Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (Δ-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established.
In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5 and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 historical healthy controls.
Δ-9-THC 1) produced transient psychotomimetic effects and perceptual alterations; 2) impaired memory and attention; 3) increased subjective effects of “high”; 4) produced tachycardia and 5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Δ-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels.
These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine and other effects of cannabinoids.
Cannabis; cannabinoids; delta-9-tetrahydrocannabinol; tolerance; abuse; cognition; memory
The neural pathways through which substance P (SP) influences fear and anxiety are poorly understood. However, the amygdala, a brain area repeatedly implicated in fear and anxiety processes, is known to contain large numbers of SP containing neurons and SP receptors. Several studies have implicated SP neurotransmission within the amygdala in anxiety processes. In the present study, we evaluated the effects of site-specific infusions of a SP receptor antagonist, GR 82334, on conditioned fear responses using the fear-potentiated startle paradigm. GR 82334 infusion into the basolateral (BLA) or the medial (MeA) nuclei of the amygdala, but not into the central nucleus (CeA) of the amygdala, dose-dependently reduced fear-potentiated startle. Similar effects were obtained with GR 82334 infusion into the ventromedial nucleus of the hypothalamus (VMH), to which the MeA projects, and into the rostral dorsolateral periaqueductal gray (PAG), to which the VMH projects, but not into the deep layers of the superior colliculus/deep mesencephalic nucleus (dSC/DpMe), an output of the CeA previously shown to be important for fear-potentiated startle. Consistent with previous findings, infusion of the AMPA receptor antagonist, NBQX, into the dSC/DpMe, but not into the PAG, did disrupt fear-potentiated startle. These findings suggest that multiple outputs from the amygdala play a critical role in fear-potentiated startle and that SP plays a critical, probably modulatory role, in the MeA to VMH to PAG to the startle pathway based on these and data from others.
Amygdala; Hypothalamus; Periaqueductal Gray; Superior Colliculus; Midbrain; GR 82334; Morphine; Anxiety; CRH; Tachykinin
Abuse of prescription opioid medications has increased dramatically in the U.S. during the past decade, as indicated by a variety of epidemiological sources. However, few studies have systematically examined the relative reinforcing effects of commonly abused opioid medications. The current double-blind, placebo-controlled inpatient study was designed to compare the effects of intravenously delivered fentanyl (0, 0.0625, 0.125, 0.187, and 0.250 mg/70 kg), oxycodone (0, 6.25, 12.5, 25, and 50 mg/70 kg), morphine (0, 6.25, 12.5, 25, and 50 mg/70 kg), buprenorphine (0, 0.125, 0.5, 2, and 8 mg/70 kg), and heroin (0, 3.125, 6.25, 12.5, and 25 mg/70 kg) in morphine-maintained heroin abusers (N=8 completers maintained on 120 mg per day oral morphine in divided doses [30 mg q.i.d.]). All of the participants received all of the drugs tested; drugs and doses were administered in non-systematic order. All of the drugs produced statistically significant, dose-related increases in positive subjective ratings, such as “I feel a good drug effect” and “I like the drug.” In general, the order of potency in producing these effects, from most to least potent, was: fentanyl > buprenorphine ≥ heroin > morphine = oxycodone. In contrast, buprenorphine was the only drug that produced statistically significant increases in ratings of “I feel a bad drug effect” and it was the only drug that was not self-administered above placebo levels at any dose tested. These data suggest that the abuse liability of buprenorphine in heroin-dependent individuals may be low, despite the fact that it produces increases in positive subjective ratings. The abuse liabilities of fentanyl, morphine, oxycodone, and heroin, however, appear to be similar under these experimental conditions.
prescription opioid abuse; self-administration; heroin; morphine; oxycodone; fentanyl; buprenorphine
There is evidence to suggest that the APOE ε4 allele (which confers an increased risk of developing dementia) might be associated with cognitive advantages earlier in life. Further, nicotine might selectively benefit ε4 carriers. We used fMRI to explore performance on a prospective memory (PM) task in young adults (age 18-30) with and without nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in ε4 carriers, but not in ε3 carriers. In an event-related analysis, extrastriate responses to PM trials were enhanced by nicotine only in ε4 carriers. These differences in early visual processing may contribute to the behavioural findings. Activity in medial BA10 (previously implicated in PM) differentiated ε4 from ε3 carriers. One BA10 subregion showed greater deactivation in ε4 carriers during PM trials. Activity in other BA10 subregions were modulated by PM reaction time, pointing to region-specific effects within medial BA10. In addition, activity in right hippocampal formation was only seen in ε4 carriers receiving nicotine. These results demonstrate that cognitive enhancement by nicotine can selectively benefit APOE ε4 carriers, and point to genotype-specific differences in neural activity during PM. In addition, these results show that the role of medial BA10 in PM likely involves varying contributions from functionally-specific subregions.
Alzheimer’s Disease; Psychopharmacology; Imaging; Learning & Memory; Nicotine; APOE; Prospective memory
One prevalent theory of learning states that dopamine neurons signal mismatches between expected and actual outcomes, called temporal difference errors (TDEs). Evidence indicates that dopamine system dysfunction plays a role in negative symptoms of schizophrenia (SZ), including avolition and anhedonia. As such, we predicted that brain responses to TDEs in dopamine midbrain nuclei and target areas would be abnormal in SZ. Eighteen clinically-stable patients with chronic schizophrenia and 18 controls participated in an fMRI study, which used a passive conditioning task. In the task, the delivery of a small amount of juice followed a light stimulus by exactly 6 seconds on approximately 75% of 78 total trials, and was further delayed by 4–7 s on the remaining trials. The delayed juice delivery was designed to elicit the two types of TDE signals, associated with the recognition that a reward was omitted at the expected time, and delivered at an unexpected time. Main effects of TDE valence and group differences in the positive – negative TDE contrast (unexpected juice deliveries – juice omissions) were assessed through whole-brain and regions-of-interest (ROI) analyses. Main effects of TDE valence were observed for the entire sample in the midbrain, left putamen, left cerebellum, and primary gustatory cortex, bilaterally. Whole-brain analyses revealed group differences in the positive – negative TDE contrast in the right putamen and left precentral gyrus, while ROI analyses revealed additional group differences in the midbrain, insula and parietal operculum, on the right, the putamen and cerebellum, on the left, and the frontal operculum, bilaterally. Further, these group differences were generally driven by attenuated responses in patients to positive TDEs (unexpected juice deliveries), whereas responses to negative TDEs (unexpected juice omissions) were largely intact. Patients also showed reductions in responses to juice deliveries on standard trials, and more blunted reinforcer responses in the left putamen corresponded to higher ratings of avolition. These results provide evidence that SZ patients show abnormal brain responses associated with the processing of a primary reinforcer, which may be a source of motivational deficits.
schizophrenia; dopamine; reinforcement; basal ganglia; temporal difference error
The metabotropic glutamate receptor 7 (mGluR7) has received much attention as a potential target for the treatment of epilepsy, major depression, and anxiety. In this study, we investigated the possible involvement of mGluR7 in cocaine reward in animal models of drug addiction. Pretreatment with the selective mGluR7 allosteric agonist N,N’-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082; 1-20 mg/kg, i.p.) dose-dependently inhibited cocaine-induced enhancement of electrical brain-stimulation reward and intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, but failed to alter either basal or cocaine-enhanced locomotion or oral sucrose self-administration, suggesting a specific inhibition of cocaine reward. Microinjections of AMN082 (1–5 μg/μl per side) into the nucleus accumbens (NAc) or ventral pallidum (VP), but not dorsal striatum, also inhibited cocaine self-administration in a dose-dependent manner. Intra-NAc or intra-VP co-administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP, 5 μg/μl per side), a selective mGluR7 allosteric antagonist, significantly blocked AMN082’s action, suggesting an effect mediated by mGluR7 in these brain regions. In vivo microdialysis demonstrated that cocaine (10 mg/kg, i.p.) priming significantly elevated extracellular DA in the NAc or VP, while decreasing extracellular GABA in VP (but not in NAc). AMN082 pretreatment selectively blocked cocaine-induced changes in extracellular GABA, but not in DA, in both naive rats and cocaine self-administration rats. These data suggest: (1) mGluR7 is critically involved in cocaine’s acute reinforcement; (2) GABA-, but not DA-, dependent mechanisms in the ventral striatopallidal pathway appear to underlie AMN082’s actions; and (3) AMN082 or other mGluR7-selective agonists may be useful in the treatment of cocaine addiction.
mGluR7; AMN082; cocaine; dopamine; GABA; self-administration
Striatal dopamine function is important for normal personality, cognitive processes and behaviour, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and ten DZ twin pairs underwent high resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33 respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.
Twin; PET; dopamine; heritability; [18F]-DOPA; environment; striatum
Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dose-dependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists.
appetite; motivation; operant; feeding; THC; rimonabant
We have previously shown that impulsivity in rats predicts the emergence of compulsive cocaine seeking and taking, and is coupled to decreased D2/3 receptor availability in the ventral striatum. As withdrawal from cocaine normalises high impulsivity in rats, we investigated, using positron emission tomography (PET), the effects of response-contingent cocaine administration on D2/3 receptor availability in the striatum. Rats were screened for impulsive behavior on the five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [18F]fallypride, rats were trained to self-administer cocaine for 15 days under a long-access schedule. As a follow-up, rats were assessed for impulsivity and underwent a second [18F]fallypride PET scan. At baseline, we found that D2/3 receptor availability was significantly lower in the left, but not right, ventral striatum of high-impulsive rats compared with low-impulsive rats. While the number of self-administered cocaine infusions was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine. This effect was accompanied by a significant increase in D2/3 receptor availability in the left, but not right, ventral striatum. We further report that D2/3 receptor availability was inversely related to baseline D2/3 receptor availability in the ventral striatum of high-impulsive rats, as well as to the left and right dorsal striatum of both low-impulsive and high-impulsive rats. These findings indicate that the reduction in impulsivity in high-impulsive rats by prior cocaine exposure may be mediated by a selective correction of deficient D2/3 receptor availability in the ventral striatum. A similar baseline-dependent mechanism may account for the therapeutic effects of stimulant drugs in clinical disorders such as ADHD.
Addiction & Substance Abuse; attention-deficit hyperactivity disorder; Dopamine; nucleus accumbens; positron emission tomography; Psychostimulants; Sexual Behavior/Related Disorders; nucleus accumbens; dopamine; psychostimulants; positron emission tomography; addiction; attention-deficit hyperactivity disorder
Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-Rs), dopamine transporter (DAT) binding potential (BP), and amphetamine (AMP)-induced dopamine release (DArel) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects.
As compared with controls, DArel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D2-R increase in left ventral striatum. SERT binding potential in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS−OCD). In 3 subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DArel and 5-HT2A BP, when compared with TS−OCD subjects and normal controls.
The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DArel is a primary defect in TS (Singer et al, 2002). The finding of decreased SERT BP, and the possible elevation in 5-HT2aR in individuals with TS who had increased DArel, suggest a condition of increased phasic DArel modulated by low 5-HT in concomitant OCD.
This study extends earlier work on the role of vascular endothelial growth factor (VEGF) in the actions of antidepressant treatment in two key areas. First, by determining the requirement for VEGF in the actions of a 5-HT selective reuptake inhibitor (SSRI), fluoxetine in behavioral models of depression/antidepressant response; and second, by examining the role of the 5-HT1A receptor subtype in the regulation of VEGF, and the cellular localization of antidepressant regulation of VEGF expression. The results show that pharmacological inhibition of VEGF receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress. Infusions of SU5416 or SU1498, two structurally dissimilar inhibitors of VEGF–Flk-1 receptor signaling, block the antidepressant effects of fluoxetine on sucrose preference, immobility in the forced swim test, and latency to feed in the novelty suppressed feeding paradigm. We also show that activation of 5-HT1A receptors is sufficient to induce VEGF expression and that a 5-HT1A antagonist blocks both the increase in VEGF and behavioral effects induced by fluoxetine. Finally, double labeling studies show that chronic fluoxetine administration increases VEGF expression in both neurons and endothelial cells in the hippocampus. Taken together these studies show that VEGF is necessary for the behavioral effects of the SSRI fluoxetine, as well as norepinephrine selective reuptake inhibitor, and that these effects may be mediated by 5-HT1A receptors located on neurons and endothelial cells.
chronic stress; VEGF; anhedonia; antidepressant; 5-HT1A; Flk-1 signaling
Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic interacting proteins of these channels are abnormally expressed in some patients with this illness. In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. Here we show that reduced expression of the neuronal RasGAP and NMDAR-associated protein, SynGAP, results in abnormal behaviors strikingly similar to that reported in mice with reduced NMDAR function. SynGAP mutant mice exhibited non-habituating and persistent hyperactivity that was ameliorated by the antipsychotic clozapine. An NMDAR antagonist, MK-801, induced hyperactivity in normal mice but SynGAP mutants were less responsive, suggesting that NMDAR hypofunction contributes to this behavioral abnormality. SynGAP mutants exhibited enhanced startle reactivity and impaired sensory-motor gating. These mice also displayed a complete lack of social memory and a propensity toward social isolation. Finally, SynGAP mutants had deficits in cued fear conditioning and working memory, indicating abnormal function of circuits that control emotion and choice. Our results demonstrate that SynGAP mutant mice have gross neurological deficits similar to other mouse models of schizophrenia. Because SynGAP interacts with NMDARs, and the signaling activity of this protein is regulated by these channels, our data indicate that SynGAP lies downstream of NMDARs and is a required intermediate for normal neural circuit function and behavior. Taken together, these data support the idea that schizophrenia may arise from abnormal signaling pathways that are mediated by NMDA receptors.
Schizophrenia; NMDA receptor; postsynaptic density; plasticity; hyperactivity; fear conditioning
A history of exposure to stressors may be a predisposing factor for developing posttraumatic stress disorder (PTSD) after trauma. Extinction of conditioned fear appears to be impaired in PTSD, but the consequences of prior stress or excess glucocorticoid exposure for extinction learning are not known. We report that prior chronic exposure to the stress hormone, corticosterone (CORT), decreases endogenous CORT secretion upon context reexposure and impairs extinction after contextual fear conditioning in rats, while leaving fear memory acquisition and expression intact. Posttraining administration of the glucocorticoid receptor (GR) antagonist, RU38486, partially mimicked prior CORT exposure effects on freezing during fear extinction training. Extinction of conditioned fear is an active learning process thought to involve glutamatergic targets—including specific NMDA and AMPA receptor subunits—in the ventromedial prefrontal cortex (vmPFC), which includes the prelimbic, infralimbic, and medial orbitofrontal cortices. After CORT exposure, decreases in the NMDA receptor NR2B subunit and AMPA receptor subunits, GluR2/3, as well as brain-derived neurotrophic factor, were detected in cortical regions, but not dorsal hippocampus (CA1). Receptor subunit expression levels in the vmPFC correlated with freezing during training. In addition, prior CORT selectively decreased sucrose preference, consistent with established models of anhedonia and with blunted affect in PTSD. Together, these data suggest a cellular mechanism by which chronically elevated glucocorticoid exposure—as may be experienced during repeated exposure to stressors—interferes with the neural systems that modulate behavioral flexibility and may thereby contribute to psychopathological fear states.
fear conditioning; stress; mifepristone; GluR3; orbitofrontal cortex; neurotrophin
We previously showed that betaxolol, a selective β1-adrenergic receptor antagonist, administered during early phases of cocaine abstinence, ameliorated withdrawal-induced anxiety and blocked increases in amygdalar β1-adrenergic receptor expression in rats. Here, we report the efficacy of betaxolol in reducing increases in gene expression of amygdalar corticotropin-releasing factor (CRF), a peptide known to be involved in mediating ‘anxiety-like’ behaviors during initial phases of cocaine abstinence. We also demonstrate attenuation of an amygdalar β1-adrenergic receptor-mediated cell signaling pathway following this treatment. Male rats were administered betaxolol at 24 and 44 hours following chronic cocaine administration. Animals were euthanized at the 48 hour time-point and the amygdala was micro-dissected and processed for quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and/or Western blot analysis. Results showed that betaxolol treatment during early cocaine withdrawal attenuated increases in amygdalar CRF gene expression and cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) regulatory and catalytic subunit (nuclear fraction) protein expression. Our data also reveal that β1-adrenergic receptors are on amygdalar neurons which are immunoreactive for CRF. The present findings suggest that the efficacy of betaxolol treatment on cocaine withdrawal-induced anxiety may be related, in part, to its effect on amygdalar β1-adrenergic receptor, modulation of its downstream cell signaling elements and CRF gene expression.
beta-adrenergic receptor; norepinephrine; corticotropin-releasing factor; amygdala; cocaine withdrawal; anxiety
Memantine provides clinically relevant efficacy in patients with Alzheimer's disease and Parkinson’s diseases. In addition to blockade of N-methyl-D-aspartate receptor on neurons, memantine has neurotrophic and neuroprotective effects in in vivo and in vitro studies, however, the mechanism underlying these effects remains unclear. To address this question, primary midbrain neuron-glia cultures and reconstituted cultures were used, and lipopolysaccharide (LPS), an endotoxin from bacteria, was used to produce inflammation-mediated dopaminegic neuronal death. Here, we show that memantine exerted both potent neurotrophic and neuroprotective effects on dopaminergic neurons in rat neuron-glia cultures. The neurotrophic effect of memantine was glia-dependent, since memantine failed to show any positive effect on dopaminergic neurons in neuron-enriched cultures. More specifically, it appears that astroglia, not microglia, are the source of the memantine-elicited neurotrophic effects through the increased production of GDNF. Mechanistic studies revealed that GDNF upregulaton was associated with histone hyperacetylation by inhibiting the cellular histone deacetylase activity. In addition, memantine also displays neuroprotective effects against LPS-induced dopaminergic neuronal damage through its inhibition of microglia over-activation revealed by both OX-42 immunostaining and by the reduction of pro-inflammatory factors production such as extracelluar superoxide anion, intracellular reactive oxygen species, nitric oxide, prostaglandin E2, and tumor necrosis factor-α. These results suggest that memantine therapy for neurodegenerative diseases acts in part through alternative novel mechanisms by reducing microglia-associated inflammation and stimulating the release of neurotrophic factors from astroglia.
GDNF; neuroinflammation; neuroprotection; neurodegenerative disease; HDAC
Estrogen (E2) has many effects in the central nervous system, including effects on anxiety and depression behavior. This review will address effects of E2 on behaviors related to anxiety and depression in women and animal models and include recent findings from our laboratory related to this topic. E2’s antianxiety and antidepressant-like effects may depend upon many factors, including the regimen of E2 utilized and interactions with the hypothalamic–pituitary–adrenal axis. Brain targets for E2’s effects on anxiety and depression include the hippocampus and amygdala. Administration of E2, compared to vehicle, subcutaneously or to the hippocampus or amygdala of ovariectomized rats decreases anxiety and depressive behavior. Intracellular estrogen receptors (ERs) may be important for E2’s anxiolytic and antidepressant-like effects. Administration of an ER antagonist to the hippocampus, but not amygdala, increases anxiety and depression behavior of naturally receptive female rats. Studies utilizing ER knockout mice or selective ER modulators suggest that ER-mediated effects of E2 on anxiety and depressive behavior may require ERβ. In addition, the behavioral effects of E2 may involve membrane actions and/or changes in cell cycle processes involved in energy expenditure. Elucidating the mechanisms by which E2 affects anxiety and depression is important in order to enhance its therapeutic potential. It is particularly important to investigate the putative receptor mechanisms and brain targets for E2 to determine whether mood-enhancing effects of E2 can occur without deleterious proliferative effects in reproductive tissues.
sex differences; affect; mood; estrogen receptor; SERMs; hippocampus; amygdala
The X-linked gene STS encodes the steroid hormone-modulating enzyme steroid sulfatase. Loss-of-function of STS, and variation within the gene, have been associated with vulnerability to developing attention deficit hyperactivity disorder (ADHD), a neurodevelopmental condition characterized by inattention, severe impulsivity, hyperactivity, and motivational deficits. ADHD is commonly comorbid with a variety of disorders, including obsessive–compulsive disorder. The neurobiological role of steroid sulfatase, and therefore its potential role in ADHD and associated comorbidities, is currently poorly understood. The 39,XY*O mouse, which lacks the Sts gene, exhibits several behavioral abnormalities relevant to ADHD including inattention and hyperactivity. Here, we show that, unexpectedly, 39,XY*O mice achieve higher ratios than wild-type mice on a progressive ratio (PR) task thought to index motivation, but that there is no difference between the two groups on a behavioral task thought to index compulsivity (marble burying). High performance liquid chromatography analysis of monoamine levels in wild type and 39,XY*O brain tissue regions (the frontal cortex, striatum, thalamus, hippocampus, and cerebellum) revealed significantly higher levels of 5-hydroxytryptamine (5-HT) in the striatum and hippocampus of 39,XY*O mice. Significant correlations between hippocampal 5-HT levels and PR performance, and between striatal 5-HT levels and locomotor activity strongly implicate regionally-specific perturbations of the 5-HT system as a neurobiological candidate for behavioral differences between 40,XY and 39,XY*O mice. These data suggest that inactivating mutations and functional variants within STS might exert their influence on ADHD vulnerability, and disorder endophenotypes through modulation of the serotonergic system.
attention deficit hyperactivity disorder; dehydroepiandrosterone sulfate; hippocampus; obsessive–compulsive disorder; progressive ratio; striatum; animal models; behavioral science; biological psychiatry; neurochemistry; attention deficit hyperactivity disorder; dehydroepiandrosterone sulfate; hippocampus; obsessive–compulsive disorder; progressive ratio
The amplitude of the acoustic startle response is increased when elicited in the presence of brief cues that predict shock (fear-potentiated startle) and also when elicited during sustained exposure to bright light (light-enhanced startle). Although both effects are thought to reflect fear or anxiety, their neuroanatomical substrates differ. Whereas fear-potentiated startle is disrupted by reversible inactivation of the central nucleus of the amygdala (CeA) but not the closely related bed nucleus of the stria terminalis (BNST), light-enhanced startle is disrupted by BNST inactivation but not by CeA inactivation. Intra-ventricular infusions of corticotropin releasing factor (CRF) also increase startle (CRF-enhanced startle) and this effect is mediated by CRF receptors within the BNST, with no involvement of the CeA. Together, these observations suggest that CeA- and BNST-dependent fear and anxiety may be differentially sensitive to CRF receptor blockade. We tested this by orally administering the novel, potent, and selective CRF-R1 antagonist GSK876008 to rats prior to CRF-enhanced, light-enhanced, or fear-potentiated startle testing. GSK876008 disrupted CRF-enhanced startle with a linear dose-response curve, and light-enhanced startle with a U-shaped dose-response curve, but did not disrupt fear-potentiated startle to a visual stimulus at any dose tested, and even augmented the response in some animals. GSK876008 also disrupted shock-related ‘baseline’ startles increases, which may have reflected context conditioning (shown elsewhere to also be BNST-dependent). Overall, these results suggest that short-duration CeA-dependent threat responses can be pharmacologically dissociated from longer-duration BNST-dependent responses in terms of their sensitivity to CRF1 receptor antagonists.
fear; anxiety; startle; amygdala; bed nucleus of the stria terminalis; corticotropin releasing factor
We utilized a cohort of 828 treatment seeking self-identified white cigarette smokers (50% female) to rank candidate gene single nucleotide polymorphisms (SNPs) associated with the Fagerström Test for Nicotine Dependence (FTND), a measure of nicotine dependence which assesses quantity of cigarettes smoked and time- and place-dependent characteristics of the respondent’s smoking behavior. 1123 SNPs at 55 autosomal candidate genes, nicotinic acetylcholine receptors and genes involved in dopaminergic function, were tested for association to baseline FTND scores adjusted for age, depression, education, sex and study site. SNP P values were adjusted for the number of transmission models, the number of SNPs tested per candidate gene, and their intragenic correlation. DRD2, SLC6A3 and NR4A2 SNPs with adjusted P values < 0.10 were considered sufficiently noteworthy to justify further genetic, bioinformatic and literature analyses. Each independent signal among the top-ranked SNPs accounted for ~1% of the FTND variance in this sample. The DRD2 SNP appears to represent a novel association with nicotine dependence. The SLC6A3 SNPs have previously been shown to be associated with SLC6A3 transcription or dopamine transporter density in vitro, in vivo and ex vivo. Analysis of SLC6A3 and NR4A2 SNPs identified a statistically significant gene-gene interaction (P=0.001), consistent with in vitro evidence that the NR4A2 protein product (NURR1) regulates SLC6A3 transcription. A community cohort of N=175 multiplex ever smoking pedigrees (N=423 ever smokers) provided nominal evidence for association with the FTND at these top ranked SNPs, uncorrected for multiple comparisons.
dopamine transporter; Fagerström Test for Nicotine Dependence; single nucleotide polymorphism; candidate gene association scan; gene-gene interaction
Olfactory impairments are a common feature of schizophrenia. Impairments in odor detection and odor identification are present early in the course of illness and among those at risk for the disorder. These behavioral impairments have been linked to both physiological and anatomical abnormalities in the neural substrates subserving olfaction, including relatively peripheral elements of the olfactory system. The location of olfactory receptor neurons in the nasal epithelium allows noninvasive access to these neurons in living subjects. This offers a unique opportunity to directly assess neuronal integrity in vivo in patients. The peripheral olfactory receptor neuron response to odor stimulation was assessed in 21 schizophrenia patients and 18 healthy comparison subjects. The electroolfactogram, representing the electrical depolarization of the olfactory receptor neurons, was recording following stimulation with different doses and durations of hydrogen sulfide, a pure olfactory nerve stimulant. Schizophrenia patients had abnormally large depolarization responses following odor stimulation, independent of clinical symptomatology, antipsychotic medication dosage or smoking history. Although the precise pathophysiological mechanism is unknown, this olfactory receptor neuron abnormality is consistent with several lines of evidence suggesting altered proliferation or maturation of olfactory receptor neuron cell lineages in schizophrenia. It is also consistent with emerging evidence of disruptions of cyclic AMP-mediated intracellular signaling mechanisms, and may be a marker of these disruptions. It unambiguously demonstrates that neurophysiological disturbances in schizophrenia are not limited to cortical and subcortical structures, but rather include even the most peripheral sensory neurons.
schizophrenia; olfaction; olfactory receptor neuron; olfactory epithelium; electroolfactogram; signal transduction
Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 μM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.
antidepressive agents; endocrine system; human; cytokines; psychiatry; immune system
The X-linked gene STS encodes the steroid hormone-modulating enzyme steroid sulfatase. Loss-of-function of STS, and variation within the gene, have been associated with vulnerability to developing Attention Deficit Hyperactivity Disorder (ADHD), a neurodevelopmental condition characterised by inattention, severe impulsivity, hyperactivity and motivational deficits. ADHD is commonly co-morbid with a variety of disorders, including Obsessive Compulsive Disorder (OCD). The neurobiological role of steroid sulfatase, and therefore its potential role in ADHD and associated co-morbidities, is currently poorly understood. The 39,XY*O mouse, which lacks the Sts gene, exhibits several behavioral abnormalities relevant to ADHD including inattention and hyperactivity. Here, we show that, unexpectedly, 39,XY*O mice achieve higher ratios than wildtype mice on a progressive ratio task thought to index motivation, but that there is no difference between the two groups on a behavioral task thought to index compulsivity (marble burying). High performance liquid chromatography (HPLC) analysis of monoamine levels in wildtype and 39,XY*O brain tissue regions (frontal cortex, striatum, thalamus, hippocampus and cerebellum) revealed significantly higher levels of 5-hydroxytryptamine (5-HT) in the striatum and hippocampus of 39,XY*O mice. Significant correlations between hippocampal 5-HT levels and progressive ratio performance, and between striatal 5-HT levels and locomotor activity strongly implicate regionally-specific perturbations of the 5-HT system as a neurobiological candidate for behavioral differences between 40,XY and 39,XY*O mice. These data suggest that inactivating mutations and functional variants within STS might exert their influence on ADHD vulnerability and disorder endophenotypes through modulation of the serotonergic system.
Attention Deficit Hyperactivity Disorder; dehydroepiandrosterone sulfate; hippocampus; Obsessive Compulsive Disorder; progressive ratio; striatum