CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats

Recent reports have provided evidence of a link between the endogenous brain cannabinoid system and the endogenous central opioid systems. Here we report that the selective CB1 receptor antagonist SR 141716A induced behavioral and endocrine alterations associated with opiate withdrawal in morphine-dependent animals in a dose-dependent manner and that naloxone induced an opiate withdrawal syndrome in animals made cannabinoid-dependent by repeated administration of the potent cannabinoid agonist HU-210. Additionally CB1 and mu-opioid receptor mRNAs were co-localized in brain areas relevant for opiate withdrawal such as the nucleus accumbens, septum, dorsal striatum, the central amygdaloid nucleus and the habenular complex. These results suggest that CB1 cannabinoid receptors may play a role in the neuroadaptive processes associated with opiate dependence, and they lend further support for the hypothesis of a potential role of cannabinoid receptors in the neurobiological changes that culminate in drug addiction.     

Fewer pigmented locus coeruleus neurons in suicide victims: preliminary results

Chronic toxicity studies were conducted with an algae (Nannochloris oculata), a rotifer (Brachionus calyciflorus), and a cladoceran (Daphnia magna) to determine their relative sensitivities to the organophosphorus insecticide fenitrothion. The cladoceran D. magna was the most sensitive of the three species. The no observed effect concentrations (NOECs) for the study with the algae (1.0 mg/liter) and for the rotifer (1.0 mg/liter) were higher than the NOEC (0.009 microgram/liter) and the LC50 of 24 hr (0.067 microgram/liter) for D. magna. Most of the algal populations were not initially affected by exposure to fenitrothion. Pesticide concentrations higher than 1.0 mg/liter significantly reduced algal densities after 72 hr exposure. The effects of chronic exposure of the rotifer B. calyciflorus to fenitrothion were evaluated using some demographic parameters: intrinsic rate of natural increase (r), generation time, net reproductive rate, and life expectancy. All the parameters studied decreased with increasing toxicant concentrations. The parameters used to determine the effect of the pesticide on D. magna reproduction were mean total young per female, mean brood size, mean time to first reproduction, and r. The r and the rest of the studied parameters were affected at 0.011-microgram/liter and higher fenitrothion concentrations. Growth, as measured by body length, was only depressed significantly at 0.011 microgram/liter pesticide.     

Insulin reduces norepinephrine transporter mRNA in vivo in rat locus coeruleus

Acute and chronic in vitro insulin treatment can inhibit the uptake of norepinephrine (NE) by adult rat brain synaptosomes and slices, fetal neuronal cultures, and PC12 cells. In the present study we tested whether chronic in vivo insulin treatment could alter the biosynthetic capacity of rat locus coeruleus neurons for the NE transporter protein (NET). Chronic third ventricular insulin treatment resulted in a suppression of NET mRNA to about one third of the level of vehicle-treated controls. Our finding suggests that insulin may play a regulatory role in the synthesis of this transporter, thereby modulating activity in CNS noradrenergic pathways.     

Dendritic arbor of locus coeruleus neurons contributes to opioid inhibition

1. The nucleus locus coeruleus (LC) is made up of noradrenergic cells all of which are hyperpolarized by opioids. Recent work has shown that the reversal potential of the opioid-induced current is more negative than the potassium equilibrium potential. The aim of the present study was to determine whether the extent of the dendritic field could contribute to the very negative opioid reversal potential. 2. Individual LC cells were labeled in the brain slice preparation. The number of dendrites found on cells in slices sectioned in the horizontal plane was greater than cells in coronal slices. However, the dimensions of the cell body slices from each plane were not significantly different. 3. The resting conductance of neurons from slices cut in the horizontal plane was significantly larger than in cells from coronal plane. 4. The amplitude of the outward current induced by [Met5]-enkephalin (ME) was larger in cells from horizontal slices and the reversal potential was more negative than that of cells in coronal slices. 5. The results show that the plane of section influences the membrane properties and opioid actions of LC neurons in vitro and suggest that these differences correlate with the numbers of dendrites. The results suggest that in vivo, in addition to intrinsic membrane properties and synaptic inputs, the structural makeup of the nucleus is an important factor in determining the activity.     

Opioid receptor-coupled G-proteins in rat locus coeruleus membranes: decrease in activity after chronic morphine treatment

The nucleus locus coeruleus is involved in the expression of opiate physical dependence and withdrawal, and has been characterized extensively with regard to chronic morphine-induced alterations in biochemical and electrophysiological responses. In the present study the effects of chronic morphine treatment on opioid receptor-coupled G-protein activity was investigated in membranes from rat locus coeruleus. Opioid agonists stimulated low Km GTPase activity with pharmacology consistent with mu receptors. Chronic morphine treatment resulted in decreases in both basal and opioid-stimulated low Km GTPase activity, with no change in the percent stimulation by agonist. The decrease in low Km GTPase activity appeared to be due to a decrease in the Vmax of the enzyme, with no change in the Km for GTP hydrolysis. These results were confirmed by assays of basal and opioid receptor-stimulated [35S]GTP gamma S binding in the presence of excess GDP. Thus, chronic morphine treatment apparently decreased inhibitory G-protein activity in the locus coeruleus without producing any detectable desensitization. These results suggest a potential adaptation at the receptor/transducer level which may contribute to other biochemical changes produced in the locus coeruleus by chronic morphine treatment.     

Antidromic burst activity of locus coeruleus neurons during cortical spreading depression

The electrical activity of locus coeruleus neurons was investigated during cortical spreading depression in urethane-anaesthetized rats. Cortical spreading depression was induced by a direct application of 1-3 M KCl solution to the surface of the cerebral cortex. The occurrence of cortical spreading depression was assessed by recording negative d.c. shifts and in some experiments by monitoring the extracellular potassium concentrations. The mean spontaneous firing rate of locus coeruleus neurons was significantly reduced during cortical spreading depression. Approximately 60% of locus coeruleus neurons recorded during cortical spreading depression revealed anomalous burst activity consisting of multiple initial segment spikes as well as full initial segment-somatodendritic spikes with a marked initial segment-somatodendritic break. Each spike of the cortical spreading depression-related burst activity occurred at intervals ranging from 15.0 ms to 90.1 ms (34.9 +/- 0.5 ms). The burst activity appeared unpredictably at variable intervals in a phasic or tonic manner during cortical spreading depression. The cortical spreading depression-related burst activity of locus coeruleus neurons mimicked antidromic spikes induced by train stimulation of the cerebral cortex at short interspike intervals during iontophoretic application of GABA to locus coeruleus neurons, whereas it was totally different from synaptically-activated burst activity induced by tail pinch. The full spikes and initial segment spikes in the cortical spreading depression-related burst activity failed to collide with cortically elicited antidromic spikes, even when they appeared within the collision interval. The proportion of initial segment spikes in the cortical spreading depression-related burst activity was reduced following an increase in membrane excitability by iontophoretic application of glutamate, and increased during a decreased membrane excitability by GABA application. The antidromic burst activity of locus coeruleus neurons also appeared for a short time during cortical spreading depression prior to the occurrence of seizure waves induced by GABA antagonists, while the burst activity could not be observed during seizure activity. These results indicate that the cortical spreading depression-related burst activity was of antidromic origin and that the marked initial segment-somatodendritic break in spontaneous spikes of locus coeruleus neurons during cortical spreading depression was due to reduced excitability of the somatodendritic membrane. The cortical spreading depression-related burst activity may cause release of a large amount of noradrenaline in vast regions of locus coeruleus terminal fields through the numerous axon collaterals, thereby playing a role in functional changes of brain neurons related to cortical spreading depression.     

The fission yeast mitotic regulator win1+ encodes an MAP kinase kinase kinase that phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity

The Schizosaccharomyces pombe win1-1 mutant has a defect in the G2-M transition of the cell cycle. Although the defect is suppressed by wis1+ and wis4+, which are components of a stress-activated MAP kinase pathway that links stress response and cell cycle control, the molecular identity of Win1 has not been known. We show here that win1+ encodes a polypeptide of 1436 residues with an apparent molecular size of 180 kDa and demonstrate that Win1 is a MAP kinase kinase kinase that phosphorylates and activates Wis1. Despite extensive similarities between Win1 and Wis4, the two MAP kinase kinase kinases have distinct functions. Wis4 is able to compensate for loss of Win1 only under unstressed conditions to maintain basal Wis1 activity, but it fails to suppress the osmosignaling defect conferred by win1 mutations. The win1-1 mutation is a spontaneous duplication of 16 nucleotides, which leads to a frameshift and production of a truncated protein lacking the kinase domain. We discuss the cell cycle phenotype of the win1-1 cdc25-22 wee1-50 mutant and its suppression by wis genes.     

Response of locus coeruleus neurons to footshock stimulation is mediated by neurons in the rostral ventral medulla

While it is well documented that locus coeruleus neurons are potently activated by foot-pinch or sciatic nerve stimulation, little is known about the circuit producing this sensory response. Previous work in our laboratory has identified the medullary nucleus paragigantocellularis as a major excitatory afferent to the locus coeruleus. Here, we use local microinjections into the paragigantocellularis to test whether this nucleus is a link in the pathway mediating the activation of locus coeruleus neurons by subcutaneous footpad stimulation, or footshock, in anesthetized rats. Lidocaine HCl microinjected into the paragigantocellularis reversibly attenuated footshock-evoked activation of 50 out of 56 locus coeruleus cells, with responses in 20 cells completely blocked. Microinjections of GABA into the paragigantocellularis reduced the footshock-evoked responses of 17 out of 27 locus coeruleus cells (seven complete blocks); microinjections of the GABAB agonist baclofen had no effect (0 out of 11 cells blocked). Microinjections of a synaptic decoupling cocktail of manganese and cadmium also attenuated locus coeruleus activation in eight out of nine cells with two complete blocks. With each agent, the most effective injection placement for complete blockade of responses was the ventromedial paragigantocellularis; injections bordering this region attenuated responses, while those outside of the paragigantocellularis (dorsal medullary reticular formation, nucleus tractus solitarius, or facial nucleus), or vehicle injections, were ineffective. These results are consistent with previous findings that pharmacologic blockade of paragigantocellularis-evoked locus coeruleus activity also blocks footshock-evoked responses of locus coeruleus neurons [Ennis and Aston-Jones (1988) J. Neurosci. 8, 3644-3657], and support the view that this somatosensory response, and perhaps other sensory-evoked responses of locus coeruleus neurons, involve the nucleus paragigantocellularis.     

Sigma-binding site ligands inhibit K+ currents in rat locus coeruleus neurons in vitro

The effect of triphenyltin on the activity of membrane-bound pyrophosphatase of Rhodospirillum rubrum was investigated. Triphenyltin inhibits the hydrolysis of chromatophore membrane-bound pyrophosphatase in a pH-dependent pattern, being maximal at pH 9-10. At basic pH values, the inhibition produced by this organotin on membrane-bound pyrophosphatase is very similar to that produced on the chromatophore H+ATPase (I50 = 14.4 and 10 microM, respectively). Detergent-solubilized membrane-bound pyrophosphatase is also inhibited by triphenyltin, but the cytoplasmic enzyme of R. rubrum is inhibited only slightly. The inhibitory effect of triphenyltin on membrane-bound pyrophosphatase is the same with Mg-PPi or Zn-PPi, and is dependent on the chromatophore membrane concentration. Triphenyltin modified mainly the Vmax of the enzyme, and only slightly its Km. Free Mg2+ does not reverse the inhibition. Reducing agents prevent triphenyltin inhibition of the membrane-bound pyrophosphatase, but their effect is due to an alteration of the inhibitor, and not to a modification of thiol groups of the enzyme. The most likely site for triphenyltin inhibition in chromatophore membrane-bound pyrophosphatase is a component either within or closely associated with the membrane.     

Opposite modulation of opiate withdrawal behaviors on microinfusion of a protein kinase A inhibitor versus activator into the locus coeruleus or periaqueductal gray

Chronic opiate administration upregulates the cAMP pathway in the locus coeruleus (LC). This adaptation is thought to increase the electrical excitability of LC neurons and contribute to the dramatic increase in LC firing induced by opioid receptor antagonists in opiate-dependent animals. The goal of the present study was to evaluate directly a role of the cAMP pathway in opiate withdrawal behaviors by studying, in vivo, whether withdrawal is influenced by intra-LC infusion of compounds known to activate or inhibit protein kinase A (PKA). Infusions into amygdala or periaqueductal gray (PAG) were studied for comparison. In one series of experiments the effect of intra-LC, intra-amygdala, or intra-PAG infusions of the PKA inhibitor Rp-cAMPS on naloxone-precipitated withdrawal from morphine was examined. Intra-LC infusions of Rp-cAMPS significantly attenuated several prominent behavioral signs of morphine withdrawal. Intra-PAG infusions of Rp-cAMPS also significantly attenuated opiate withdrawal behaviors, although different behaviors were affected. In contrast, intra-amygdala infusions of Rp-cAMPS were without significant effect. In a second series of experiments the effect of intra-LC or intra-PAG infusions of the PKA activator Sp-cAMPS on behavior in nondependent drug-naive animals was determined. Sp-cAMPS infusions into either brain region induced a quasi-withdrawal syndrome, but the observed behaviors differed between the two groups. Analysis of the phosphorylation state of tyrosine hydroxylase, a well characterized substrate for PKA, confirmed the ability of Rp-cAMPS and Sp-cAMPS to inhibit and activate, respectively, PKA activity in vivo. Together, these data provide direct evidence for involvement of the cAMP-PKA system in the LC, as well as in the PAG, in opiate withdrawal and withdrawal-related behaviors.     

Stimulation of locus coeruleus neurons by non-I1/I2-type imidazoline receptors: an in vivo and in vitro electrophysiological study

1. Imidazoline binding sites have been reported to be present in the locus coeruleus (LC). To investigate the role of these sites in the control of LC neuron activity, we studied the effect of imidazolines using in vivo and in vitro single-unit extracellular recording techniques. 2. In anaesthetized rats, local (27 pmoles) and systemic (1 mg kg(-1), i.v.) administrations of 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a selective I-imidazoline receptor ligand, increased the firing rate of LC cells (maximal increase: 22+/-5%, P<0.001 and 16+/-7%, P<0.001 respectively). Chronic pretreatment with the irreversible monoamine oxidase inhibitor clorgyline (3 mg kg(-1), i.p., every 12 h for 14 days) abolished this effect. 3. In rat midpontine brain slices containing the LC, bath application (1 mM) of the imidazolines 2-BFI, 2-(4,5-dihydroimidaz-2-yl)-quinoline (BU224), idazoxan, efaroxan, phentolamine and (2-2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline (RX821002) reversibly stimulated LC cells. The maximal effect was approximately 90% except for RX821002 and efaroxan which induced smaller maximal effects (approximately 58% and approximately 35% respectively). Simultaneous application of idazoxan and 2BFI did not lead to additive effects. 4. Bath application of the alpha2-adrenoceptor antagonists, yohimbine (1 - 10 microM) and N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (10 microM), failed to modify LC activity. The irreversible blockade of alpha2-adrenoceptors with EEDQ (10 microM) did not alter the effect of idazoxan or that of efaroxan. Previous application of clorgyline (10 microM) did not modify the excitatory effect of 2-BFI or efaroxan. 5. Changes in the pH of the bathing solution (6.84-7.84) did not influence the effect caused by idazoxan. Bath application of 2-BFI (1 mM) reversed the inhibition induced by diazoxide (300 microM), an ATP-sensitive K+ channel opener, whereas application of glibenclamide (3 microM), an ATP-sensitive K+ channel blocker, partially blocked the effect of 2-BFI. 6. This study shows that imidazoline compounds stimulate the firing rate of LC neurons. This effect is not mediated by alpha2-adrenoceptors nor by I1 or I2-imidazoline receptors but involves a different subtype of imidazoline receptor. Our results indicate that this receptor is located extracellularly and modulates ATP-sensitive K+ channels.     

Activation of noradrenergic neurons in the locus coeruleus by corticotropin-releasing factor. A microdialysis study

In the present study the effects of different doses of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF on locus coeruleus (LC) neurons were studied in anesthetized male Wistar rats. To monitor the release of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a microdialysis probe was implanted into the parietal cortex, a major projection area of the LC. Saline, 0.17, 0.51 nmol CRF and a combination of 5.1 nmol alpha-helical CRF and 0.51 nmol CRF were applied to the LC via a fused silica capillary. While both doses of CRF augmented NA in parietal cortex dialysates (0.51 nmol CRF: from 0.0206 to 0.0266 pmol/sample; 0.17 nmol CRF: from 0.0147 to 0.0170 pmol/sample), saline did not affect NA concentration. The metabolite MHPG also increased, but in a more prolonged time course. The antagonist alpha-helical CRF attenuated the CRF effects. The increase of extraneuronal NA concentration monitored in the cortical samples indicates an augmented depolarization rate of noradrenergic LC neurons. This clearly demonstrates the activation of these neurons by CRF, suggesting physiological interactions of CRF and noradrenergic neurons.     

Electrocortical desynchronization after microinfusion of kainic acid into the locus coeruleus in rats

CD-1, a genetically-engineered CHO cell line, was cultivated with a Biosilon microcarrier culture system. We successfully cultivated CD-1 cells to a very high density (over 1 x 10(7) cells/ml). Prourokinase was stably secreted at about 180 IU/10(6) cells/24 h. Experiments showed that CD-1 cells growing on Biosilon microcarriers were able to spontaneously release from the microcarriers, then reattach and proliferate on fresh microcarriers. This makes it very easy to scale up production. The microcarriers could be reused several times without affecting adhesion, proliferation and prourokinase secretion. With CM-PECC membrane radial flow chromatography and MPG chromatography, the prourokinase in conditioned medium could be purified to a specific activity of 1 x 10(5) IU/mg of protein. The purification factor was about 600 fold, and approximately 90% of the biological activity was recovered.     

Electron microscopic distribution of mu opioid receptors on noradrenergic neurons of the locus coeruleus

The distribution of mu opioid receptors was examined by light and electron microscopic autoradiography in the locus coeruleus of the rat following in vitro labelling with the iodinated agonist [125I]FK-33824. At the light microscopic level, specific mu opioid binding sites were concentrated over the perikarya and dendrites of neurons that were tyrosine hydroxylase-immunopositive in adjacent sections. Accordingly, both the number of tyrosine hydroxylase-immunoreactive neurons and the density of labelled mu receptors decreased markedly throughout the rostrocaudal extent of the nucleus following treatment with the catecholaminergic neurotoxin 6-hydroxydopamine. By electron microscopy, specifically labelled receptors were detected both inside and on the surface of locus coeruleus neurons. Intracellular sites were found by resolution circle analysis to be highly concentrated within the endoplasmic reticulum and Golgi apparatus, suggesting that the ligand recognizes both glycosylated and preglycosylated forms of receptor. The remainder were found mainly over the cytoplasmic matrix or intracytoplasmic vesicles, and were attributed to newly synthesized or recycled receptors in transit. Cell surface receptors were present over both dendritic and perikaryal membranes of noradrenergic cells. These were most highly concentrated opposite abutting axon terminals, suggesting the existence of receptor 'hot spots' at sites of putative endogenous ligand release. However, only a small proportion of these sites was associated with synaptic specializations. Furthermore, an important contingent was detected opposite non-axonal elements, such as dendrites and glial cells, suggesting that mu opioid ligands act mainly parasynaptically on locus coeruleus neurons. Finally, approximately 5% of labelled receptors were associated with axoglial interfaces, indicating that a minor action of mu opioids in the locus may be presynaptic and/or glial.     

The role of the locus coeruleus and N-methyl-D-aspartic acid (NMDA) and AMPA receptors in opiate withdrawal

The turnover rates of plasma lactate, normalized for O2 consumption rate, are higher in the fetus than in the adult. This occurs despite very low rates of fetal gluconeogenesis which preclude the recycling of lactate carbon into glucose. In an effort to establish the main routes of disposal of fetal plasma lactate, 12 midgestation ovine fetuses (age 74 +/- 1 days) were infused intravenously at constant rate with L-[U-14C]lactate for a 4-hour period. At the end of the infusion, the amounts of 14C retained by the fetus and by the placenta, and the distribution of the retained 14C in free and protein-bound amino acids and in lipids were measured. Of the total 14C infused, 17.0 +/- 1.4% was recovered in the placenta, 4.0 +/- 0.3% in the fetal liver, and 15.0 +/- 0.8% in the extrahepatic fetal tissues. Of the retained radioactive carbon, 45-57% was recovered in the free and protein-bound amino acid fractions and 11-17% in the lipid fractions. Approximately 90% of the 14C in the free amino acid fractions was present as glutamate/glutamine, serine, glycine, and alanine carbon. In conjunction with data on fetal CO2 production from lactate carbon, these results demonstrate that the main routes of fetal lactate disposal are oxidation and synthesis of nonessential amino acids and lipids.     

Conditioned responses of monkey locus coeruleus neurons anticipate acquisition of discriminative behavior in a vigilance task

Impulse activity was recorded extracellularly from noradrenergic neurons in the nucleus locus coeruleus of three cynomolgus monkeys performing a visual discrimination (vigilance) task. For juice reward, the subjects were required to release a lever rapidly in response to an improbable target stimulus (20% of trials) that was randomly intermixed with non-target stimuli presented on a video display. All locus coeruleus neurons examined were phasically and selectively activated by target stimuli in this task. Other task events elicited no consistent response from these neurons (juice reward, lever release, fix spot stimuli, non-target stimuli). With reversal of the task contingency, locus coeruleus neurons ceased responding to the former target stimuli, and began responding instead to the new target (old non-target) stimuli. In addition, the latency of locus coeruleus response to target stimuli increased after reversal (by about 140 ms) in parallel with a similar increase in the latency of the behavioral response. These results indicate that the conditioned locus coeruleus responses reflect stimulus meaning and cognitive processing, and are not driven by physical sensors attributes. Notably, the reversal in locus coeruleus response to stimuli after task reversal occurred rapidly, hundreds of trials before reversal was expressed in behavioral responses. These findings indicate that conditioned responses of locus coeruleus neurons are plastic and easily altered by changes in stimulus meaning, and that the locus coeruleus may play an active role in learning the significance of behaviorally important stimuli.     

Alteration in the brain content of substance P (1-7) during withdrawal in morphine-dependent rats

OBJECTIVE: To evaluate hoof size, shape, and balance as risk factors for catastrophic musculoskeletal injuries (CMI), including suspensory apparatus failure (SAF) and cannon bone condylar fracture (CDY) in Thoroughbred racehorses. ANIMALS: 95 Thoroughbred racehorses that died between 1994 and 1996. PROCEDURE: 38 quantitative measures of hoof size, shape, and balance were obtained from orthogonal digital images of the hoof and were compared between case horses with forelimb CMI (70), SAF (43), and CDY (10) injuries and control horses whose death was unrelated to the musculoskeletal system (non-CMI, 25). Comparison of group means between cases and controls was done using ANOVA, and multivariable logistic regression was used to estimate odds ratios. RESULTS: Odds of CMI were 0.62 times lower for a 5mm increase in ground surface width difference and 0.49 times lower for a 100-mm2 increase in sole area difference. Odds of SAF were 6.75 times greater with a 10 degrees increase in toe-heel angle difference and 0.58 times lower with a 100-mm2 increase in sole area difference. Odds of CDY were 0.26 times lower with a 3 degrees increase in toe angle, 0.15 times lower with a 5-mm increase in lateral ground surface width, and 0.35 times lower with a 100-mm2 increase in sole area difference. CLINICAL RELEVANCE: Decreasing the difference between toe and heel angles should decrease risk of SAF for Thoroughbred racehorses and should be considered in addition to increasing toe angle alone to help prevent catastrophic injury. Trimming the hoof to perfect mediolateral symmetry may not be a sound approach to avoiding injury.     

Neonatal handling reduces the number of cells in the locus coeruleus of rats.

Neonatal handling induces long-lasting effects on behaviors and stress responses. The objective of the present study was to analyze the effects of neonatal handling (from the 1st to the 10th day after delivery) on the number of cells and volume of locus coeruleus (LC) nucleus in male and female rats at 4 different ages: 11, 26, 35, and 90 days. Results showed significant reductions in the number of cells and the volume of the LC nucleus in neonatally handled males and females compared with nonhandled rats. Environmental stimulation early in life induced a stable structural change in a central noradrenergic nucleus, which could be one of the causal factors for the behavioral and hormonal alterations observed in adulthood. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic cold stress alters the basal and evoked electrophysiological activity of rat locus coeruleus neurons

In vivo extracellular single-unit recording techniques revealed that chronic cold stress significantly alters both the basal and the evoked electrophysiological activity of noradrenergic neurons in the locus coeruleus of the anaesthetized rat. Following 17-21 days of chronic cold exposure (5 degrees C), the single-unit activity of histologically-identified locus coeruleus neurons in chloral hydrate-anaesthetized rats was recorded and analysed in terms of their basal firing rate and pattern of spike activity, as well as their response to footshock stimulation. There was no significant difference in the incidence of spontaneously active cells/electrode track between cold-stressed rats and control rats. However, the basal spike activity of locus coeruleus cells recorded from cold-stressed rats differed significantly from that of control rats along two dimensions: i) they displayed significantly higher basal firing rates (mean = 1.88 Hz vs 1.20 Hz, respectively); and ii) they frequently exhibited spontaneous burst-firing activity that was not observed in control rats (observed in 15/17 cold-stressed rats vs 1/26 control rats). The evoked spike activity of locus coeruleus cells in cold-stressed rats also differed significantly from that of control rats along two dimensions: i) they were more likely to respond to footshock stimulation (mean = 90.3% vs 74.4%, respectively); and ii) these responses were more likely to consist of multispike bursts of action potentials (mean = 8 bursts/50 stimulations vs 1 burst/50 stimulations, respectively). These results indicate that alterations in the electrophysiological activity of noradrenergic locus coeruleus neurons may contribute to the phenomenon of stress-induced sensitization of norepinephrine release that is thought to underlie some of the neuropathological changes that accompany long-term stress.