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Cannabinoid receptor and WIN-55,212-2-stimulated [35S]GTPgammaS binding and cannabinoid receptor mRNA levels in several brain structures of adult male rats chronically exposed to R-methanandamide.

We and others have recently demonstrated that the pharmacological tolerance observed after prolonged exposure to plant and synthetic cannabinoids in adult individuals seems to have a pharmacodynamic basis, based on the observed down-regulation of cannabinoid receptors in the brain of cannabinoid-tolerant rats. However, we were unable to elicit a similar receptor down-regulation after a chronic exposure to anandamide, the first discovered endogenous cannabinoid, possibly because of its rapid metabolic breakdown in arachidonic acid and ethanolamine. The present study was designed to progress in these previous studies, by using R-methanandamide, a more stable analog, instead anandamide. In addition, we examined not only cannabinoid receptor binding, but also WIN-55,212-2-stimulated [35S]-GTPgammaS binding, by autoradiography, and cannabinoid receptor mRNA levels, by in situ hybridization. Results were as follows. The daily administration of R-methanandamide for a period of five days produced decreases in cannabinoid receptor binding in the lateral caudate-putamen, cerebellum, entopeduncular nucleus and substantia nigra. The remaining areas, the medial caudate-putamen, globus pallidus, cerebral cortex (layers I and VI), hippocampus (dentate gyrus and Ammon's horn) and several limbic structures (nucleus accumbens, septum nuclei and basolateral amygdaloid nucleus), exhibited no changes in cannabinoid receptor binding. Similarly, the levels of cannabinoid receptor mRNA expression decreased in the lateral and medial caudate-putamen and in the CA1 and CA2 subfields of the Ammon's horn in the hippocampus after the chronic exposure to R-methanandamide, whereas the remaining areas showed no changes. WIN-55,212-2-stimulated [35S]-GTPgammaS binding did not change in the lateral caudate-putamen, cerebral cortex (layer I), septum nuclei and hippocampal structures (dentate gyrus and Ammon's horn) of animals chronically exposed to R-methanandamide, whereas a certain trend to decrease could be observed in the substantia nigra and deep layer (VI) of the cerebral cortex in these animals. In summary, as reported for other cannabinoid receptor agonists, the prolonged exposure of rats to R-methanandamide, a more stable analog of anandamide, was able to produce cannabinoid receptor-related changes in contrast with the absence of changes observed early with the metabolically labile anandamide. The observed changes exhibited an evident regional pattern with areas, such as basal ganglia, cerebellum and hippocampus, responding to chronic R-methanandamide treatment while regions, such as the cerebral cortex and limbic nuclei, not responding.

Animals↗

Brain structures involved in the hypotensive effects of rilmenidine: evaluation by [14C]2-deoxyglucose autoradiography.

The centrally acting, antihypertensive drug rilmenidine has activity at both imidazoline-preferring receptors (IPRs) and alpha 2-adrenoceptors: the IPR has been proposed to be the predominant receptor responsible for the hypotensive effects of rilmenidine. In the present study, the neuroanatomic regions of the brain involved in mediating the hypotensive response to rilmenidine were investigated in spontaneously hypertensive rats with the use of [14C]2-deoxyglucose autoradiography. The selective alpha 2-adrenoceptor agonist B-HT 933 was also studied for comparison. Rilmenidine (1 mg/kg s.c.) and B-HT 933 (2 mg/kg s.c.) induced significant and similar reductions in mean arterial pressure (-24 +/- 2 and -18 +/- 5 mm Hg. respectively) and in heart rate (-62 +/- 29 and -69 +/- 14 beats/min. respectively), whereas the vehicle had no significant hemodynamic effects. [14C]2-Deoxyglucose autoradiography revealed significant reductions in glucose use in the following structures of rilmenidine-treated rats: intermediolateral cell column of the thoracic spinal cord, area postrema, ventrolateral medulla, nucleus tractus solitarius, and cuneate nucleus, B-HT 933 did not significantly influence glucose use in any neuroanatomic structure examined. These results provide support for the functional involvement of brainstem cardiovascular control centres and the involvement of IPRs in the hypotensive response to rilmenidine.

Adrenergic alpha-Agonists↗

Please pass the cauliflower: a recipe for introducing undergraduate students to brain structure and function.

Neurophysiology/pathophysiology content is a frequent source of anxiety for undergraduate students and their instructors. This learning module supplements traditional lecture and overhead presentations to offer a novel, nonthreatening, and entertaining introduction to neuropathology. The module is based on a ridiculous analogy between the human brain and the cauliflower. This module has been used with both underclassmen and more advanced health science undergraduate students and has produced enthusiastic student responses while deescalating both student and instructor anxiety.

Aphasia↗

Effects of chronic cocaine on monoamine levels in discrete brain structures of lactating rat dams.

Chronic gestational cocaine administration has been correlated with high levels of postpartum maternal aggression towards intruders and altered levels of oxytocin in the amygdala. Cocaine may alter both oxytocin and maternal aggression either directly or indirectly through changes in monoamine levels in relevant brain regions. In this study, pregnant female rats were randomly assigned to one of four groups; three cocaine dose groups (7.5, 15 or 30 mg/kg), or a saline-treated group (0.9% normal saline) and given subcutaneous injections twice daily (total volume 2 ml/kg) throughout gestation. Behavioral responses to an inanimate object placed in the homecage were assessed on Postpartum Day (PPD) 6. Immediately following testing, animals were sacrificed and four brain regions implicated in maternal/aggressive behavior (medial preoptic area [MPOA], ventral tegmental area [VTA], hippocampus, and amygdala) were removed for monoamine level analyses using high-performance liquid chromatography. Dams given 30 mg/kg cocaine throughout gestation had significantly higher levels of dopamine (DA) and nonsignificantly elevated serotonin (5-HT) levels relative to saline-treated controls. These dams also exhibited higher frequencies of defensive behavior toward an inanimate object compared to saline-treated controls. Potential mechanisms mediating cocaine-induced increases in responding are proposed.

3,4-Dihydroxyphenylacetic Acid↗

Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans.

Neural regions modulating prepulse inhibition (PPI) of the startle response, an operational measure of sensorimotor gating, are well established from animal studies using surgical and pharmacological procedures. The limbic and cortico-pallido-striato-thalamic circuitry is thought to be responsible for modulation of PPI in the rat. The involvement of this circuitry in human PPI is suggested by observations of deficient PPI in a number of neuropsychiatric disorders characterized by abnormalities at some level in this circuitry and recent functional neuroimaging studies in humans. The current study sought to investigate structural neural correlates of PPI in a sample of twenty-four right-handed, healthy subjects (10 men, 14 women). Subjects underwent magnetic resonance imaging (MRI) at 1.5 T and were assessed (off-line) on acoustic PPI using electromyographic recordings of the orbicularis oculi muscle beneath the right eye. Optimized volumetric voxel-based morphometry (VBM) implemented in SPM99 was used to investigate the relationship of PPI (prepulse onset-to-pulse onset interval 120 ms) to regional grey matter volumes, covarying for sex. Significant positive correlations were obtained between PPI and grey matter volume in the hippocampus extending to parahippocampal gyrus, basal ganglia including parts of putamen, globus pallidus, and nucleus accumbens, superior temporal gyrus, thalamus, and inferior frontal gyrus. These findings identify the relationship between PPI and grey matter availability on a highly spatially localized scale in brain regions shown to be activated in recent functional neuroimaging studies in association with PPI in healthy humans and demonstrate the validity of structural neuroimaging methods in delineating the neural mechanisms underlying human PPI.

Acoustic Stimulation↗

Neuropsychological outcome at adolescence of very preterm birth and its relation to brain structure.

Neuropsychological outcome at 14 to 15 years of age of a cohort of 75 participants (39 male, 36 female) born at <33 weeks' gestation was investigated. Research was conducted parallel to a recent MRI study by Stewart and colleagues which reported that 55% of this cohort had evidence of brain abnormality. One aim of the study was to compare neuropsychological function in those very preterm children with and without MRI abnormality. Compared to a control sample of term adolescents, very preterm participants had impairment only on a measure of word production. On measures of attention, memory, perceptual skill, and visuomotor and executive function, the adolescents born very preterm performed in the normal range, whether or not they had evidence of MRI abnormality. Our findings are encouraging as the neuropsychological consequences of damage to the very preterm brain, still evident on MRI at 14 to 15 years of age, appear to be minor.

Adolescent↗

Chronic neuropsychological sequelae of cholinesterase inhibitors in the absence of structural brain damage: two cases of acute poisoning.

Here we describe two cases of carbamate poisoning. Patients AMF and PVM were accidentally poisoned by cholinesterase inhibitors. The medical diagnosis in both cases was overcholinergic syndrome, as demonstrated by exposure to cholinesterase inhibitors. The widespread use of cholinesterase inhibitors, especially as pesticides, produces a great number of human poisoning events annually. The main known neurotoxic effect of these substances is cholinesterase inhibition, which causes cholinergic overstimulation. Once AMF and PVM had recovered from acute intoxication, they were subjected to extensive neuropsychological evaluation 3 and 12 months after the poisoning event. These assessments point to a cognitive deficit in attention, memory, perceptual, and motor domains 3 months after intoxication. One year later these sequelae remained, even though the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans were interpreted as being within normal limits. We present these cases as examples of neuropsychological profiles of long-term sequelae related to acute poisoning by cholinesterase inhibitor pesticides and show the usefulness of neuropsychological assessment in detecting central nervous system dysfunction in the absence of biochemical or structural markers.

Adult↗

Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage.

In multiple sclerosis, the mechanisms underlying the accumulation of disability are poorly understood. Recently, it has been suggested that adaptive cortical changes may limit the clinical impact of multiple sclerosis injury. In this study, functional magnetic resonance imaging and a general search method were used to assess patterns of brain activation associated with a simple motor task in 14 right-handed, nondisabled relapsing-remitting multiple sclerosis patients that were compared to those from 15 right-handed, sex- and age-matched healthy volunteers. Also investigated were the extent to which the functional magnetic resonance imaging changes correlated with T2 lesion volume and severity of multiple sclerosis pathology in lesions and normal-appearing brain tissue, measured using magnetisation transfer and diffusion tensor magnetic resonance imaging. Compared to controls, multiple sclerosis patients showed increased activation in the contralateral primary sensorimotor cortex, bilaterally in the supplementary motor area, bilaterally in the cingulate motor area, in the contralateral ascending bank of the sylvian fissure, and in the contralateral intraparietal sulcus. T2 lesion volume was correlated with relative activation in the ipsilateral supplementary motor area, and in the ipsilateral and contralateral cingulate motor area. Average lesion magnetisaiton transfer ratio and average lesion water diffusivity were correlated with relative activation in the contralateral sensorimotor cortex. Average lesion magnetisation transfer ratio was also correlated with relative activation in the ipsilateral cingulate motor area. Average water diffusivity and peak height of the normal-appearing brain tissue diffusivity histogram were both correlated with relative activation in the contralateral intraparietal sulcus. This study shows that cortical activation occurs over a rather distributed sensorimotor network in nondisabled relapsing-remitting multiple sclerosis patients. It also suggests that increased recruitment of this cortical network contributes to the limitation of the functional impact of white matter multiple sclerosis injury.

Adaptation, Physiological↗

Brain structures involved in interoceptive awareness and cardioafferent signal processing: a dipole source localization study.

Afferent signals from the body play an important role for emotional and motivational aspects of behavior. Nevertheless, little is known about the cortical and subcortical structures involved in interoceptive processes. Recently, a functional MRI study demonstrated that insula, somatomotor, and cingulated cortices are activated when subjects focus attention on their heartbeats. Aside from the use of imaging data, cardiac awareness has frequently been studied by using the heartbeat-evoked potential (HEP), a brain wave that appears contingent on the heartbeat. The present study aimed at localizing sources of the HEP. Multichannel EEG was recorded in 44 subjects while they performed a heartbeat perception task. This task was used to quantify interoceptive awareness and to subdivide the subjects into good and poor heartbeat perceivers. Analyses showed highest HEP amplitudes over frontal and frontocentral electrode locations in the time range of later than 200 ms after R-wave onset. By means of a BESA dipole-source-analysis, four sources of the HEP were identified which were located in the anterior cingulate, the right insula, the prefrontal cortex, and the left secondary somatosensory cortex. Good heartbeat perceivers showed both significantly higher HEP amplitudes and higher dipole strength than poor heartbeat perceivers in all four cortical sources. We conclude that the identified structures are involved in the processing of cardiac signals, whereby anterior cingulate and right insula seem to serve as interoceptive centers for cardioception.

Adolescent↗

Preliminary study of the effects of morphine treatment on opioid receptor gene expression in brain structures of the female rat.

Opioid receptors play an important role in female physiology. They modulate directly and indirectly neuroendocrine phenomena that influence pregnancy maintenance, pain threshold, parturition, lactation, maternal behavior, rewarding and addiction. Thus understanding the gene expression levels of the three major opioid receptors, mu, delta and kappa in different brain regions is essential for investigating dynamic mechanisms of opioidergic transmission. Adult virgin female rats were treated acutely with morphine sulfate (3.5 mg/kg or 20 mg/kg s.c.) or chronically for 5 days (3.5 mg/kg). Rats were killed 1 h after the last injection. In the acute treatment, expression levels for the encoded mu-opioid receptor Oprm1, as detected by reverse transcription-polymerase chain reaction, were significantly decreased in the periaqueductal gray. In chronic treatment, both Oprk1 and Oprm1 expression levels, that encoded kappa and mu-opioid receptor respectively, showed significant decreases in the periaqueductal gray and striatum. Regional changes in opioid receptor gene expression levels might reflect highly specialized roles for these receptors with possible functional meaning for the plasticity of the opioidergic transmission.

Analysis of Variance↗

Role of different brain structures in the behavioural expression of WIN 55,212-2 withdrawal in mice.

We have evaluated several responses induced by the cannabinoid agonist WIN 55,212-2 related to its addictive properties, including rewarding effects and the development of physical dependence in mice. Moreover, we have studied the specific involvement of several brain regions with high density of CB1 cannabinoid receptors, such as striatum, hippocampus, amygdala and cerebellum, in the behavioural expression of SR 141716A-precipitated WIN 55,212-2 withdrawal. The systemic administration of the CB1 receptor antagonist SR 141716A (10 mg kg(-1), s.c.) precipitated behavioural signs of withdrawal in mice chronically treated with WIN 55,212-2 (1 and 2 mg kg(-1), intraperitoneal (i.p.)), revealing the development of physical dependence. The microinjection of SR 141716A (1.5 and 3 micrograms) into the cerebellum induced severe manifestations of abstinence in mice dependent on WIN 55,212-2 (1 mg kg(-1), i.p.). Out of 10 signs evaluated, seven were statistically significant: wet dog shakes, body tremor, paw tremor, piloerection, mastication, genital licks and sniffing. When the cannabinoid antagonist was administered into the hippocampus and the amygdala, a moderate but significant withdrawal syndrome was also observed. However, no signs of abstinence were induced when SR 141716A was microinjected into the striatum. WIN 55,212-2 produced rewarding effects in the place-conditioning paradigm in mice pre-exposed to a priming injection of the drug. These results show a reliable behavioural model to reveal rewarding effects and physical dependence induced by the repeated administration of WIN 55,212-2 in mice. The cerebellum and to a lesser extent the hippocampus and the amygdala participate in the behavioural expression of cannabinoid withdrawal.

Animals↗

[Brain structural monoamines under inhalation anesthesia].

It was established in albino rats that the activity of the processes that are responsible for the functioning of the metabolic link in noradrenaline synthesis varies under ether and ftorotan anesthesia. It was recorded that there is an increase in the activity of DOPA decarboxylation in the brain under deep ether anesthesia as well as in the activity of dopamine decarboxylation during egress from anesthesia. Ftorotan anesthesia is characterized by increased hydroxylation of phenylalanine and decarboxylation of DOPA, and by inhibition of the activity of tyrosine and dopamine hydroxylation. Egress of animals from ftorotan anesthesia is associated with an intensive noradrenaline formation in the brain.

Anesthesia, Inhalation↗

The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic ethanol exposure.

BACKGROUND: Neuropeptide Y (NPY) has been implicated in the alcohol-drinking behaviors of rodents. This study investigated the possible involvement of NPY in the neuroadaptational mechanisms to chronic ethanol exposure and its withdrawal. METHODS: Male Sprague-Dawley rats were treated either with Lieber-DeCarli ethanol diet or control diet for 15 days, and ethanol-fed rats were withdrawn for 0 and 24 hr. The protein expression of NPY was determined in cortical, hippocampal, amygdaloid, striatal, and hypothalamic structures by using the gold-immunolabeling histochemical procedure. RESULTS: It was found that ethanol withdrawal, but not ethanol treatment, produced significant reductions in NPY protein levels in (1) layers IV and V of the frontal and parietal cortex, (2) layer II of the piriform cortex, (3) the central and medial nuclei of the amygdala, and (4) the paraventricular nucleus of the hypothalamus in rat brain. Chronic ethanol exposure and its withdrawal had no effect on the NPY protein levels in layers II, III, and VI of the frontal and parietal cortex or cingulate gyrus, in hippocampal (CA1, CA2, CA3, and dentate gyrus) and striatal (caudate putamen and globus pallidus) structures, or in the ventro-medial hypothalamus and basolateral amygdala. However, chronic ethanol exposure and its withdrawal produced significant reductions in NPY protein levels in the arcuate nucleus of the hypothalamus and in layers IV and V of the cingulate gyrus. CONCLUSIONS: These results suggest that the decreased protein levels of NPY in the central and medial nuclei of the amygdala, as well as in the cortical and hypothalamic structures, during ethanol withdrawal may play an important role in the neuromechanisms of some ethanol withdrawal symptoms.

Alcohol Drinking↗

The effects of peptide and nonpeptide antagonists of angiotensin II receptors on the noradrenaline uptake of different brain structures in rats with angiotensin II-induced increase of water intake.

Angiotensin II (ANG II) significantly increased noradrenaline (NA) uptake by cortical, hypothalamic and hippocampal synaptosomes thus activating noradrenergic neurotransmission. ANG II did not affect NA uptake by striatal synaptosomes. The interaction between AT1 receptors and noradrenergic neurons and the involvement of brain noradrenergic neurotransmitter system in ANG II-induced drinking in rats is suggested by the increase of NA uptake in hypothalamus and frontal cortex which are rich in AT1 receptors and are of importance for drinking behavior. The ANG II-receptor antagonists losartan, EXP 3174, sarmesin and saralasin decreased NA uptake in all brain regions studied as compared to the uptake in the same brain regions of ANG II-injected animals thus antagonising the effect of ANG II. There is no relationship between the inhibition of ANG II-induced water intake and the changes of NA uptake under the effect of the ANG II-receptor antagonists.

Analysis of Variance↗

Perception and judgement of physical causality involve different brain structures.

One basic type of 'mechanical' causality is that which occurs between physical objects. Subjects were presented with mechanically causal events (ball collides with and causes movement of another ball) or two non-causal events (a ball either passes underneath another ball, or rolls across the screen and changes colour). We investigated which brain regions exhibit increased activity during the judgement of causality ('judged causality') as compared with judgement of movement direction ('perceived causality'). We show an increase of medial frontal cortex activity when subjects were explicitly instructed to search for causality. Moreover, this increase was specifically associated with the search for causality and not with the perception of causality because the signal increase occurs whatever the nature of the stimulus (causal or non causal). Our study provides evidence for brain regions involved in a conscious level of inference about the presence of causality.

Adult↗

[Role of adrenergic mechanisms in regulating memory engram retrieval and energy metabolism in the brain structures of the rat].

In conditions of stimulation of adrenergic mechanisms with ephedrine, there was an improvement of the memory engrams reproduction (MER). Blockade of the alpha-adrenergic system by pyrroxan more expressively impeded reproduction of a passive defensive habit in comparison with the action of a beta-adrenolytic, the obsidan. Stimulation of MER processes was accompanied by a parallel activation of glucose-6-phosphate- and 6-phosphategluconatedehydrogenases of pentose path in the tissues of the frontal area of the cerebral cortex and pons Varolii. Blockade of alpha-adrenoreceptors suppressed the activity of the given enzymes in the same structures, while the obsidan suppressed the dehydrogenases of the pentose path only in the frontal zone of the neocortex.

Animals↗

[Neurochemical analysis of the brain structures in the formation of adaptive behavior in chicken embryogenesis].

Studies have been made on the rate of biosynthesis of high molecular and neurospecific proteins in the hippocamp and archistriatum of chick embryos during the formation of adaptive changes in motor activity under controlled experimental conditions and unmonitored occasional stimulation. It was shown that during uncontrolled sensory stress the rate of synthesis of high molecular and neurospecific proteins in the structures investigated is increased whereas during learning these changes are absent.

Adaptation, Physiological↗