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Pretreatment of rats with dexamethasone (2.5 μmol/kg, a dose which blocks the release of ACTH from the pituitary gland) abolished the reserpine-mediated increase in cAMP and the increase in the cAMP/cGMP ratio in the adrenal medulla. In contrast, the reserpine-mediated induction of tyrosine hydroxylase (TH) remained unchanged. Hypophysectomy had a similar effect to dexamethasone treatment. Since changes in cAMP and changes in the cAMP/cGMP ratio are not indispensible prerequisites for the subsequent induction of TH, a causal relationship between the two phenomena seems to be excluded. [ABSTRACT FROM AUTHOR]

It was the aim of the present study to elucidate the mechanisms involved in specific tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) induction by potassium depolarization and cholinomimetics in rat superior cervical ganglia kept in organ culture. The effect of high (54 mM) potassium concentration on intact ganglia seems to result in a dual action: In decentralized superior cervical ganglia potassium depolarization failed to produce the specific TH and DBH induction although a small increase in DDC activity persisted. Carbamylcholine, acetylcholine and nicotine at concentrations of 10 M elicited a selective induction of TH and DBH both in intact and decentralized ganglia via nicotinic receptor stimulation. Bethanechol, predominantly stimulating muscarinic receptors had no significant effect on TH activity. A 4 h pulse of 10 M carbamylcholine produced optimal induction of DBH and TH 24 h and 48 h later respectively. Longer exposure to carbamylcholine resulted in a significantly smaller rise in TH activity. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) was localized in the submandibular gland of adult male mice by a direct immunocytochemical method using highly purified antibodies against NGF coupled to horseradish peroxidase. In light microscopic sections the reaction product was entirely confined to the cells of the secretory tubules. The acinar part of the gland was free of reaction product. This finding was confirmed by electron microscopy. Within the cells NGF was localized exclusively in the apical secretory granules. No reaction was observed in the rough endoplasmic reticulum, the Golgi region or in the granules of the basal part of the cells. This observation favours the assumption that NGF is derived from a precursor molecule and that the precursor is transformed into immunologically active NGF within the secretory granules during their transport from the basal to the apical part of the tubular cells. Stimulation of the submandibular gland with carbachol (2 mg/kg) led to a massive release of the content of the secretory granules, including NGF, into the salivary duct. [ABSTRACT FROM AUTHOR]

It was the purpose of the present experiments to establish whether the reserpine-mediated changes in adrenomedullary c-AMP result from α- or β-adrenergic activation of adenylate cyclase by catecholamines liberated from adrenal chromaffin cells and whether a causal relationship exists between these changes and subsequent induction of tyrosine hydroxylase (TH). The reserpine-mediated increase in c-AMP was blocked by neither α- nor β-adrenergic blocking agents. However, propranolol abolished the increase in c-AMP by a mechanism which is not related to the β-blocking properties of this drug. Although propranolol abolished the reserpine-mediated increase in c-AMP it did not interfere with the subsequent TH induction. Moreover, administration of aminophylline together with reserpine produced a larger and more prolonged increase in c-AMP in denervated adrenals than reserpine alone in intact glands. Denervation prevented TH induction in spite of the more extensive increase in c-AMP in the adrenal medulla after the combined treatment. It is concluded that there is no causal relationship between the overall increase in c-AMP in the adrenal medulla and the subsequent TH induction. However, the possibility that a small pool of c-AMP which is overshadowed by the non-related overall changes may be involved in trans-synaptic TH induction cannot be excluded. [ABSTRACT FROM AUTHOR]

Changes in the levels of cyclic AMP were studied in the superior cervical ganglion and adrenal medulla of male Sprague-Dawley rats under experimental conditions which lead to a trans-synaptic induction of tyrosine hydroxylase (TH) in these organs. In the superior cervical ganglion an intermittent 2-hour swimming stress or treatment with reserpine (5 or 10 mg/kg s.c.) failed to change cyclic AMP levels significantly ( P>0.1) while 48 h later TH was markedly ( P<0.001) increased. In the adrenal medulla the increase in cyclic AMP occurring during cold exposure was much greater than that observed during swimming stress. However, the increase in TH activity resulting from swimming stress was markedly greater then that resulting from cold exposure. The same inverse relationship holds true when comparing the effect of reserpine with that of cold stress. Moreover, during cold exposure cyclic AMP levels were maximal (700%) within 20 min and had fallen almost to control levels (180%) after 60 min. However, no significant increase in TH ( P>0.1) was observed 48 h after a 1-hour cold stress whereas a 2-hour cold stress produced a marked ( P<0.001) increase in TH activity. Thus, the second hour of cold stress during which cyclic AMP was only marginally elevated seems to be essential for initiating the biochemical events ultimately leading to an increased synthesis of TH. It is concluded that either cyclic AMP is not involved in trans-synaptic induction of TH or that changes in a small pool are essential and are overshadowed by a much larger pool of cyclic AMP not reacting in the same way. [ABSTRACT FROM AUTHOR]

In genetically hypertensive rats, the norepinephrine turnover of peripheral and central adrenergic neurons was determined either by the decline in endogenous norepinephrine after inhibition of tyrosine hydroxylase or by the decay in the specific activity of norepinephrine after labelling the stores by intravenous or intraventricular injection ofH-norepinephrine. In the periphery (heart and submaxillary gland), the norepinephrine turnover of genetically hypertensive rats was reduced in proportion to the rise in systolic blood pressure. In the hypothalamus, medulla-pons and the residual parts of the brain, the turnover was unchanged both in the prehypertensive and the hypertensive state. The results indicate that the central adrenergic neurons, involved in the control of blood pressure, may act independently from the activity of peripheral baroreceptors. The elevated blood pressure resulting from an enhanced peripheral vascular reactivity to the physiological neurotransmitter norepinephrine may induce a compensatory inhibition of the activity of the peripheral adrenergic neurons. In the genetically hypertensive rats, neither the peripheral nor the central adrenergic nervous system seems to play a primary role in the development of hypertension. [ABSTRACT FROM AUTHOR]

Cold-exposure of rats for 1-4 days leads to a gradual increase in tyrosine hydroxylase and dopamine β-hydroxylase activity in superior cervical ganglia and adrenals. This increase is neurally mediated, since it can be abolished by decentralization of the ganglia and transsection of the splanchnic fibres supplying the adrenal medulla. Enzyme kinetic data suggest that the increased enzyme activity results from an increased synthesis of enzyme protein. The activity of dopa decarboxylase, the third enzyme involved in the synthesis of norepinephrine, remains unchanged both in ganglia and in adrenals. In the adrenals, the gradual rise in tyrosine hydroxylase and dopamine β-hydroxylase activity is virtually parallel and reaches more than twice the control values. In the superior cervical ganglion, however, there is a marked difference between the rise in activity of the two enzymes. The increase in tyrosine hydroxylase activity amounts to 217% after 4 days of cold-exposure, that of dopamine β-hydroxylase to 131% of controls (100%) only. The determination of enzyme turnovers by measuring the decay in activity after inhibition of protein synthesis by cycloheximide was attempted but the turnover of tyrosine hydroxylase both in adrenals and superior cervical ganglia was too slow to be determined by this method. The same was true for dopamine β-hydroxylase in the adrenal medulla. However, in the superior cervical ganglion the turnover of the latter enzyme could be determined; the half-life amounts to 13 h. The fact that the turnover of dopamine β-hydroxylase in the superior cervical ganglion is more rapid than that of tyrosine hydroxylase could explain the difference in the increase in enzyme activity in spite of a similar rise in the rate of synthesis. It is concluded that the enzymes involved in the synthesis of norepinephrine are not regulated as an operational unit, but that the results are compatible with the assumption that the synthesis of the two enzymes, tyrosine hydroxylase and dopamine β-hydroxylase, which are specifically located in adrenergic neurons, may be regulated by a common mechanism. [ABSTRACT FROM AUTHOR]

In experimental hypertensive rats (DOCA-implantation, 1% saline as drinking-water, encapsulation of the left kidney), the norepinephrine turnover in peripheral sympathetically innervated organs and the central nervous system was determined either by the decay in endogenous norepinephrine after inhibition of tyrosine hydroxylase or by the ecayd in the specific norepinephrine activity after intravenous or intraventricular administration ofH-norepinephrine. In the heart, the norepinephrine turnover was accelerated in proportion to the rise in blood pressure. In hypothalamus and medulla oblongata, the turnover was delayed reciprocally to the acceleration in the heart. No changes were seen in the residual parts of the brain. Administration of chlorisondamine, a quaternary ganglionic blocking agent which does not cross the blood-brain barrier, resulted in a normalization of the increased cardiac norepinephrine turnover, whereas the changes in the brain persisted. Implantation of DOCA alone produced neither a rise in blood pressure nor changes in norepinephrine turnover. The results presented are compatible with the hypothesis that, in this form of experimental hypertension, the delay in norepinephrine turnover in the brain-stem is causally related to the increased activity of the peripheral sympathetic nervous system. [ABSTRACT FROM AUTHOR]

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Background: Spinal cord injury (SCI) treatment remains a formidable challenge, as current therapeutic approaches provide only marginal relief and fail to reverse the underlying tissue damage. This study aims to develop a novel composite material combining enzymatic nanoparticles and nerve growth factor (NGF) to modulate the immune microenvironment and enhance SCI repair. Methods: CeMn nanoparticles (NP) and CeMn NP-polyethylene glycol (PEG) nanozymes were synthesized via sol–gel reaction and DSPE-mPEG modification. Transmission Electron Microscopy, Selected-Area Electron Diffraction, X-ray Diffraction and X-ray Photoelectron Spectroscopy confirmed their crystalline structure, mixed-valence states, and redox properties. Size uniformity, biocompatibility, and catalytic activity were assessed via hydrodynamic diameter, zeta potential, and elemental analysis. The Lightgel/NGF/CeMn NP-PEG composite was synthesized and characterized via electron microscopy, compression testing, rheological analysis, NGF release kinetics, and 30-day degradation studies. Both in vitro and in vivo experiments were conducted to evaluate the therapeutic effects of the composite on SCI. Results: The Lightgel/NGF/CeMn NP-PEG composite was successfully synthesized, exhibiting favorable physical properties. At a CeMn NP-PEG concentration of 4 µg/mL, the composite maintained cell viability and demonstrated enhanced biological activity. It also showed superior mechanical properties and an effective NGF release profile. Notably, the composite significantly upregulated the expression of nerve growth-associated proteins, reduced inflammatory cytokines, scavenged reactive oxygen species (ROS), and promoted M2 macrophage polarization by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. In a rat SCI model, it facilitated functional recovery and attenuated inflammation. Conclusion: The Lightgel/NGF/CeMn NP-PEG composite shows significant therapeutic promise for SCI, effectively eliminating ROS, promoting M2 macrophage polarization, reducing pro-inflammatory cytokines, and supporting neuronal regeneration. These effects substantially enhance motor function in SCI rats, positioning it as a promising candidate for future clinical applications. [ABSTRACT FROM AUTHOR]

In the ventricular-subventricular-zone (V-SVZ) of the postnatal mammalian brain, immature neurons (neuroblasts) are generated from neural stem cells throughout their lifetime. These V-SVZ-derived neuroblasts normally migrate to the olfactory bulb through the rostral migratory stream, differentiate into interneurons, and are integrated into the preexisting olfactory circuit. When the brain is injured, some neuroblasts initiate migration toward the lesion and attempt to repair the damaged neuronal circuitry, but their low regeneration efficiency prevents functional recovery. Elucidation of the molecular basis of neuroblast migration toward lesions is expected to lead to the development of new therapeutic strategies for brain regenerative medicine. Here, we show gene expression profiles of neuroblasts migrating in the peri-injured cortex compared with those migrating in the V-SVZ using photo-isolation chemistry, a method for spatial transcriptome analysis. Differentially expressed gene analysis showed that the expression levels of 215 genes (97 upregulated and 118 downregulated genes) were significantly different in neuroblasts migrating in the peri-injured cortex from those migrating in the V-SVZ. Gene Ontology analysis revealed that in neuroblasts migrating in the peri-injured cortex, expression of genes involved in regulating migration direction and preventing cell death was upregulated, while the expression of genes involved in cell proliferation and maintenance of the immature state was downregulated. Indeed, neuroblasts migrating in the peri-injured cortex had significantly lower Cyclin D2 mRNA and Ki67 protein expression levels than those in the V-SVZ. In the injured brain, amoeboid microglia/macrophages expressed transforming growth factor- β (TGF- β), and neuroblasts migrating in the peri-injured cortex expressed TGF- β receptors. Experiments using primary cultured neuroblasts showed that application of TGF- β significantly decreased proliferating cells labeled with BrdU. These data suggest that the proliferative activity of neuroblasts migrating toward lesions is suppressed by TGF- β secreted from cells surrounding the lesion. This is the first comprehensive study characterizing the gene expression profiles of neuroblasts migrating in the peri-injured cortex. [ABSTRACT FROM AUTHOR]

Semaphorin 3A (Sema3A) is an axon guidance molecule, which is also abundant in the adult central nervous system (CNS), particularly in perineuronal nets (PNNs). PNNs are extracellular matrix structures that restrict plasticity. The cellular sources of Sema3A in PNNs are unknown. Most Sema3A-bearing neurons do not express Sema3A mRNA, suggesting that Sema3A may be released from other neurons. Another potential source of Sema3A is the choroid plexus. To identify sources of PNN-associated Sema3A, we focused on the cerebellar nuclei, which contain Sema3A+ PNNs. Cerebellar nuclei neurons receive prominent input from Purkinje cells (PCs), which express high levels of Sema3A mRNA. By using a non-invasive viral vector approach, we overexpressed Cre in PCs, the choroid plexus, or throughout the CNS of Sema3Afl/fl mice. Knocking out Sema3A in PCs or the choroid plexus was not sufficient to decrease the amount of PNN-associated Sema3A. Alternatively, knocking out Sema3A throughout the CNS induced a decrease in PNN-associated Sema3A. However, motor deficits, microgliosis, and neurodegeneration were observed, which were due to Cre toxicity. Our study represents the first attempt to unravel cellular sources of PNN-associated Sema3A and shows that non-invasive viral-mediated Cre expression throughout the CNS could lead to toxicity, complicating the interpretation of Cre-mediated Sema3A knock-out. [ABSTRACT FROM AUTHOR]

Background: The safe timing window for surgery during the acute phase of inflammation due to traumatic brain injury (TBI) has not been studied extensively. We aimed to elucidate the relationship between the timing of surgery and changes in perioperative serum levels of inflammatory cytokines and factors associated to optimize TBI management in low-middle-income countries. Methods: A prospective cohort study was conducted among TBI Patients with depressed skull fractures with a GCS > 8 operated at different timing from injury and followed up peri-operatively. We collected the clinical-radiological data, as well as pre-and postoperative venous samples from participants; we then did Luminex Assay to quantify the serum levels of pro/anti-inflammatory cytokines using the kits of 96-well human cytokine "27-Plex-Assay (#M500KCAF0Y®)." We performed the analysis with STATA version 17 and R_studio applying both descriptive and inferential methods. Results: We enrolled 82 TBI patients with a median (IQR) age of 25.5 (20–34) years, and the majority were male (85.4%). There were 48.8% victims of assaults, and 73.2% had a post-resuscitation admission GCS of 14–15. There were 38 (46.3%) who were operated within 48 h of injury versus 44 (53.7%) after 48 h. Serum levels of TNF- α were significantly higher after surgeries done >48 h compared to those done ≤48 h (p = 0.0327); whereas, the difference in post-operative mean serum levels of IL-10 was significantly increased in patients who developed later SSI compared to those who did not (11.56 versus −0.58 pg./mL, p = 0.0489). In multivariate analysis, the history of post-traumatic seizure (PTS) was associated with a postoperative increase in TNF- α (p = 0.01), the hemoglobin of 10–12 with a postoperative decrease of IL-4 (p = 0.05); the presence of focal neurological deficit was associated with a significant postoperative increased of TNF-α, IL-6, and IL-4 (p = 0.05). The presence of extra-axial hemorrhage was associated with a postoperative increase of IL-10 (p = 0.05). Conclusion: Delayed surgical intervention beyond 48 h post-injury in mild–moderate TBI patients results in a significantly increased postoperative inflammatory response, as evidenced by elevated serum levels of TNF- α and IL-6. Neurological deficits, PTS, reduced hemoglobin rate, and extra-axial intracranial hemorrhage are factors associated with this heightened response. [ABSTRACT FROM AUTHOR]

Background and aim: The administration of growth and neurotrophic factors has been attempted experimentally as a new therapeutic strategy for severe facial paralysis. Granulocyte colony-stimulating factor (G-CSF) has an effect on the treatment of central nervous system injuries, such as cerebral infarction and spinal cord injury. This study aimed at examining the effects of G-CSF on facial nerve regeneration in rats. Methods: The left facial nerve of rats was either partially resected (resection group) or severed and sutured (suture group) at the main trunk outside the temporal bone. In each surgical group, saline or G-CSF was administered via the gelatin hydrogel drug delivery system. The suture group was further divided into two subgroups for the late administration of G-CSF (2 weeks after surgical treatment) or immediate administration of G-CSF after surgical treatment. Recovery of the facial nerve was assessed by the evaluation of facial movements (after 12 weeks), complex muscle action potential amplitude measurements (after 2, 4, 8, and 12 weeks), electroneurography values (after 12 weeks), and histological evaluation (comparison of myelinated axon diameters among the groups). Results: Recovery of the function and morphology of damaged nerves was faster in the suture groups than in the resection group. In the suture groups, recovery was faster for G-CSF-treated rats than for saline-treated rats. Furthermore, recovery was faster in the group that received G-CSF immediately after surgical treatment than in the group that received G-CSF 2 weeks later. However, the group that received G-CSF 2 weeks later also showed faster recovery than did the control group. Conclusion: G-CSF effectively promoted nerve regeneration during facial nerve paralysis. Thus, G-CSF may be a potential treatment strategy for injured facial nerves as it has been safely administered in clinical treatments for hematological diseases. [ABSTRACT FROM AUTHOR]

Thus far, no manufacturing process able to support industrialization has been reported for the recombinant human brain-derived neurotrophic factor (rhBDNF). Here, we described the setup of a new protocol for its production in Escherichia coli (E. coli) and its purification to homogeneity. A synthetic gene, codifying for the neurotrophin precursor, was inserted into an E. coli expression vector and transformed into BL21 (DE3) strain. The recombinant protein accumulates, at high yields, into inclusion bodies. With the developed strategy, more than 50% of the precursor can be refolded. The protein is successively digested by trypsin and the rhBDNF mature form is finally purified by two additional chromatographic steps If the wild-type precursor can be efficiently obtained by the proposed methodology, its pro-peptide remotion, through enzymatic digestion, is however problematic. To circumvent this difficulty, the precursor hinge region, containing the natural furin recognition site, was engineered to be more specifically cleaved by trypsin. Notwithstanding the substitution of three residues in the pro-region carboxyterminal, the precursor correctly refolds and is efficiently cleaved to generate a biologically active mature rhBDNF. This efficient high-yield process fills the current need of a scalable protocol to produce GMP-grade material and unlocks the rhBDNF employment in future clinical investigations. [ABSTRACT FROM AUTHOR]

Myelin sheath, as the multilayer dense structure enclosing axons in humans and other higher organisms, may rupture due to various injury factors after spinal cord injury, thus producing myelin debris. The myelin debris contains a variety of myelin-associated inhibitors (MAIs) and lipid, all inhibiting the repair after spinal cord injury. Through summary and analysis, the present authors found that the inhibition of myelin debris can be mainly divided into two categories: firstly, the direct inhibition mediated by MAIs; secondly, the indirect inhibition mediated by lipid such as cholesterol. It is worth noting that phagocytes are required in the latter indirect inhibition, such as professional phagocytes (macrophages et al.) and non-professional phagocytes (astrocytes et al.). Moreover, complement and the immune system also participate in the phagocytosis of myelin debris, working together with phagocytes to aggravate spinal cord injury. In conclusion, this paper focuses on the direct and indirect effects of myelin debris on spinal cord injury, aiming to provide new inspiration and reflection for the basic research of spinal cord injury and the conception of related treatment. [ABSTRACT FROM AUTHOR]

Introduction: The study aimed to determine whether heterozygous BDNF-deficient (BDNF-knockout, SD-BDNF) rats exhibit pathological changes in the myocardium and to assess whether a 5-week moderate-intensity endurance training program can reverse adverse changes in the heart muscle. Methods: Experiments were conducted on four groups of rats: control wild-type, control BDNF knockout, trained wild-type and trained BDNF knockout. Knockout rats were selected due to the presence of symptoms resembling metabolic syndrome in serum and liver while 5-week moderate endurance training was used as an intervention targeted at restoring heart function. Measurements of BDNF/Trk-B concentrations and molecules levels and activities, such as cardiac specific enzymes like creatine kinase and creatine kinase myocardial band, lipids as total cholesterol, low-density lipoprotein and triglycerides, metabolic enzymes including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and lactate dehydrogenase and interleukin-1 were carried out in myocardium homogenates. Results: In BDNF-deficient rats, the myocardium showed significantly reduced lipid concentrations, decreased metabolic and cardiac enzyme activity, and elevated Trk-B levels, all of which are indicative of myocardial ischemia or hypoxia. These changes in critical biomarkers were consistent with those earlier observed in the livers of BDNF-deficient rats, suggesting a link between the liver and cardiac function. Moderate endurance training led to an increase in creatine kinase activity in the myocardium of trained rats, suggesting increased production and utilization of energy required for myocardial contraction in trained wild-type and knockout populations of rats. Discussion: BDNF-deficient rats exhibited numerous myocardial abnormalities, most of which were not reversible after moderate-intensity endurance training. These findings provide a basis for a deeper understanding of the mechanisms underlying myocardial disorders in BDNF-deficient rats, which appear to be a suitable model for studying various aspects of metabolic disorders. [ABSTRACT FROM AUTHOR]

A conundrum in Alzheimer's disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering. [ABSTRACT FROM AUTHOR]

Numerous experimental studies suggest the potential for resveratrol (RVT) to be useful in the Alzheimer's disease treatment, but its low bioavailability limits its application. This study aimed to assess the potential of resveratrol-loaded micelles as a neuronal delivery platform to protect rats from scopolamine-induced memory impairment. Resveratrol was incorporated into Pluronic micelles, and the effects of micellar (mRVT) and pure resveratrol (RVT) were compared in the model of scopolamine-induced dementia in male Wistar rats. Memory performance was assessed by a T maze test. The effect of the treatment on specific neurotransmitter levels and protein expression in the cortex and the hippocampus were evaluated biochemically. Our results revealed that the polymeric micelles were in nanoscale (approximately 33 nm) and reached 79% encapsulation efficiency. The treatment with mRVT demonstrated better spatial memory protective effect. The biochemical assays showed that mRVT in a dose of 10 mg/kg enhanced the effects of the pure drug in regard to noradrenalin neurotransmission and acetylcholinesterase inhibitory activity in the hippocampus. Furthermore, micellar resveratrol increased the cAMP-response element-binding protein expression in the cortex and hippocampus of rats as well as the Bcl2/BAX ratio, which indicated an anti-apoptotic effect in the experimental dementia model. In conclusion, our results indicated the potential of a micellar system loaded with resveratrol for neurodegenerative diseases treatment. [ABSTRACT FROM AUTHOR]

It was the aim of this study to investigate the mechanisms responsible for changes in 3′,5′-cyclic adenosine monophosphate (cAMP) in the rat adrenal medulla occuring after administration of carbamylcholine, histamine, ACTH and various phenylethylamines. Carbamylcholine, ACTH, histamine, noradrenaline and dopamine produced marked (500-900%) increases in adrenal cAMP which were very similar in both adrenal cortex and medulla both with respect to time-course and relative extent. Interestingly isoprenaline and adrenaline did not influence cAMP levels even at excessively high doses. In all cases studied transsection of the splanchnic fibers supplying the adrenals reduced the increase in medullary cAMP by not more than 25-30%, suggesting that cAMP levels in the adrenal medulla are predominantly regulated by non-neuronal mechanisms. This assumption was strongly supported by the observation that hypophysectomy completely abolished the 500-600% increase in cAMP produced by 50 μmol/kg of dopamine and reduced the 700% increase resulting from 4.4 μmol/kg of carbamylcholine to 70%. In spite of the marked increase in cAMP produced by single and repeated doses of dopamine in the adrenal medulla there was no subsequent induction of tyrosine hydroxylase (TH). Moreover carbamylcholine (8.2 μmol/kg) evoked TH induction only in innervated adrenals whereas after denervation, in spite of the large (+500%) and prolonged (more than 90 min) increase in cAMP, no TH induction could be observed. It is concluded that adrenal medullary cAMP is predominantly regulated by the pituitary gland via the adrenal cortex and only to a much smaller extent - if at all-by direct cholinergic mechanisms, which are responsible for the initiation of TH induction. [ABSTRACT FROM AUTHOR]