of MPC. This assumption is discussed and criticized in connection with previous literature on SS. It is suggested that only specific areas and their projections are good candidates for the neural mechanisms involved in the reward produced by electrical stimulation of the prefrontal cortex.

Suppression of self-stimulation of the medial prefrontal cortex after local micro-injection of kainic acid in the rat

The question of whether neurons versus fibers of passage in the medial prefrontal cortex (MPC) are essential in maintaining self-stimulation of this same area of the brain was examined. Rats were prepared with electrode-guide cannulae implanted stereotaxically to rest within MPC. A micro-injection of (KA), 10 nmol/1.0 microliter, into the right MPC produced a clear degeneration of neuronal cell bodies characterized by picnocytosis and glial invasion of the tissue surrounding the tip of the electrode. These histopathological changes were correlated with a permanent abolition of self-stimulation of the right MPC. In contrast, self-stimulation of the contralateral side of the MPC, micro-injected with 0.9% NaCl vehicle as a control, was unaffected. These results suggest that neurons of the MPC are part of the neural substrate underlying self-stimulation behavior in this cortical area of the rat.

Peptides and self-stimulation of the medial prefrontal cortex in the rat: effects of intracerebral microinjections of substance P and cholecystokinin.

The effects of intracerebral microinjections of substance P and cholecystokinin on self-stimulation of the medial prefrontal cortex of the rat were studied. Intracerebroventricular administration of substance P at doses of 2.5, 5, 10 and 20 micrograms produced a dose-related decrease in self-stimulation of the medial prefrontal cortex; spontaneous motor activity, measured as a control, was not affected. Unilateral microinjections into the medial prefrontal cortex of substance P at doses of 10 and 20 micrograms produced a decrease of self-stimulation of the ipsilateral side, but self-stimulation of the contralateral cortex, used as a control, was not affected. On the contrary, cholecystokinin in both intracerebroventricular administration at doses of 100, 200 and 400 ng, or intracortical microinjections into the medial prefrontal cortex at doses of 200, 400 and 800 ng, had no effect on self-stimulation of this cortical area. These results suggest that substance P, but not cholecystokinin, could be part of the neurochemical substrate underlying self-stimulation of the medial prefrontal cortex in the rat.

Lesions of connections of the medial prefrontal cortex in rats: differential effects on self-stimulation and spontaneous motor activity.

The effects of lesions of the mediodorsal nucleus of the thalamus (MD) and the nucleus caudate putamen (CP) on self-stimulation (SS) of the medial prefrontal cortex (MPC) were investigated. After bilateral electrolytic lesions of the MD or the anteromedial segment of the CP, SS rate and spontaneous motor activity (SMA) were measured. Both MD and CP lesions induced a significant decrease in SS. After 8 days post-lesion, SS rate recovered to pre-lesion levels. SMA did not change significantly after MD lesion. However, SMA showed a significant decrease the 1st and the 5th days after lesioning the CP. The results suggest that the MD and possibly the CP are associated with SS, although it appears that they do not have an essential but rather a modulatory role. The recovery of SS occurs within a few days, presumably due to the compensatory effect of other pathways and structures. The results are also discussed in relation to the effect found after electrolytic lesion of ventrotegmental area and locus coeruleus.

The basolateral limbic circuit and self-stimulation of the medial prefrontal cortex in the rat

The effects of lesions of the basolateral nucleus of the amygdala (ABL) and the mediodorsal nucleus of the thalamus (MD) on self-stimulation (SS) of the medial prefrontal cortex (MPC) were investigated. Spontaneous motor activity (SMA) was measured as a control for possible non-specific effects of the lesions. Bilateral electrolytic lesions of ABL or MD produced a parallel transient decrease of SS and SMA. However, combined lesion of ABL and MD produced clearly different effects on both parameters. SMA decreased during the 1st day post-lesion and recovered to control levels by the 3rd day post-lesion. SS, on the contrary, was significantly decreased during the first five days post-lesion and after that time SS rate recovered to control levels. These results suggest the involvement of the basolateral limbic circuit in the neural substate underlying SS behavior of the MPC.

Cerebral cortex and amino acid neurotransmitters: Higher levels of aspartic acid but not GABA in the frontal cortex of the rat

Endogenous levels of Aspartic acid, GABA and Glutamic acid plus Glutamine were measured in the frontal, occipital, temporal and parietal cortex. Aspartic acid levels were found higher in the frontal cortex than in the rest of the cortical areas studied. GABA, however, had a homogenous distribution among all cortical areas.

Differential effects produced by an anticholinergic on the neuroleptic inhibition of motor behaviour and self-stimulation of the prefrontal cortex in the rat.

A specific dopamine receptor blocker, spiroperidol (0.016, 0.032, 0.064 and 0.128 mg/kg) alone or in combined treatment with the centrally acting anticholinergic, dexetimide (0.5, 1.0 mg/kg) was given intraperitoneally to rats pressing a lever for brain self-stimulation through electrodes implanted in the medial prefrontal cortex. The same treatment was also given to rats in which the spontaneous motor behaviour was measured. Spiroperidol produced a dose-related inhibtion of both self-stimulation and spontaneous motor activity. Dexetimide, given to spiroperidol treated rats, was able to antagonize the motor impairment produced by spiroperidol, but prefrontal cortex self-stimulation remained decreased. These data support the suggested role for dopamine in self-stimulation of the prefrontal cortex in the rat.