Striatal mechanism of action of corticoliberin on behavior in dogs in conditions of dopamine deficiency

This report describes studies of the interaction of the integrative dopaminergic and corticoliberin systems in the neostriatum during performance of situational food-related conditioned reflexes. Studies were performed in dogs with chemotrodes implanted in the substantia nigra and the head of the caudate nucleus. 6-Hydroxydopamine was injected into the substantia nigra at a dose of 50 μg, and 10 μg of corticoliberin was injected into the caudate nucleus. Blood cortisol and catecholamine levels were determined. Analysis of the result showed that an interaction takes place in the neostriatum between the corticoliberin and dopaminergic systems, and that in conditions in which dopaminergic structures are excluded, the efficacy of corticoliberin in the performance of behavioral acts decreases by 30–40%, i.e., complete expression of its regulatory role of motor situational conditioned reflexes is lost. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 84, No. 8, pp. 728–734, August, 1998.     

Dopaminergic mechanisms of neostriatum in the regulation of adaptive behavior by corticoliberin

A conditioned active avoidance response was developed in rats with high (KHA) and low (KLA) rates of learning and the effects of injection of corticoliberin into the dorsal striatum on orientational-investigative and avoidance behavior were studied in normal animals and after depletion of striatal dopamine by preliminary injection of 6-hydroxydopamine. These studies showed that corticoliberin, like 6-hydroxydopamine, produced similar trends in the animals' behavior. Their effects were mediated by opposite mechanisms in animals with initial active and passive learning strategies for adaptive behavior. The role of dopaminergic structures of the striatum in mediating the behavioral effects of corticoliberin is discussed. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 84, No. 10, pp. 1146–1151, October, 1998.     

Expression of early genes in the rat brain after administration of corticoliberin into the neostriatum

In situ hybridization using oligonucleotide probes was used to study the effects of intrastriatal microinjection of corticoliberin on the expression of the early genes c-fos, jun B, c-jun, and NGFIA in the rat brain. Administration of corticoliberin (0.25 g) into the neostriatum induced the expression of mRNA encoded by the early genes c-fos, jun B, and NGFIA in both the neostriatum itself and in its efferent structures, particularly the nucleus accumbens and various parts of the cortex. Intrastriatal microinjection of corticoliberin had no effect on the expression of mRNA for the oncogene c-jun in the brain. These results suggest that neuronal activation in the neostriatum and its projection targets manifest as the expression of early genes is one of the mechanisms underlying the adaptive effects of corticoliberin in stress.     

Anatomical and ontogenetic studies of the human paraventriculo-infundibular corticoliberin system

In human fetus, newborn, infant and adult hypothalami, antibodies to ovine corticoliberin-41 stain a paraventriculo-infundibular neuroglandular pathway. The perikarya are located in the paraventricular nucleus, they mainly project to the ventral and lateral areas of the median eminence. Eminential corticoliberin-positive fibres appear during the 16th week of fetal life, and increase in number during the following weeks. Perikarya were first revealed in the 19th week. In some areas of the median eminence, corticoliberin-, vasopressin- or [Met]enkephalin-immunoreactive terminals are similarly distributed. Sequential stainings or staining comparison of contiguous semi-thin sections failed to prove the coexpression of corticoliberin and [Met]enkephalin immunoreactivities in fibres, but indicated that corticoliberin and vasopressin immunoreactivities may be coexpressed in a few fibres. Those methods enabled us to observe, in the paraventricular nucleus, perikarya revealed by corticoliberin and vasopressin antisera. Our results suggest a possible release of corticoliberin in portal vessels of the median eminence beginning in the 16th week of fetal life, i.e. 8 weeks later than appearance of the corticotrophs in the pituitary. Establishment of a corticoliberin hypothalamic control of pituitary corticotrophs at mid gestation agrees with previous physiological and teratological studies. Abundance, as well as immunostaining intensity of the corticoliberin processes, in the infant and adult median eminence attest to the physiological importance of this system. Close vicinity of corticoliberin, vasopressin and [Met]enkephalin fibres, in some eminential areas and coexpression of corticoliberin and vasopressin immunoreactivities in some neurons, are morphological correlates of functional relations which were reported.     

Modification of the behavioral effects of corticoliberin by early post-natal administration of corticosteroid hormones

Experiments on rats in which hydrocortisone was given in the early postnatal period were used to study the effects of intrastriatal microinjection of corticoliberin on behavior in an open field test. Bilateral microinjection of corticoliberin into the neostriatum led to a sharp reduction in orientational-investigative activity. Rats given hydrocortisone in the first five days of life had elevated movement activity, and the anxiogenic effect of corticoliberin was absent in these animals. I. P. Pavlov Institute of Physiology, St. Petersburg. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 47. No. 1, pp. 130–135. January–February, 1997.     

Selective Effects of Dehydroepiandrosterone Sulfate on Corticoliberin-Induced Anxiety

The effects of dehydroepiandrosterone sulfate (DHEA-S) on changes in the levels of anxiety induced by administration of the stress neurohormone corticoliberin were studied. A T maze was used to select Wistar rats with active and passive strategies of adaptive behavior. Testing of the active group in an elevated plus maze was used to select low- and high-anxiety individuals. Intranasal administration of corticoliberin to low-anxiety active rats resulted in decreases in total activity and increases in the level of anxiety, while high-anxiety animals had low sensitivity to this neurohormone. Prior administration of DHEA-S at a dose of 3 mg/100 g had antistress effects in low-anxiety rats and anxiolytic effects in high-anxiety rats. In passive animals, which were characterized by initially high levels of anxiety and were resistant to corticoliberin, administration of DHEA-S also had antistress actions. These results led to the conclusion that the effects of DHEA-S depended on the initial psychoemotional state and behavioral sensitivity to corticoliberin.     

Localization of Corticoliberin Receptors in the Rat Brain

In situ hybridization was used to study the distribution of corticoliberin receptors of subtypes 1 and 2 (CL-R1 and CL-R2 respectively) in different structures of the rat brain. Levels of CL-R1 mRNA in the brain were significantly greater than levels of CL-R2 mRNA, and the most intense expression of the CL-R1 gene was seen in forebrain structures, especially various neocortical, archicortical, and paleocortical regions in the cerebellar cortex. In addition, significant levels of CL-R1 mRNA expression were noted in the red nucleus and the reticular nucleus of the tegmentum. Intense expression of CL-R2 mRNA was observed in structures of the olfactory system, corticomedial parts of the amygdala, fields CA1–CA4 of the hippocampus, the ventromedial hypothalamus, and several brain stem nuclei. Moderate levels of CL-R2 mRNA were seen in the dorsolateral neostriatum. These results provide evidence that corticoliberin receptors of both subtypes are widespread in the brain. The different patterns of expression of CL-R1 and CL-R2 in the brain probably provide the basis for the functional specificity of action of corticoliberin in brain structures.     

Effects of Corticoliberin on Synaptic Transmission in Rat Olfactory Cortex Slices in a Water Immersion Model of Depression

Corticoliberin (corticotrophin-releasing factor, CRF, CRH) is an active regulator of endocrine, autonomic, and immune functions in stress, as well as a mediator of anxiety, determining the behavioral stress response. The present report describes studies of its action on neuron activity evoked by microstimulation of olfactory cortex slices. Behavioral testing in a T maze was used to select individuals with a passive behavioral strategy from a population of Wistar rats, and the animals were subjected to water immersion. Olfactory cortex slices were prepared 10 days later and evoked focal potentials were recorded on perfusion with medium containing corticoliberin (0.1 μM). Among active rats, 60% of slices retained high excitability after stress, and corticoliberin produced only insignificant reductions in the amplitudes of excitatory potentials in these slices, simultaneously increasing the amplitudes of inhibitory potentials. Low excitability was found in 40% of slices from active stressed rats, and corticoliberin had a significant inhibitory effect in these slices. Addition of corticoliberin to the incubation medium used for slices from passive rats with initially low excitability led to complete blockade of synaptic transmission. These data support the involvement of corticoliberin in the development of depression. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 8, pp. 952–961, August, 2008.     

The Effects of Corticoliberin at Different Concentrations on Long-Term Potentiation in Slices of Rat Olfactory Cortex

Experiments were performed to investigate evoked focal potentials in slices of rat olfactory cortex. The results showed that 1 M corticotropin-releasing factor (CRF; corticoliberin) increases the frequency of posttetanic potentiation, which had a shorter delay phase than in control experiments. Posttetanic potentiation during perfusion with 0.1 M corticoliberin had a longer delay phase than in control experiments.     

Effects of corticoliberin CRF<Subscript>4–6</Subscript> fragment on pain sensitivity in rats

The effects of the tripeptide fragment corticoliberin CRF_4–6 (Pro-Pro-Ile) on pain sensitivity were studied in rats using the hotplate method. CRF_4–6 given centrally (6, 30, and 150 nmol/rat) had dose-dependent antinociceptive actions: the latent period of the paw-licking response increased by 7.4 ± 1.4, 10.1 ± 1.5, and 16.7 ± 4.2 sec from the control level of 10.2 ± 0.9 sec. The durations of the effect were 30 min for CRF_4–6 at a dose of 6 nmol and 60 min for doses of 30 and 150 nmol of tripeptide. Administration of the corticoliberin antagonist ηhCRF_9–41 (centrally, 6.5 nmol) 60 min before tripeptide completely blocked the antinociceptive effects of CRF_4–6 (6 nmol). Thus, corticoliberin receptors are involved in mediating the antinociceptive influence of CRF_4–6. It can be suggested that the tripeptide either directly interacts with corticoliberin receptors or modulates the activity of CRFergic neurons. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 91, No. 9, pp. 1060–1065, September, 2005.     

Effects of corticoliberin fragment CRF4–6 on sexual behavior in male mice

Centrally administered doses of the tripeptide corticoliberin fragment CRF_4–6 (Pro-Pro-Ile) suppressed mating behavior in male rats. Doses of 1 and 2 μg of the tripeptide produced dose-dependent increases in the latent periods of mounting, intromission, and ejaculation. Changes in measures of sexual behavior demonstrated that the corticoliberin fragment CRF_4–6 suppressed both sexual motivation and sexual performance. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 91, No. 7, pp. 785–790, July, 2005. An erratum to this article is available at.     

Management of neuroendocrine disorders in traumatic toxicosis using mielopid

The object of the study was to determine the possibility of using myelopid in correction of the functional condition of the melatonin-opioid and the hypothalamo-hypophyseal-adrenal systems and of the activity of the neurohypophysis in traumatic toxicosis. It was demonstrated in rat experiments that in traumatic toxicosis myelopid modulates synthesis of neuropeptides (melatonin, corticoliberin) and their release into blood plasma. By reducing the blood plasma vasopressin content, myelopid promotes increase in the corticoliberin content in the hypothalamus and increase of 11-OCS biosynthesis in the adrenals. At the same time, the agent increases the melatonin content in the epiphysis cerebri of intact animals and in rats with traumatic toxicosis and reduces the content of leuenkephalin in blood plasma. The role of myelopid in correction of neuroendocrine disorders in traumatic toxicosis is discussed.     

Corticoliberin Protects Neurons from the Negative Influences of “Dysfunctins” in Living Olfactory Cortex Slices

The protective effects of corticoliberin on living rat olfactory cortex slices during perfusion with dysfunctins extracted from cerebrospinal fluid of drug addicts were studied. Isolated perfusion of slices with medium containing dysfunctins led to irreversible suppression of the amplitude of individual components of focal potentials induced by electrical stimulation of the lateral olfactory tract. The maximum level of depression was seen for the AMPA and NMDA components of EPSP. Preliminary perfusion of slices with medium containing corticoliberin (100 nM) for 15 min partially, and for 30 min completely protected processes mediated by activation of AMPA and NMDA receptor mechanisms from the negative influences of dysfunctins. It is suggested that corticoliberin can induce its protective effects either via its own specific receptors or non-specifically via glutamate receptors. It is also possible that both of these mechanisms act in combination.     

Blockade of corticoliberin receptors prevents the development of post-stress psychopathology in rats with an active strategy of adaptive behavior

Active and passive Wistar rats were subjected to single water immersions, after which they showed signs of post-stress depression. Administration on this background of the peptide CRH-R₁ receptor blocker astressin prevented the development of behavioral deficit in active individuals but had no effect on the behavior of passive rats. These results lead to the conclusion that corticoliberin receptor blockers are effective in the treatment of post-stress depression only for individuals with an initially active behavioral strategy. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 92, No. 11, pp. 1345–1350, November, 2006.     

Corticoliberin, somatocrinin and amine contents in normal and parkinsonian human hypothalamus

We have compared hypothalamic contents of various neurotransmitters (dopamine (DA), norepinephrine and serotonin) and their metabolites (dihydroxyphenyl acetic acid, homovanilic acid, 5-hydroxyindoleacetic acid) in post-mortem human controls and parkinsonian hypothalami. Neurotransmitters and their metabolites were measured in 0.1 N HCl hypothalami extracts using electrochemical detection after high performance liquid chromatography. Using specific radioimmunoassays we have also measured corticoliberin and somatocrinin contents in these hypothalami. Despite a 50% decrease of DA contents in parkinsonian hypothalami, no variations of corticoliberin and somatocrinin contents were found: 16.6 +/- 1.78 pg/mg tissue in Parkinson disease vs 16.71 +/- 1.89 in controls for human corticotropin-releasing factor (hCRF 1-41) and 37.38 +/- 11 vs 45.16 for human growth-hormone-releasing factor (hGRF 1-44).     

Stable Modifications to the Expression of Neurohormones in the Rat Hypothalamus in a Model of Post-Traumatic Stress Disorder

We report studies of the neuroendocrine mechanisms of development of an anxiety state in rats using the “stress-restress” experimental model of post-traumatic stress disorder. Immunocytochemical methods demonstrated significant increases in corticoliberin expression in both the parvo- and magnocellular parts of the paraventricular nucleus persisting to 10 days after presentation of the animals with repeated stress. Decreases in vasopressin expression were seen in the paraventricular nucleus of the animals on the first day after repeated stress. Vasopressin contents in the parvocellular part of the nucleus in animals of the experimental group were no different at 10 days from those in animals of the control group, while levels in the magnocellular part were increased. These data provide evidence for the involvement of the hypothalamic component of the vasopressinergic system (along with the corticoliberinergic system) in the pathogenetic mechanisms of the analog of post-traumatic stress disorder generated in this model.     

Experimental Modeling of Functional Deficiency of the Nigrostriatal Dopaminergic System in Mice

The dopaminergic nigrostriatal system of the brain is a key component in controlling motor behavior. The bodies of dopaminergic neurons are located in the compact zone of the substantia nigra and their axons, forming the nigrostriatal tract, project to the striatum. The aim of the present work was to develop an experimental model of functional deficiency of the dopaminergic neurons of the nigrostriatal system with no impairment to motor behavior, i.e., the presymptomatic stage of parkinsonism. The model was created in mice by administration of single subcutaneous injections of low doses (12 mg/kg) of 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is converted to MPP⁺ in the brain, this being a neurotoxin for dopaminergic neurons. These experiments showed that 14 days after administration of MPTP the animals a) lacked any impairment to motor behavior; b) had no decrease in the dopamine level or any dopamine neuron degeneration in the substantia nigra; c) showed significant reductions in dopamine levels in the striatum due to degeneration of half of its dopaminergic fibers. The absence of changes in motor behavior in the presence of significant changes in dopamine metabolism and structural damage to dopaminergic axons in the striatum provides evidence for the activation of compensatory mechanisms in the brain. Thus, we have developed an experimental model of the presymptomatic stage of parkinsonism, which is characterized by degeneration of the axons of dopaminergic neurons in the striatum with no changes in the bodies of these neurons in the substantia nigra; this model will be used for further studies of compensatory mechanisms.     

Nociceptive responses of midbrain dopaminergic neurones are modulated by the superior colliculus in the rat

Midbrain dopaminergic neurones exhibit a short-latency phasic response to unexpected, biologically salient stimuli. In the rat, the superior colliculus is critical for relaying short-latency visual information to dopaminergic neurones. Since both collicular and dopaminergic neurones are also responsive to noxious stimuli, we examined whether the superior colliculus plays a more general role in the transmission of short-latency sensory information to the ventral midbrain. We therefore tested whether the superior colliculus is a critical relay for nociceptive input to midbrain dopaminergic neurones. Simultaneous recordings were made from collicular and dopaminergic neurones in the anesthetized rat, during the application of noxious stimuli (footshock). Most collicular neurones exhibited a short-latency, short duration excitation to footshock. The majority of dopaminergic neurones (92/110; 84%) also showed a short-latency phasic response to the stimulus. Of these, 79/92 (86%) responded with an initial inhibition and the remaining 14/92 (14%) responded with an excitation. Response latencies of dopaminergic neurones were reliably longer than those of collicular neurones. Tonic suppression of collicular activity by an intracollicular injection of the local anesthetic lidocaine reduced the latency, increased the duration but reduced the magnitude of the phasic inhibitory dopaminergic response. These changes were accompanied by a decrease in the baseline firing rate of dopaminergic neurones. Activation of the superior colliculus by the local injections of the GABA(A) antagonist bicuculline also reduced the latency of inhibitory nociceptive responses of dopaminergic neurones, which was accompanied by an increased in baseline dopaminergic firing. Aspiration of the ipsilateral superior colliculus failed to alter the nociceptive response characteristics of dopaminergic neurones although fewer nociceptive neurones were encountered after the lesions. Together these results suggest that the superior colliculus can modulate both the baseline activity of dopaminergic neurones and their phasic responses to noxious events. However, the superior colliculus is unlikely to be the primary source of nociceptive sensory input to the ventral midbrain.