Biomedical subjects

Steven J Henriksen

Publications and source records attributed to Steven J Henriksen.

At least 19 recordsLinked to original sources

PubMed2006

Contingent and non-contingent effects of heroin on mu-opioid receptor-containing ventral tegmental area GABA neurons.

Opiate activation of mu-opioid receptors (muORs) in the ventral tegmental area (VTA) modulates gamma-aminobutyric acid (GABA) neurotransmission within the mesocorticolimbic dopamine (DA) reward system. We combined in vivo extracellular electrophysiological recordings in anesthetized and freely behaving rats with intracellular Neurobiotin filling and immunocytochemistry to characterize the effects of opiates on VTA GABA neurons, evaluate their discharge activity during opiate self-administration, and identify the cellular sites for opiate activation. We identified a subpopulation of VTA GABA neurons that was characterized by location, spike discharge profile, activation by microelectrophoretic DA, and response to internal capsule (IC) stimulation. Systemic administration of heroin or microelectrophoretic application of the selective muOR agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) reduced VTA GABA neuron firing rate (heroin IC(50) = 0.35 mg/kg) and was blocked by the muOR antagonist naloxone. Heroin also reduced IC-evoked post-stimulus spike discharges, a manifestation of gap-junction-mediated electrical coupling between VTA GABA neurons. The baseline firing rate of VTA GABA neurons significantly increased (239%) following the acquisition of heroin self-administration behavior and transiently increased during each response for heroin (105%), but decreased (49%) following heroin, similar to non-contingent heroin. Electrophysiologically characterized VTA GABA neurons were filled with Neurobiotin and labeled dendrites contained plasmalemmal muOR immunoreactivity. Dually labeled muOR dendrites contained dendrodendritic appositions characteristic of gap junctions. These findings indicate that inhibition of this population of GABAergic neurons by opiates acting on dendritic muORs has implications for modulation of electrical coupling between VTA GABA neurons and dopamine (DA) neurotransmission in the VTA and terminal field regions.

Action Potentials↗

PubMed2006

Host response and dysfunction in the CNS during chronic simian immunodeficiency virus infection.

CNS abnormalities can be detected during chronic human immunodeficiency virus (HIV) infection, before the development of opportunistic infections or other sequelae of immunodeficiency. However, although end-stage dementia caused by HIV has been linked to the presence of infected and activated macrophages and microglia in the brain, the nature of the changes resulting in the motor and cognitive disorders in the chronic stage is unknown. Using simian immunodeficiency virus-infected rhesus monkeys, we sought the molecular basis for CNS dysfunction. In the chronic stable stage, nearly 2 years after infection, all animals had verified CNS functional abnormalities. Both virus and infiltrating lymphocytes (CD8+ T-cells) were found in the brain. Molecular analysis revealed that the expression of several immune response genes was increased, including CCL5, which has pleiotropic effects on neurons as well as immune cells. CCL5 was significantly upregulated throughout the course of infection, and in the chronic phase was present in the infiltrating lymphocytes. We have identified an altered state of the CNS at an important stage of the viral-host interaction, likely arising to protect against the virus but in the long term leading to damaging processes.

Animals↗

PubMed2006

Connexin-36 gap junctions mediate electrical coupling between ventral tegmental area GABA neurons.

Communication between neurons in the mammalian brain is primarily through chemical synapses; however, evidence is accumulating in support of electrical synaptic transmission between some neuronal types in the mature nervous system. The authors have recently demonstrated that the gap junction (GJ) blocker quinidine suppresses stimulus-induced and dopamine-evoked coupling of gamma amino butyric acid (GABA) neurons in the ventral tegmental area (VTA) of mature rats (Stobbs et al., 2004). The aim of this study was to evaluate the role of connexin-36 (Cx36) GJs in mediating electrical coupling between VTA GABA neurons in P50-80 rats in vivo and P25-50 rats in vitro. Single stimulation of the internal capsule (IC) evoked VTA GABA neuron spike couplets in mature rats when activated antidromically, and multiple poststimulus spike discharges (PSDs) when activated with brief high-frequency stimulation of the IC (ICPSDs). The Cx36 GJ blocker mefloquine (30 mg/kg) suppressed VTA GABA neuron ICPSDs in mature freely behaving rats. VTA GABA neurons recorded via whole-cell patch clamp in the midbrain slice preparation of P25-50 rats showed robust expression of Cx36 transcripts when tested with single-cell quantitative reverse transcription polymerase chain reaction. In P50-80 rats, Cx36 protein immunoreactivity was evident in the VTA and surrounding structures. Dye-coupling between VTA neurons was observed following Neurobiotin labeling of VTA GABA neurons, as well as with the fluorochrome Alexa Fluor 488 using real-time video fluorescent microscopy. Thus, mature VTA GABA neurons appear to be connected by electrical synapses via Cx36 GJs, whose coupling is enhanced by corticotegmental input and by dopamine.

Animals↗

PubMed2005

Tissue-resident memory CD8+ T cells can be deleted by soluble, but not cross-presented antigen.

Under noninflammatory conditions, both naive and central memory CD8 T cells can be eliminated in the periphery with either soluble peptide or cross-presented Ag. Here, we assess the tolerance susceptibility of tissue-resident memory CD8 T cells in mice to these two forms of tolerogen. Soluble peptide specifically eliminated the majority of memory CD8 cells present in both lymphoid and extralymphoid tissues including lung and liver, but was unable to reduce the number present in the CNS. In contrast, systemic cross-presentation of Ag by dendritic cells resulted in successful elimination of memory cells only from the spleen, with no significant reduction in the numbers of tissue-resident memory cells in the lung. The fact that tissue-resident memory cells were unable to access cross-presented Ag suggests that either the memory cells in the lung do not freely circulate out of the tissue, or that they circulate through a region in the spleen devoid of cross-presented Ag. Thus, although tissue-resident memory cells are highly susceptible to tolerance induction, both the form of tolerogen and location of the T cells can determine their accessibility to tolerogen and the degree to which they are successfully deleted from specific tissues.

Animals↗

PubMed2005

Cortistatin overexpression in transgenic mice produces deficits in synaptic plasticity and learning.

Cortistatin-14 (CST) is a neuropeptide expressed in cortical and hippocampal interneurons that shares 11 of 14 residues with somatostatin. In contrast to somatostatin, infusion of CST decreases locomotor activity and selectively enhances slow wave sleep. Here, we show that transgenic mice that overexpress cortistatin under the control of neuron-specific enolase promoter do not express long-term potentiation in the dentate gyrus. This blockade of dentate LTP correlates with profound impairment of hippocampal-dependent spatial learning. Exogenously applied CST to slices of wild-type mice also blocked induction of LTP in the dentate gyrus. Our findings implicate cortistatin in the modulation of synaptic plasticity and cognitive function. Thus, increases in hippocampal cortistatin expression during aging could have an impact on age-related cognitive deficits.

Aging↗

PubMed2005

5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern.

BACKGROUND: The 5-hydroxytryptamine7 receptor (5-HT7) is implicated in circadian rhythm phase resetting, and 5-HT7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameters in a pattern opposite from those in patients with clinical depression. METHODS: As sleep, circadian rhythm, and mood regulation are related, we examined 5-HT7 receptor knockout mice in two behavioral models of depression. The forced swim and tail suspension tests are highly predictive for antidepressant drug activity. RESULTS: Unmedicated 5-HT7-/- mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepressant, decreased immobility in both 5-HT7+/+ and 5-HT7-/- mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT7-/- mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state. CONCLUSIONS: The 5-HT7 receptor might have a role in mood disorders and antagonists might have therapeutic value as antidepressants.

Animals↗

PubMed2005

Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons.

Urotensin II (UII) is a cyclic neuropeptide with strong vasoconstrictive activity in the peripheral vasculature. UII receptor mRNA is also expressed in the CNS, in particular in cholinergic neurons located in the mesopontine tegmental area, including the pedunculopontine tegmental (PPT) and lateral dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local administration of UII into the PPT nucleus increases REM sleep without inducing changes in the cortical blood flow. Intracerebroventricular injection of UII enhances both REM sleep and wakefulness and reduces slow-wave sleep 2. Intracerebroventricular, but not local, administration of UII increases cortical blood flow. Moreover, whole-cell recordings from rat-brain slices show that UII selectively excites cholinergic PPT neurons via an inward current and membrane depolarization that were accompanied by membrane conductance decreases. This effect does not depend on action potential generation or fast synaptic transmission because it persisted in the presence of TTX and antagonists of ionotropic glutamate, GABA, and glycine receptors. Collectively, these results suggest that UII plays a role in the regulation of REM sleep independently of its cerebrovascular actions by directly activating cholinergic brainstem neurons.

Acetylcholinesterase↗

PubMed2005

Modeling human methamphetamine exposure in nonhuman primates: chronic dosing in the rhesus macaque leads to behavioral and physiological abnormalities.

Acute high dose methamphetamine (METH) dosing regimens are frequently used in animal studies, however, these regimens can lead to considerable toxicity and even death in experimental animals. Acute high dosing regimens are quite distinct from the chronic usage patterns found in many human METH abusers. Furthermore, such doses, especially in nonhuman primates, can result in unexpected death, which is unacceptable, especially when such deaths fail to accurately model effects of human usage. As a model of chronic human METH abuse we have developed a nonlethal chronic METH administration procedure for the rhesus macaque that utilizes an escalating dose protocol. This protocol slowly increases the METH dosage from 0.1 to 0.7 mg/kg b.i.d. over a period of 4 weeks, followed by a period of chronic METH administration at 0.75 mg/kg b.i.d. (= total daily METH administration of 1.5 mg/kg). In parallel to human usage patterns, METH injections were given 20-23 times a month. This regimen produced a number of behavioral and physiological effects including decreased food intake and a significant increase in urinary cortisol excretion.

Amphetamine-Related Disorders↗

PubMed2004

Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects.

Arousal and anxiety are behavioral responses that involve complex neurocircuitries and multiple neurochemical components. Here, we report that a neuropeptide, neuropeptide S (NPS), potently modulates wakefulness and could also regulate anxiety. NPS acts by activating its cognate receptor (NPSR) and inducing mobilization of intracellular Ca2+. The NPSR mRNA is widely distributed in the brain, including the amygdala and the midline thalamic nuclei. Central administration of NPS increases locomotor activity in mice and decreases paradoxical (REM) sleep and slow wave sleep in rats. NPS was further shown to produce anxiolytic-like effects in mice exposed to four different stressful paradigms. Interestingly, NPS is expressed in a previously undefined cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus. These results indicate that NPS could be a new modulator of arousal and anxiety. They also show that the LC region encompasses distinct nuclei expressing different arousal-promoting neurotransmitters.

Amino Acid Sequence↗

PubMed2004

Characterization of the sleep-wake patterns in mice lacking fatty acid amide hydrolase.

STUDY OBJECTIVES: Oleamide and anandamide are fatty acid amides implicated in the regulatory mechanisms of sleep processes. However, due to their prompt catabolism by fatty acid amide hydrolase (FAAH), their pharmacologic and behavioral effects, in vivo, disappear rapidly. To determine if, in the absence of FAAH, the hypnogenic fatty acid amides induce an increase of sleep, we characterized the sleep-wake patters in FAAH-knockout mice [FAAH (-/-)] before and after sleep deprivation. DESIGN: FAAH (-/-), FAAH (+/-), and FAAH (+/+) mice were implanted chronically for sleep, body temperature (Tb), and locomotor activity (LMA) recordings. Sleep-wake states were recorded during a 24-hour baseline session followed by 8 hours of sleep deprivation. Recovery recordings were done during the 16 hours following sleep deprivation. Total amount of wake, slow-wave sleep, and rapid eye movement sleep were calculated and compared between genotypes. The electroencephalographic spectral analysis was performed by fast Fourier transform analysis. Telemetry recordings of Tb and LMA were carried out continuously during 4 days under baseline conditions. SETTING: N/A. PATIENTS OR PARTICIPANTS: FAAH (-/-) mice and their heterozygote (+/-) and control (+/+) littermates were used. INTERVENTIONS: Sleep deprivation. MEASUREMENTS AND RESULTS: FAAH (-/-) mice possess higher values of slow-wave sleep and more intense episodes of slow-wave sleep than do control littermates under baseline conditions that are not related to differences in Tb and LMA. A rebound of slow-wave sleep and rapid eye movement sleep as well an increase in the levels of slow-wave activity were observed after sleep deprivation in all genotypes. CONCLUSION: These findings support the role of fatty acid amides as possible modulators of sleep and indicate that the homeostatic mechanisms of sleep in FAAH (-/-) mice are not disrupted.

Amidohydrolases↗

PubMed2004

Oleamide and anandamide effects on food intake and sexual behavior of rats.

Oleamide is a lipid with diverse properties, including cannabinoid-like activity. For example, it induces the classic triad of effects attributable to these molecules: decrease in core temperature, hypolocomotion, and reduction in pain perception. However, as it binds to the cannabinoid receptors (CB1) only at high concentrations, it is not considered an actual endocannabinoid. In this study, we tested the effect of oleamide on food intake and sexual behavior and compared it to the effect induced by anandamide. Results indicate that oleamide and anandamide increased food intake during the 3h post-injection. In addition, anandamide but not oleamide induced changes in sexual performance. This study further supports the role of endocannabinoids in food ingestion and male sexual behavior and gives additional support to the notion that, although oleamide might not be an endocannabinoid, it shares some effects with them.

Animals↗

PubMed2004

Opiate state controls bi-directional reward signaling via GABAA receptors in the ventral tegmental area.

The neural mechanisms that mediate the transition from a drug-naive state to a state of drug dependence and addiction are not yet known. Here we show that a discrete population of GABA(A) receptors in the mammalian ventral tegmental area (VTA) serves as a potential addiction switching mechanism by gating reward transmission through one of two neural motivational systems: either a dopamine-independent (opiate-naive) or a dopaminergic (opiate-dependent or opiate-withdrawn) system. Bi-directional transmission of reward signals through this GABA(A) receptor substrate is dynamically controlled by the opiate state of the organism and involves a molecular alteration of the GABA(A) receptor. After opiate exposure and subsequent withdrawal, the functional conductance properties of the rat VTA GABA(A) receptor switch from an inhibitory to an excitatory signaling mode.

Animals↗

PubMed2004

Physiological and behavioral effects of methamphetamine in a mouse model of endotoxemia: a preliminary study.

We investigated the effects of methamphetamine (METH) on core body temperature (Tb) and motor activity (MA) with or without exposure to a peripheral immune challenge. Mice were exposed to an escalating METH treatment and then to a METH treatment known to cause neurotoxicity (binge METH treatment). This was followed by a challenge with lipopolysaccharide (LPS). Three days later, METH and saline-treated control groups were challenged with an acute test dose of METH (METH test). Animals exposed to the escalating METH treatment exhibited a significant increase in Tb only after the initial exposure to METH (Day 1) and following the METH test (Day 7). The hyperthermic effect produced by the METH test (Day 7) was reduced in mice previously exposed to combined exposure to binge METH and LPS treatments. The escalating METH treatment produced MA sensitization to the METH test. Animals treated with the binge METH, LPS injection or both treatments combined prevented MA sensitization to the METH test. These findings suggest that induction of peripheral endotoxemia in animals with a history of METH reduced the hyperthermic response to a subsequent challenge with METH.

Animals↗

PubMed2004

CD8+ cell depletion amplifies the acute retroviral syndrome.

The duration and severity of the symptomatology present during the early phase of human immunodeficiency virus (HIV) infection (known as the acute retroviral syndrome) is associated with alterations in the clinical profile of infection, such as a shortening of duration between infection with HIV and the onset of neurocognitive impairment and acquired immunodeficiency syndrome (AIDS). Viral-specific CD8+ cytotoxic T lymphocytes (CTLs) and CD8+ natural killer (NK) cells play a key role in antiviral immunity. Loss of CD8+ cells or their functional impairment during the early period of infection is associated with a rapid progression to AIDS in nonhuman primate studies. However, no studies have determined whether CD8+ cell loss or impairment is associated with symptoms of acute retroviral illness such as fever. In this study, the authors compared the early phase of simian immunodeficiency virus (SIV) infection in animals that were treated with the anti-CD8 monoclonal antibody cM-T807 to deplete CD8+ cells during the early period of infection (SIV+ CD8- group) to those with intact CD8+ cells (SIV+ CD8+ group). The SIV+ CD8- group had an enhanced acute retroviral syndrome when compared to the SIV+ CD8+ group. The SIV+ CD8- group also had prolonged high viral loads and distinct alterations in the proinflammatory cytokines interleukin (IL)-6 and interferon (IFN)-alpha, as well as in monocyte chemoattractant protein (MCP)-1. CD8+ cell depletion, therefore, appears to enhance symptoms of the acute retroviral syndrome and alters several of the immunological factors associated with the early phase of infection.

Acute Disease↗

PubMed2003

Escalating morphine exposures followed by withdrawal in feline immunodeficiency virus-infected cats: a model for HIV infection in chronic opiate abusers.

Opiate abuse is a risk factor for human immunodeficiency virus (HIV) infection. Because the direct effects of opiates on HIV infection are difficult to determine epidemiologically, animal models of lentivirus infection are relied upon to study the effects of opiates in the absence of confounding factors. Morphine, the predominant metabolite of heroin, is used in most experimental systems examining heroin abuse. In this study, morphine treatment of feline immunodeficiency virus (FIV)-infected cats modeled a typical pattern of escalating drug use interspersed with withdrawals. Plasma cortisol levels were measured for evidence of stress associated with morphine withdrawal. In the morphine-treated cats, cortisol levels peaked at time points corresponding to morphine withdrawal and returned to baseline levels during treatment and several weeks after the final withdrawal. Morphine-treated cats displayed clear behavioral and physical signs of opiate exposure and evidence of withdrawal when the drug was stopped. Morphine-exposed cats did not experience enhanced severity of FIV-related disease; in fact, morphine demonstrated a protective effect on FIV-associated changes in brainstem auditory evoked potentials. Our research suggests that opiate exposure is unlikely to adversely affect the progression of acute lentivirus infection and might be beneficial in controlling associated neurological disease.

Animals↗

PubMed2003

Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6.

Transgenic mice with glial fibrillary acidic protein (GFAP) promoter driven-astrocyte production of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) were used to determine whether the pre-existing production of these cytokines in vivo might modulate the sensitivity of neurons to excitotoxic agents. Low doses of kainic acid (5 mg/kg) that produced little or no behavioral or electroencephalogram (EEG) alterations in wild type or glial fibrillary acidic protein (GFAP)-TNF animals induced severe tonic-clonic seizures and death in GFAP-IL6 transgenic mice of 2 or 6 months of age. GFAP-IL6 mice were also significantly more sensitive to N-methyl-D-aspartate (NMDA)- but not pilocarpine-induced seizures. Kainic acid uptake in the brain of the GFAP-IL6 mice was higher in the cerebellum but not in other regions. Kainic acid binding in the brain of GFAP-IL6 mice had a similar distribution and density as wild type controls. In the hippocampus of GFAP-IL6 mice that survived low dose kainic acid, there was no change in the extent of either neurodegeneration or astrocytosis. Immunostaining revealed degenerative changes in gamma aminobutyric acid (GABA)- and parvalbumin-positive neurons in the hippocampus of 2-month-old GFAP-IL6 mice which progressed to the loss of these cells at 6 months of age. Thus, GFAP-IL6 but not GFAP-TNF mice showed markedly enhanced sensitivity to glutamatergic- but not cholinergic-induced seizures and lethality. This may relate, in part, to a compromise of inhibitory interneuron function. Therefore, pre-existing IL-6 production and inflammation in the central nervous system (CNS) not only causes spontaneous neurodegeneration but also synergizes with other neurotoxic insults to induce more severe acute functional neurological impairment.

Animals↗

PubMed2003

Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS.

The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, alpha1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function.

Animals↗

PubMed2003

MDMA exposure alters cognitive and electrophysiological sensitivity to rapid tryptophan depletion in rhesus monkeys.

Repeated treatment with (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces lasting depletions in serotonin (5-HT) markers in the brains of New and Old World monkeys. We have previously shown that macaques treated with MDMA (4 days, 10 mg/kg im, b.i.d.), exhibit an immediate, approximately 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and 76-93% reductions in neocortical 5-HT content postmortem, but no lasting behavioral deficits under unchallenged conditions. Those monkeys were, however, more behaviorally sensitive to challenge with the 5-HT(2C) agonist 1-(3-chlorophenyl)piperazine (mCPP ) 1 year after the MDMA regimen. A rapid tryptophan-depletion protocol was employed to determine further if these MDMA-exposed monkeys are more behaviorally and electrophysiologically sensitive to perturbation of 5-HT neurotransmission. Acute intragastric administration of a tryptophan-deficient (TRYP(-)) mixture of amino acids resulted in significant reductions in CSF 5-HIAA in both MDMA-exposed and control monkeys. The TRYP(-) mixture also reduced the brainstem auditory-evoked potential (BSAEP) P4 latency in MDMA-exposed monkeys, similar to an effect observed for 13 weeks post-MDMA. Spatial working memory performance was improved by the TRYP(-) mixture in the control group, but not the MDMA-exposed monkeys. Other behavioral capabilities [visual recognition memory, reaction time (RT), reinforcer efficacy and fine motor control] were not significantly affected by the TRYP(-) mixture in either group of monkeys. Thus, underlying alterations in brain function resulting from prior exposure to MDMA, that were not observed under normal conditions, may be revealed following perturbation of 5-HT signaling. The BSAEP response and spatial working memory appear particularly sensitive to lasting functional differences associated with MDMA exposure.

Animals↗