Primary Site Of Action Research Articles

Efavirenz and neuropsychiatric effects–When the treatment complicates matter further

IntroductionEfavirenz, a non-nucleoside analogue inhibitor of the reverse transcriptase, has become commonly used in the treatment of HIV infection. Although highly effective, efavirenz is associated with causing neuropsychiatric side effects in approximately 50% of patients.ObjectivesTo provide an overview of efavirenz-induced neuropsychiatric effects.MethodsLiterature review based on PubMed/Medline.ResultsThe neuropsychiatric side effects of efavirenz usually begin quickly, commonly peak in the first two weeks after the start of therapy, and can include depression, anxiety, sleep disturbances, impaired concentration, aggressive behavior, paranoia, psychosis. Generally, these events are mild to moderate in severity and time limited, however, in a small number of cases, are late, persistent or intolerable. They are often associated with a negative impact on treatment adhesion. Some factors are known to increase the risk of neuropsychiatric effects in HIV-positive patients. The behavioral effects of efavirenz appear to be dose-dependent and mediated predominately by the 5-HT2A receptor, a primary site of action of lysergic acid diethylamine (LSD). Importantly, the efavirenz-induced neuropsychiatric effects may be difficult to distinguish from HIV-related neuropsychiatric symptoms, preexisting mental disorder or substance use. The neuropsychiatric effects should be treated with non-pharmacologic or pharmacologic interventions, according to severity. The psychiatric status of patients should be closely monitored for at least the first 6 to 12 months of treatment.ConclusionTaking into account the high rates of neuropsychiatric side effects, it is crucial that the physicians are familiar with this important subject, and the decision to initiate efavirenz in psychiatric patients is individualized.Disclosure of interestThe authors have not supplied their declaration of competing interest.

(206) Modulation of multiple modalities of somatosensory information by peripheral kappa opioid receptors

Peripherally-restricted kappa opioid receptor (KOR) agonists are emerging as a novel treatment for pain and itch conditions and have shown efficacy in several recent clinical trials. One primary site of action is thought to be at KORs on primary afferent nerves that innervate the body. Yet, the subtypes of primary afferent somatosensory neurons that express the kappa opioid receptor remain undefined. Using a newly developed KOR-cre knockin allele, viral tracing, and single-cell RT-PCR we discovered that that KOR is expressed in a specific subset of peptidergic afferents. This subset targeted multiple tissue types and expressed higher levels of transcripts known to be involved in neurogenic inflammation. Consistent with this, peripherally-restricted KOR agonists inhibited behavioral responses to chemical pain and itch stimuli, but not acute heat stimuli, and also decreased mechanical hypersensitivity following an incision injury. Unexpectedly, we also found that KOR is expressed in subsets of primary afferents that form lanceolate or circumferential endings around hair follicles, suggesting an unappreciated role for KOR signaling in the modulation of low-threshold mechanosensation. At a functional level, genetically-labeled afferents showed inhibition of voltage-gated calcium current in response to kappa agonists, and optogenetic experiments revealed that dynorphin inhibited evoked-EPSCs from the central terminals of KOR-expressing afferents. These experiments provide key insight for the rationale use of peripherally-restricted KOR agonists for the modulation of inflammatory pain, itch, and potentially mechanical allodynia.

Brevibacillus laterosporus pathogenesis and local immune response regulation in the house fly midgut

The insect midgut represents the primary site of action of the entompathogenic bacterium Brevibacillus laterosporus. While most studies on this microorganism focus on the identification and characterization of possible virulence factors and toxins, little is known about the insect immune defense mechanisms that are activated against this pathogen. In this study we have investigated the local immune response of different house fly stages to B. laterosporus at the transcriptional level, and we tested the hypothesis that an improvement in entomopathogenicity can be achieved by impairing host innate immunity. Gene expression analyses showed that immediately after spore ingestion (6–12h) both larvae and adults increased the transcription rate of immune related genes in the midgut tissues, with special regard to those encoding for the main house fly antimicrobial peptides (AMPs) (i.e., attacin, cecropin, defensin, diptericin, domesticin, muscin) and for prophenoloxydase that is normally involved in the cascade of events leading to the generation of reactive oxygen species (ROS) and other factors with antibacterial properties. In experiments evaluating the use of an immunosuppressive agent to enhance the virulence of B. laterosporus against adult house flies, a significant downregulation of the same genes was observed 12–24h after the administration of sub-lethal doses of the botanical compound azadirachtin. Consequently, a significant increase in B. laterosporus entomopathogenic action was observed when flies were preliminarily or simultaneously exposed to a sub-lethal dose of azadirachtin. These results provide an important contribution to the prospect of employing immune-impairing tools to implement pest management strategies.

Secondary Effects of Glyphosate Action in Phelipanche aegyptiaca: Inhibition of Solute Transport from the Host Plant to the Parasite

It is currently held that glyphosate efficiently controls the obligate holoparasite Phelipanche aegyptiaca (Egyptian broomrape) by inhibiting its endogenous shikimate pathway, thereby causing a deficiency in aromatic amino acids (AAA). While there is no argument regarding the shikimate pathway being the primary site of the herbicide's action, the fact that the parasite receives a constant supply of nutrients, including proteins and amino acids, from the host does not fit with an AAA deficiency. This apparent contradiction implies that glyphosate mechanism of action in P. aegyptiaca is probably more complex and does not end with the inhibition of the AAA biosynthetic pathway alone. A possible explanation would lie in a limitation of the translocation of solutes from the host as a secondary effect. We examined the following hypotheses: (a) glyphosate does not affects P. aegyptiaca during its independent phase and (b) glyphosate has a secondary effect on the ability of P. aegyptiaca to attract nutrients, limiting the translocation to the parasite. By using a glyphosate-resistant host plant expressing the “phloem-mobile” green fluorescent protein (GFP), it was shown that glyphosate interacts specifically with P. aegyptiaca, initiating a deceleration of GFP translocation to the parasite within 24 h of treatment. Additionally, changes in the entire sugars profile (together with that of other metabolites) of P. aegyptiaca were induced by glyphosate. In addition, glyphosate did not impair germination or seedling development of P. aegyptiaca but begun to exert its action only after the parasite has established a connection to the host vascular system and became exposed to the herbicide. Our findings thus indicate that glyphosate does indeed have a secondary effect in P. aegyptiaca, probably as a consequence of its primary target inhibition—via inhibition of the translocation of phloem-mobile solutes to the parasite, as was simulated by the mobile GFP. The observed disruption in the metabolism of major sugars that are abundant in P. aegyptiaca within 48 h after glyphosate treatment provides a possible explanation for this inhibition of translocation and might reflect a critical secondary effect of the herbicide's primary action that results in loss of the parasite's superior sink for solutes.

Cocaine Potency at the Dopamine Transporter Tracks Discrete Motivational States During Cocaine Self-Administration.

Although the dopamine transporter (DAT) is the primary site of action for cocaine, and the dopamine system is known to mediate the reinforcing effects of cocaine, the dopaminergic variations underlying individual differences in cocaine self-administration behaviors are not fully understood. Recent advances in the application of economic principles to operant tasks in rodents have allowed for the within-subject, within-session determination of both consummatory and appetitive responding for reinforcers. Here we combined a behavioral economics approach with cocaine self-administration and ex vivo voltammetric recording of dopamine signaling in the core of the nucleus accumbens of rats to determine the relationship between dopamine signaling and discrete aspects of cocaine taking and seeking. We found neither dopamine release or uptake tracked individual differences in cocaine consumption or the reinforcing efficacy of cocaine. Cocaine potency at the DAT was correlated with reinforcing efficacy, but was not related to cocaine consumption. Further, we introduce a novel analysis that determines perseverative responding within the same procedure, and find that cocaine potency at the DAT also tracks differences in perseverative responding. Together, we demonstrate that cocaine effects at the DAT determine the reinforcing efficacy of cocaine, and perseverative responding for sub-threshold doses of cocaine that do not maintain responding when presented in isolation. Surprisingly, we find that variations in cocaine potency do not account for differences in cocaine consumption, suggesting that satiation for cocaine is determined by other targets or mechanisms. Finally, we outline a novel approach for relating drug-target interactions and potency to discrete motivational states during a single self-administration session.

Photosynthetic Performance of the Imidazolinone Resistant Sunflower Exposed to Single and Combined Treatment by the Herbicide Imazamox and an Amino Acid Extract.

The herbicide imazamox may provoke temporary yellowing and growth retardation in IMI-R sunflower hybrids, more often under stressful environmental conditions. Although, photosynthetic processes are not the primary sites of imazamox action, they might be influenced; therefore, more information about the photosynthetic performance of the herbicide-treated plants could be valuable for a further improvement of the Clearfield technology. Plant biostimulants have been shown to ameliorate damages caused by different stress factors on plants, but very limited information exists about their effects on herbicide-stressed plants. In order to characterize photosynthetic performance of imazamox-treated sunflower IMI-R plants, we carried out experiments including both single and combined treatments by imazamox and a plant biostimulants containing amino acid extract. We found that imazamox application in a rate of 132 μg per plant (equivalent of 40 g active ingredient ha−1) induced negative effects on both light-light dependent photosynthetic redox reactions and leaf gas exchange processes, which was much less pronounced after the combined application of imazamox and amino acid extract.

Ivermectin exhibits potent anti-mitotic activity

Ivermectin (IVM) is a pharmaceutical used as an anti-parasitic drug in livestock, companion animals and humans. The primary site of action of IVM is believed to be glutamate-gated chloride channels (GluCls). However we have recently reported a direct interaction between IVM and nematode tubulin with micromolar affinity. Here we report that IVM also interacts with mammalian tubulin. To test this possibility, we used the tubulin polymerization assay and found that IVM increased the degree of polymerization of mammalian tubulin. Furthermore when HeLa cells were exposed to IVM it stabilized the mammalian tubulin against the depolymerizing effects of cold temperatures, and prevented the replication of the HeLa cells in vitro. However, the IVM-induced inhibition of HeLa cell division was reversible. The data suggests that mammalian microtubules bound IVM and were stabilized by IVM at micromolar concentrations. IVM may thus affect the dynamics of tubulin polymerization and depolymerization, which in turn can result in cell death. Given that IVM is already approved for use in humans, its development as an anti-mitotic is a potentially appealing option.

A ten fold reduction of nicotine yield in tobacco smoke does not spare the central cholinergic system in adolescent mice

The tobacco industry has gradually decreased nicotine content in cigarette smoke but the impact of this reduction on health is still controversial. Since the central cholinergic system is the primary site of action of nicotine, here, we investigated the effects of exposure of adolescent mice to tobacco smoke containing either high or low levels of nicotine on the central cholinergic system and the effects associated with cessation of exposure. From postnatal day (PN) 30 to 45, male and female Swiss mice were exposed to tobacco smoke (whole body exposure, 8h/day, 7 days/week) generated from 2R1F (HighNic group: 1.74mg nicotine/cigarette) or 4A1 (LowNic group: 0.14mg nicotine/cigarette) research cigarettes, whereas control mice were exposed to ambient air. Cholinergic biomarkers were assessed in the cerebral cortex and midbrain by the end of exposure (PN45), at short- (PN50) and long-term (PN75) deprivation. In the cortex, nicotinic cholinergic receptor upregulation was observed with either type of cigarette. In the midbrain, upregulation was detected only in HighNic mice and remained significant in females at short-term deprivation. The high-affinity choline transporter was reduced in the cortex: of HighNic mice by the end of exposure; of both HighNic and LowNic females at short-term deprivation; of LowNic mice at long-term deprivation. These decrements were separable from effects on choline acetyltransferase and acetylcholinesterase activities, suggesting cholinergic synaptic impairment. Here, we demonstrated central cholinergic alterations in an animal model of tobacco smoke exposure during adolescence. This system was sensitive even to tobacco smoke with very low nicotine content.

The actions of isoprenaline and mirabegron in the isolated whole rat and guinea pig bladder.

β3-adrenoceptor agonists influence overactive bladder in humans and animal models. However, data is emerging that the mode of action of these drugs is complex. The present study explored the actions of the β3-adrenergic agonist mirabegron and the non-selective agonist isoprenaline on the contractile systems in the rat and guinea pig bladder. Intravesical pressure was measured in isolated whole bladders from female adult animals. In both species spontaneous contractile activity was observed. The muscarinic agonist arecaidine produced complex responses consisting of an initial transient pressure rise followed by complex phasic activity. Three contractile elements were identified: intrinsic micro-contractile activity, initial transient response and steady state phasic activity. The intrinsic and steady state activity could be further divided into a baseline pressure with superimposed phasic activity. The effects of isoprenaline and mirabegron were investigated on these elements. In the rat, the micro-contractile activity could be completely inhibited by isoprenaline (full agonist). The arecaidine-induced initial and steady state baseline pressures were partially reduced, while the phasic activity was little affected. In the guinea pig, both the arecaidine-induced baseline pressure and the phasic activity were affected by isoprenaline. Mirabegron didn't produce significant inhibitory effects in any of the contractile elements in either species. These results show that complex contractile systems operate in the rat and guinea pig bladder that can be modulated by β1/β2-adrenoceptor mechanisms. No evidence was obtained for any β3-dependent regulation of contraction. These data support similar data in humans. Therefore the primary site of therapeutic action of β3-adrenergic agonists remains unknown.

Impaired ergosterol biosynthesis mediated fungicidal activity of Co(II) complex with ligand derived from cinnamaldehyde

In this study, we have used aldehyde function of cinnamaldehyde to synthesize N, N′-Bis (cinnamaldehyde) ethylenediimine [C20H20N2] and Co(II) complex of the type [Co(C40H40N4)Cl2]. The structures of the synthesized compounds were determined on the basis of physiochemical analysis and spectroscopic data (1H NMR, FTIR, UV–visible and mass spectra) along with molar conductivity measurements. Anticandidal activity of cinnamaldehyde its ligand [L] and Co(II) complex was investigated by determining MIC80, time-kill kinetics, disc diffusion assay and ergosterol extraction and estimation assay. Ligand [L] and Co(II) complex are found to be 4.55 and 21.0 folds more efficient than cinnamaldehyde in a liquid medium. MIC80 of Co(II) complex correlated well with ergosterol inhibition suggesting ergosterol biosynthesis to be the primary site of action. In comparison to fluconazole, the test compounds showed limited toxicity against H9c2 rat cardiac myoblasts. In confocal microscopy propidium iodide (PI) penetrates the yeast cells when treated with MIC of metal complex, indicating a disruption of cell membrane that results in imbibition of dye. TEM analysis of metal complex treated cells exhibited notable alterations or damage to the cell membrane and the cell wall. The structural disorganization within the cell cytoplasm was noted. It was concluded that fungicidal activity of Co(II) complex originated from loss of membrane integrity and a decrease in ergosterol content is only one consequence of this.

Ultrastructural effects of acetamizuril on endogenous phases of Eimeria tenella.

To explore the primary stage or site of action of acetamizuril (AZL), a novel triazine anticoccidial compound, the ultrastructural development of Eimeria tenella at different endogenous stages was studied in experimentally infected chickens treated with a single oral dose of 15 mg/kg AZL. As a result of drug action, the differentiations of second-generation schizonts and microgamonts were largely inhibited and merozoites became irregular in shape. Meanwhile, the outer membrane blistering and perinuclear space enlargement were obvious in the second-generation schizonts and microgamonts, which were never observed in the classic triazine anticoccidiosis drug diclazuril-treated E. tenella. The chromatin aggregation, anachromasis, and marginalization were visible in merozoites and microgamonts. Furthermore, the abnormal evagination of microgametes finally resulted in the degeneration of microgamonts and the failure of subsequent fertilization. The most marked micromorphological alteration occurring in the macrogamonts was the WFB2. Even if the fertilization occurred, the formation of oocyst wall became malformed and the zygote proceeded to the obvious degeneration. In addition, mitochondria swelling and cytoplasm vacuolization were discerned in respective intracellular stages, while endoplasmic reticulum and Golgi body swelling was less seen. These alterations may be the causes leading to the final death of E. tenella and also provide some information for further exploring the mechanism of action of AZL at the molecular level.

Insider trading: Extracellular matrix proteins and their non-canonical intracellular roles.

In metazoans, the extracellular matrix (ECM) provides a dynamic, heterogeneous microenvironment that has important supportive and instructive roles. Although the primary site of action of ECM proteins is extracellular, evidence is emerging for non-canonical intracellular roles. Examples include osteopontin, thrombospondins, IGF-binding protein 3 and biglycan, and relate to roles in transcription, cell-stress responses, autophagy and cancer. These findings pose conceptual problems on how proteins signalled for secretion can be routed to the cytosol or nucleus, or can function in environments with diverse redox, pH and ionic conditions. We review evidence for intracellular locations and functions of ECM proteins, and current knowledge of the mechanisms by which they may enter intracellular compartments. We evaluate the experimental methods that are appropriate to obtain rigorous evidence for intracellular localisation and function. Better insight into this under-researched topic is needed to decipher the complete spectrum of physiological and pathological roles of ECM proteins.

An Overview of Pharmacologic Management of Chronic Pain.

Patients with chronic pain can be challenging to manage and historically providers have relied on opiates to treat pain. Recent studies have brought into question the safety and efficacy of chronic opiate therapy in the noncancer population. There is a vast amount of literature to support the use of nonsteroidal anti-inflammatory medications, antidepressants, anticonvulsants, topical agents, cannabinoids, and botulinum toxin either in conjunction with or in lieu of opioids. Intrathecal drug delivery systems can deliver some of these medications directly to their primary site of action while minimizing the side effects seen with systemic administration.

Opioids and TRPV1 in the peripheral control of neuropathic pain – Defining a target site in the injured nerve

Targeting peripheral neuropathic pain at its origin may prevent the development of hypersensitivity. Recently we showed this can be mediated by opioid receptors at the injured nerve trunk. Here, we searched for the most relevant peripheral site to block transient receptor potential vanilloid 1 (TRPV1), and investigated analgesic interactions between TRPV1 and opioids in neuropathy. In a chronic constriction injury (CCI) of the sciatic nerve in mice, we assessed the effects of μ-, δ- and κ-opioid receptor agonists and TRPV1 antagonist (SB366791) injected at the CCI site or into the injured nerve-innervated paw on spontaneous paw lifting, heat and mechanical sensitivity. We also examined TRPV1 expression in total membrane and plasma membrane fractions from nerves and paws. We found that opioids and SB366791 co-injected in per se nonanalgesic doses at the CCI site or into the paw diminished heat and mechanical sensitivity. SB366791 alone dose-dependently alleviated heat and mechanical sensitivity. TRPV1 blockade in the paw was more effective than at the CCI site. None of the treatments diminished spontaneous paw lifting. TRPV1 expression analysis suggests that the levels of functional TRPV1 do not critically determine the TRPV1 antagonist-mediated analgesia. Together, the identification of the primary action site in damaged nerves is crucial for effective pain control. Contrary to opioids, the TRPV1 blockade in the injured nerve peripheral terminals, rather than at the nerve trunk, appears promising against heat pain. Opioid/TRPV1 antagonist combinations at both locations partially reduced neuropathy-triggered heat and mechanical pain.

Closer to the Site of Action

Everolimus (EVE) is an immunosuppressive drug dosed according to therapeutic drug monitoring in renal transplant recipients. The primary site of action is within activated lymphocytes. EVE is a substrate of the efflux transporter ABCB1 also known as P-glycoprotein. Limited data exist regarding a possible association between whole blood and intralymphocyte concentrations of EVE and the potential influence of ABCB1. Twelve renal transplant recipients (5 men and 7 women) treated with EVE underwent a pharmacokinetic investigation where EVE concentrations in whole blood and in peripheral blood mononuclear cells (PBMC) were determined within a dosing interval. In addition, the activity of ABCB1 in PBMC was determined using the Rhodamine123 efflux assay and the patients' genotypes of ABCB1 were determined. There was a significant correlation between EVE AUC0-12 in whole blood and in PBMC (r = 0.90, P < 0.01), and no association was demonstrated between the ABCB1 activity and EVE PBMC/whole blood ratio of trough concentrations (r = 0.23, P = 0.76). Furthermore, ABCB1 1236C>T, 3435C>T, and 2677G>T/A polymorphism did not influence EVE AUC0-12 PBMC/whole blood ratio. The results revealed a significant association between EVE whole blood and PBMC concentrations, suggesting that ABCB1-mediated efflux from PBMC to be of minor importance for the distribution of EVE.

Isoeugenol has a non-disruptive detergent-like mechanism of action.

Isoeugenol is an essential oil constituent of nutmeg, clove, and cinnamon. Despite isoeugenol's promising antimicrobial activity, no studies have yet investigated its mode of antibacterial action at the molecular level. The aim of this study is to clarify isoeugenol's antibacterial mode of action using the Gram-negative and Gram-positive model organisms Escherichia coli and Listeria innocua, respectively. We determined the antimicrobial activity of isoeugenol against the model organisms, and examined how isoeugenol affects cell morphology, cell membrane permeabilization, and how isoeugenol interacts with phospholipid membranes using vesicle and supported lipid bilayer models. Isoeugenol demonstrated a bactericidal activity against E. coli and L. innocua that did not affect cell morphology, although the cell membrane was permeabilized. We hypothesized that the cell membrane was the primary site of action, and studied this interaction in further detail using purified membrane model systems. Isoeugenol's permeabilization of calcein-encapsulated vesicles was concentration dependent, and isoeugenol's interaction with giant unilamellar vesicles indicated increased membrane fluidity and a non-disruptive permeabilization mechanism. This contradicted membrane fluidity measurements on supported lipid bilayers (SLBs), which indicated decreased membrane fluidity. However, further investigations demonstrated that the interaction between isoeugenol and bilayers was reversible, and caused membranes to display heterogeneous topography, an increased mass, and a higher degree of hydration. In conclusion, we propose that isoeugenol interacts with membranes in a reversible non-disruptive detergent-like manner, which causes membrane destabilization. Furthermore, we argue that isoeugenol increases membrane fluidity. Our work contributes to the understanding of how essential oil constituents interact with cell components.

Cellular and molecular remodeling of inguinal adipose tissue mitochondria by dietary methionine restriction

Dietary methionine restriction (MR) produces a coordinated series of biochemical and physiological responses that improve biomarkers of metabolic health, increase energy expenditure, limit fat accretion and improve overall insulin sensitivity. Inguinal white adipose tissue (IWAT) is a primary target and site of action where the diet initiates transcriptional programs linked to enhancing both synthesis and oxidation of lipid. Using a combination of ex vivo approaches to assess dietary effects on cell morphology and function, we report that dietary MR produced a fourfold increase in multilocular, UCP1-expressing cells within this depot in conjunction with significant increases in mitochondrial content, size and cristae density. Dietary MR increased expression of multiple enzymes within the citric acid cycle, as well as respiratory complexes I, II and III. The physiological significance of these responses, evaluated in isolated mitochondria by high-resolution respirometry, was a significant increase in respiratory capacity measured using multiple substrates. The morphological, transcriptional and biochemical remodeling of IWAT mitochondria enhances the synthetic and oxidative capacity of this tissue and collectively underlies its expanded role as a significant contributor to the overall increase in metabolic flexibility and uncoupled respiration produced by the diet.

A novel role for xenopsin: Stimulation of food intake

Xenopsin (XPN), an extract from frog skin, is comprised of 80 amino acids and exerts effects on the mammalian digestive tract. The purpose of the study presented here was to determine if XPN would affect food intake using chicks as models. Chicks which had been fasted for 180min did not change food or water intake after central injection of XPN. However, ab libitum fed chicks which received 1 and 3nmol central XPN increased food intake while water intake was not affected. When the dose was increased to 9nmol chicks did not increase food intake but their water intake was reduced suggesting malaise. Chicks injected with XPN had increased c-Fos immunoreactivity in the lateral hypothalamus, but other hypothalamic appetite-associated nuclei were not affected. When XPN was directly injected into the lateral hypothalamus food intake was increased, suggesting a primary site of action. When the expression of appetite-associated neuropeptide mRNA was quantified chicks injected with XPN had increased proopiomelanocortin mRNA. Lastly, a comprehensive behavior analysis was performed and while XPN injected chicks had an increase in the number of feeding pecks, jumping, preening, deep rest and sitting were all decreased. Thus, we conclude that exogenous XPN functions as an orexigenic factor in chicks and its effects are mediated by the lateral hypothalamus.

Attenuation of high-frequency (50-200 Hz) thalamocortical EEG rhythms by propofol in rats is more pronounced for the thalamus than for the cortex.

BackgroundThalamocortical EEG rhythms in gamma (30-80 Hz) and high-gamma (80-200 Hz) ranges have been linked to arousal and conscious processes. To test the hypothesis that general anesthetics attenuate these rhythms, we characterized the concentration-effect relationship of propofol on the spectral power of these rhythms. In view of the ongoing debate about cortex versus thalamus as the primary site of anesthetic action for unconsciousness, we also compared the relative sensitivity of cortex and thalamus to this effect propofol.MethodsAdult male Long-Evans rats were chronically implanted with electrodes in somatosensory (barrel) cortex and ventroposteromedial thalamus. Propofol was delivered by a computer-controlled infusion using real-time pharmacokinetic modeling to obtain the desired plasma concentration. Spectral power was assessed during baseline, at four stable propofol plasma-concentrations (0, 3,6,9,12 μg/ml) and during recovery over four frequency ranges (30-50, 51-75, 76-125, 126-200 Hz). Unconsciousness was defined as complete loss of righting reflex. Multiple regression was used to model the change of power (after logarithmic transformation) as a function of propofol concentration and recording site.ResultsUnconsciousness occurred at the 9 μg/ml concentration in all animals. Propofol caused a robust linear concentration-dependent attenuation of cortical power in the 76-200 Hz range and of thalamic power in the 51-200 Hz range. In all instances the concentration-effect slope for the thalamus was markedly steeper than for the cortex. Furthermore the lowest concentration causing unconsciousness significantly reduced cortical power in the 126-200 Hz range and thalamic power in the 51-200 Hz range.ConclusionsPropofol causes a concentration-dependent attenuation of the power of thalamocortical rhythms in the 51-200 Hz range and this effect is far more pronounced for the thalamus, where the attenuation provides a robust correlate of the hypnotic action of propofol.

A population-based Swedish Twin and Sibling Study of cannabis, stimulant and sedative abuse in men

BackgroundPrior studies, utilizing interview-based assessments, suggest that most of the genetic risk factors for drug abuse (DA) are non-specific with a minority acting specifically on risk for abuse of particular psychoactive substance classes. We seek to replicate these findings using objective national registry data. MethodsWe examined abuse of cannabis, stimulants (including cocaine) and sedatives ascertained from national Swedish registers in male–male monozygotic (1720 pairs) and dizygotic twins (1219 pairs) combined with near-age full siblings (76,457 pairs) to provide sufficient power. Modeling was performed using Mx. ResultsA common pathway model fitted better than an independent pathway model. The latent liability to DA was highly heritable but also influenced by shared environment. Cannabis, stimulant and sedative abuse all loaded strongly on the common factor. Estimates for the total heritability for the three forms of substance abuse ranged from 64 to 70%. Between 75 and 90% of that genetic risk was non-specific, coming from the common factor with the remainder deriving from substance specific genetic risk factors. By contrast, all of the shared environmental effects, which accounted for 18–20% of the variance in liability, were non-specific. ConclusionsIn accord with prior studies based on personal interviews, the large preponderance of genetic risk factors for abuse of specific classes of psychoactive substance are non-specific. These results suggest that genetic variation in the primary sites of action of the psychoactive drugs, which differ widely across most drug classes, play a minor role in human individual differences in risk for DA.