The Effect of Midazolam and Propranolol on Fear Memory Reconsolidation in Ethanol-Withdrawn Rats: Influence of D-Cycloserine

Background:

Withdrawal from chronic ethanol facilitates the formation of contextual fear memory and delays the onset to extinction, with its retrieval promoting an increase in ethanol consumption. Consequently, manipulations aimed to reduce these aversive memories, may be beneficial in the treatment of alcohol discontinuation symptoms. Related to this, pharmacological memory reconsolidation blockade has received greater attention due to its therapeutic potential.

Methods:

Here, we examined the effect of post-reactivation amnestic treatments such as Midazolam (MDZ, 3 mg/kg i.p) and Propranolol (PROP, 5 mg/kg i.p) on contextual fear memory reconsolidation in ethanol- withdrawn (ETOH) rats. Next, we examined whether the activation of N-methyl-D-aspartate (NMDA) receptors induced by d-cycloserine (DCS, 5 mg/kg i.p., a NMDA partial agonist) before memory reactivation can facilitate the disruptive effect of PROP and MDZ on fear memory in ETOH rats.

Results:

We observed a resistance to the disruptive effect of both MDZ and PROP following memory reactivation. Although intra-basolateral amygdala (BLA; 1.25 ug/side) and systemic PROP administration attenuated fear memory in DCS pre-treated ETOH rats, DCS/MDZ treatment did not affect memory in these animals. Finally, a decrease of both total and surface protein expression of the α1 GABAA receptor (GABAA-R) subunit in BLA was found in the ETOH rats.

Conclusions:

Ethanol withdrawal facilitated the formation of fear memory resistant to labilization post-reactivation. DCS administration promoted the disruptive effect of PROP on memory reconsolidation in ETOH rats. The resistance to MDZ’s disruptive effect on fear memory reconsolidation may be, at least in part, associated with changes in the GABAA-R composition induced by chronic ethanol administration/withdrawal.     

Both α1- and β1-adrenoceptors in the bed nucleus of the stria terminalis are involved in the expression of conditioned contextual fear

BACKGROUND AND PURPOSE

The bed nucleus of the stria terminalis (BNST) is a limbic structure that is involved in the expression of conditioned contextual fear. Among the numerous neural inputs to the BNST, noradrenergic synaptic terminals are prominent and some evidence suggests an activation of this noradrenergic neurotransmission in the BNST during aversive situations. Here, we have investigated the involvement of the BNST noradrenergic system in the modulation of behavioural and autonomic responses induced by conditioned contextual fear in rats.

EXPERIMENTAL APPROACH

Male Wistar rats with cannulae bilaterally implanted into the BNST were submitted to a 10 min conditioning session (6 footshocks, 1.5 ma/ 3 s). Twenty-four hours later freezing and autonomic responses (mean arterial pressure, heart rate and cutaneous temperature) to the conditioning box were measured for 10 min. The adrenoceptor antagonists were administered 10 min before the re-exposure to the aversive context.

KEY RESULTS

L-propranolol, a non-selective β-adrenoceptor antagonist, and phentolamine, a non-selective α-adrenoceptor antagonist, reduced both freezing and autonomic responses induced by aversive context. Similar results were observed with {"type":"entrez-protein","attrs":{"text":"CGP20712","term_id":"874704353"}}CGP20712, a selective β₁-adrenoceptor antagonist, and WB4101, a selective α₁-antagonist, but not with ICI118,551, a selective β₂-adrenoceptor antagonist or RX821002, a selective α₂-antagonist.

CONCLUSIONS AND IMPLICATIONS

These findings support the idea that noradrenergic neurotransmission in the BNST via α₁- and β₁-adrenoceptors is involved in the expression of conditioned contextual fear.     

Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory

Rationale

Environmental stimuli or contexts previously associated with rewarding drugs contribute importantly to relapse among addicts, and research has focused on neurobiological processes maintaining those memories. Much research shows contributions of cell surface receptors and intracellular signaling pathways in maintaining associations between rewarding drugs (e.g., cocaine) and concurrent cues/contexts; these memories can be degraded at the time of their retrieval through reconsolidation interference. Much less studied is the consolidation of drug-cue memories during their acquisition.

Objective

The present experiments use the cocaine-conditioned place preference (CPP) paradigm in rats to directly compare, in a consistent setting, the effects of N-methyl-d-aspartate (NMDA) glutamate receptor antagonists MK-801 and memantine on the consolidation and reconsolidation of cocaine-cue memories.

Methods

For the consolidation studies, animals were systemically administered MK-801 or memantine immediately following training sessions. To investigate the effects of these NMDA receptor antagonists on the retention of previously established cocaine-cue memories, animals were systemically administered MK-801 or memantine immediately after memory retrieval.

Results

Animals given either NMDA receptor antagonist immediately following training sessions did not establish a preference for the cocaine-paired compartment. Post-retrieval administration of either NMDA receptor antagonist attenuated the animals’ preference for the cocaine-paired compartment. Furthermore, animals given NMDA receptor antagonists post-retrieval showed a blunted response to cocaine-primed reinstatement.

Conclusions

Using two distinct NMDA receptor antagonists in a common setting, these findings demonstrate that NMDA receptor-dependent processes contribute both to the consolidation and reconsolidation of cocaine-cue memories, and they point to the potential utility of treatments that interfere with drug-cue memory reconsolidation.     

Over-expectation generated in a complex appetitive goal-tracking task is capable of inducing memory reconsolidation

Rationale

Discrepancies in an expected outcome have been demonstrated to result in modification of behaviour in both appetitive and aversive conditioning settings.

Objectives

In this study, we sought to establish whether overexpectation generated from compound conditioning with two previously rewarded stimuli was able to induce memory destabilisation and subsequent reconsolidation in a Pavlovian conditioned approach setting.

Results

It was shown that 4 days, but not 1 day, of overexpectation training was required to induce memory reconsolidation, and this was disrupted by application of the NMDA subtype of glutamate receptor antagonist MK-801 prior to overexpectation training, but not by MK-801 application 6 h post-training.

Conclusions

These data provide evidence that the memories underlying Pavlovian conditioned approach do undergo reconsolidation and that such reconsolidation can be triggered by overexpectation. Therefore, the updating of appetitive conditioned stimulus and unconditioned stimulus associations underpinning conditioned responding in manners other than extinction training is likely achieved through memory reconsolidation.     

Formation of aversive memories associated with conditioned drug withdrawal requires BDNF expression in the amygdala in acute morphine-dependent rats

Aim:

Brain-derived neurotrophic factor (BDNF) plays an important role in learning and memory in multiple brain areas. In the present study, we investigated the roles of BDNF in aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats.

Methods:

Conditioned place aversion (CPA) was induced in male SD rats exposed to a single dose of morphine (10 mg/kg, sc) followed by naloxone (0.3 mg/kg, sc). In some rats, BDNF receptor antagonist K252a (8.5 ng per side) or BDNF scavenger TrkB-FC (0.65 μg per side) was bilaterally microinjected into amygdala before naloxone injection. BDNF mRNA and protein expression levels in amygdala were detected after the behavior testing.

Results:

CPA behavior was induced in rats by the naloxone-precipitated morphine withdrawal, which was accompanied by significantly increased levels of BDNF mRNA and protein in the amygdala. Bilateral microinjection of TrkB-FC or K252a into the amygdala completely blocked CPA behavior in the rats.

Conclusion:

Formation of aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats requires BDNF expression in the amygdala.     

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

BACKGROUND AND PURPOSE

Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT_1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide.

EXPERIMENTAL APPROACH

Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure.

KEY RESULTS

Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment.

CONCLUSIONS AND IMPLICATIONS

Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain.     

Preclinical Evaluation of Reconsolidation Blockade by Clonidine as a Potential Novel Treatment for Posttraumatic Stress Disorder

Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an α₂-adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.     

Investigation of the distribution and function of ��-adrenoceptors in the sheep isolated internal anal sphincter

BACKGROUND AND PURPOSE

We have investigated the distribution of α-adrenoceptors in sheep internal anal sphincter (IAS), as a model for the human tissue, and evaluated various imidazoline derivatives for potential treatment of faecal incontinence.

EXPERIMENTAL APPROACH

Saturation and competition binding with ³H-prazosin and ³H-RX821002 were used to confirm the presence and density of α-adrenoceptors in sheep IAS, and the affinity of imidazoline compounds at these receptors. A combination of in vitro receptor autoradiography and immunohistochemistry was used to investigate the regional distribution of binding sites. Contractile activity of imidazoline-based compounds on sheep IAS was assessed by isometric tension recording.

KEY RESULTS

Saturation binding confirmed the presence of both α₁- and α₂-adrenoceptors, and subsequent characterization with sub-type-selective agents, identified them as α_1A- and α_2D-adrenoceptor sub-types. Autoradiographic studies with ³H-prazosin showed a positive association of α₁-adrenoceptors with immunohistochemically identified smooth muscle fibres. Anti-α₁-adrenoceptor immunohistochemistry revealed similar distributions of the receptor in sheep and human IAS. The imidazoline compounds caused concentration-dependent contractions of the anal sphincter, but the maximum responses were less than those elicited by l-erythro-methoxamine, a standard non-imidazoline α₁-adrenoceptor agonist. Prazosin (selective α₁-adrenoceptor antagonist) significantly reduced the magnitude of contraction to l-erythro-methoxamine at the highest concentration used. Both prazosin and RX811059 (a selective α₂-adrenoceptor antagonist) reduced the potency (pEC₅₀) of clonidine.

CONCLUSIONS AND IMPLICATIONS

This study shows that both α₁- and α₂-adrenoceptors are expressed in the sheep IAS, and contribute (perhaps synergistically) to contractions elicited by various imidazoline derivatives. These agents may prove useful in the treatment of faecal incontinence.     

Chronic nicotine treatment differentially modifies acute nicotine and alcohol actions on GABA(A) and glutamate receptors in hippocampal brain slices

BACKGROUND AND PURPOSE

Tobacco and alcohol are often co-abused producing interactive effects in the brain. Although nicotine enhances memory while ethanol impairs it, variable cognitive changes have been reported from concomitant use. This study was designed to determine how nicotine and alcohol interact at synaptic sites to modulate neuronal processes.

EXPERIMENTAL APPROACH

Acute effects of nicotine, ethanol, and both drugs on synaptic excitatory glutamatergic and inhibitory GABAergic transmission were measured using whole-cell recording in hippocampal CA1 pyramidal neurons from brain slices of mice on control or nicotine-containing diets.

KEY RESULTS

Acute nicotine (50 nM) enhanced both GABAergic and glutamatergic synaptic transmission; potentiated GABA_A receptor currents via activation of α7* and α4β2* nAChRs, and increased N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor currents through α7* receptors. While ethanol (80 mM) also increased GABA_A currents, it inhibited NMDA currents. Although ethanol had no effect on AMPA currents, it blocked nicotine-induced increases in NMDA and AMPA currents. Following chronic nicotine treatment, acute nicotine or ethanol did not affect NMDA currents, while the effects of GABAergic responses were not altered.

CONCLUSIONS AND IMPLICATIONS

Acute ethanol ingestion selectively attenuated nicotine enhancement of excitatory glutamatergic NMDA and AMPA receptor function, suggesting an overall reduction in excitatory output from the hippocampus. It also indicated that ethanol could decrease the beneficial effects of nicotine on memory performance. In addition, chronic nicotine treatment produced tolerance to the effects of nicotine and cross-tolerance to the effects of ethanol on glutamatergic activity, leading to a potential increase in the use of these drugs.     

Epinephrine,phenylephrine, and methoxamine induce infiltrative anesthesia via α1-adrenoceptors in rats

Aim:

To assess whether epinephrine, phenylephrine, and methoxamine act via certain subtypes of adrenoceptors to exert their local anesthetic activity.

Methods:

We investigated cutaneous anesthesia from adrenoceptor agonists and/or antagonists in conscious, unanesthetized Sprague-Dawley male rats (weight 200−250 g). Cutaneous anesthesia was evidenced by a block of the cutaneous trunci muscle reflex, which is characterized by reflex movement of the skin over the back produced by twitches of lateral thoracispinal muscles in response to local dorsal cutaneous noxious pinprick.

Results:

Local infiltration of epinephrine, L-phenylephrine, or methoxamine alone induces cutaneous anesthesia in rats in a dose-dependent way. Epinephrine is found to be 19 and 29 times more potent than those of methoxamine and L-phenylephrine, respectively. The cutaneous anesthesia induced by epinephrine, phenylephrine, or methoxamine can be significantly reduced by α₁-adrenoceptor antagonists (eg, prazosin), α1, α2-adrenoceptor antagonist, α_1A-adrenoceptor antagonist (eg, 5-methylurapdil), α_1B-adrenoceptor antagonist (eg, chloroethylclonidine), or α_1D-adrenoceptor antagonist (eg, BMY7873).

Conclusion:

Our results indicate that epinephrine, phenylephrine and methoxamine all act mainly via mixed subtypes of α₁-adrenoceptors to induce cutaneous anesthesia in the rat.     

High concentrations of dexmedetomidine inhibit compound action potentials in frog sciatic nerves without ��2 adrenoceptor activation

BACKGROUND AND PURPOSE

Dexmedetomidine, an α₂-adrenoceptor agonist, exhibits anti-nociceptive actions at the spinal cord and enhances the effect of local anaesthetics in the peripheral nervous system. Although the latter action may be attributed in part to inhibition of nerve conduction produced by dexmedetomidine, this has not been fully examined yet.

EXPERIMENTAL APPROACH

We examined the effects of various adrenoceptor agonists including dexmedetomidine, and tetracaine, a local anaesthetic, on compound action potentials (CAPs) recorded from the frog sciatic nerve, using the air-gap method.

KEY RESULTS

Dexmedetomidine reversibly and concentration-dependently reduced the peak amplitude of CAPs (IC₅₀ = 0.40 mmol·L⁻¹). This action was not antagonized by two α₂-adrenoceptor antagonists, yohimbine and atipamezole; the latter antagonist itself reduced CAP peak amplitude. Clonidine and oxymetazoline, two other α₂-adrenoceptor agonists, also inhibited CAPs; the maximum effect of clonidine was only 20%, while oxymetazoline was less potent (IC₅₀ = 1.5 mmol·L⁻¹) than dexmedetomidine. On the other hand, (±)-adrenaline, (±)-noradrenaline, α₁-adrenoceptor agonist (-)-phenylephrine and β-adrenoceptor agonist (-)-isoprenaline (each 1 mmol·L⁻¹) had no effect on CAPs. Tetracaine reversibly reduced CAP peak amplitude (IC₅₀ of 0.014 mmol·L⁻¹).

CONCLUSIONS AND IMPLICATIONS

Dexmedetomidine reduced CAP peak amplitude without α₂-adrenoceptor activation (at concentrations >1000-fold higher than those used as α₂ adrenoceptor agonist), with a lower potency than tetracaine. CAPs were inhibited by other α₂ adrenoceptor agonists, oxymetazoline and clonidine, and also an α₂ adrenoceptor antagonist atipamezole. Thus, some drugs acting on α₂ adrenoceptors are able to block nerve conduction.     

Rosiglitazone reverses salbutamol-induced ��2-adrenoceptor tolerance in airway smooth muscle

BACKGROUND AND PURPOSE

β₂-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)γ agonist rosiglitazone modulated salbutamol-induced β₂-adrenoceptor desensitization in vivo and in vitro.

EXPERIMENTAL APPROACH

An in vivo model of homologous β₂-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent β₂-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study.

KEY RESULTS

In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of β₂-adrenoceptor gene and a marked decrease in β-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored β₂-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPARγ agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitroβ₂-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and β₂-adrenoceptor expression. Rosiglitazone and 15-deoxy-Δ^12,14-prostaglandin J₂ restored salbutamol sensitivity in homologously desensitized cells.

CONCLUSIONS AND IMPLICATIONS

These data suggest a potential pharmacodynamic interaction between PPARγ agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.     

Does β-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study

AIMS

To examine the effect of β-adrenoceptor blocker treatment on cancer survival.

METHODS

In a UK primary care database, we compared patients with a new cancer diagnosis receiving β-adrenoceptor blockers regularly (n = 1406) with patients receiving other antihypertensive medication (n = 2056).

RESULTS

Compared with cancer patients receiving other antihypertensive medication, patients receiving β-adrenoceptor blocker therapy experienced slightly poorer survival (HR = 1.18, 95% CI 1.04, 1.33 for all β-adrenoceptor blockers; HR = 1.21, 95% CI 0.94, 1.55 for non-selective β-adrenoceptor blockers). This poorer overall survival was explained by patients with pancreatic and prostate cancer with no evidence of an effect on survival for patients with lung, breast or colorectal cancer. Analysis in a cancer-free matched parallel cohort did not suggest selection bias masked a beneficial effect.

CONCLUSION

Our study does not support the hypothesis that β-adrenoceptor blockers improve survival for common cancers.     

Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes

BACKGROUND AND PURPOSE

Astrocytes of the mouse neocortex express functional NMDA receptors, which are not blocked by Mg²⁺ ions. However, the pharmacological profile of glial NMDA receptors and their subunit composition is far from complete.

EXPERIMENTAL APPROACH

We tested the sensitivity of NMDA receptor-mediated currents to the novel GluN2C/D subunit-selective antagonist UBP141 in mouse cortical astrocytes and neurons. We also examined the effect of memantine, an antagonist that has substantially different affinities for GluN2A/B and GluN2C/d-containing receptors in physiological concentrations of extracellular Mg²⁺.

KEY RESULTS

UBP141 had a strong inhibitory action on NMDA receptor-mediated transmembrane currents in the cortical layer II/III astrocytes with an IC₅₀ of 2.29 µM and a modest inhibitory action on NMDA-responses in the pyramidal neurons with IC₅₀ of 19.8 µM. Astroglial and neuronal NMDA receptors exhibited different sensitivities to memantine with IC₅₀ values of 2.19 and 10.8 µM, respectively. Consistent with pharmacological differences between astroglial and neuronal NMDA receptors, NMDA receptors in astrocytes showed lower Ca²⁺ permeability than neuronal receptors with P_Ca/P_Na ratio of 3.4.

CONCLUSIONS AND IMPLICATIONS

The biophysical and pharmacological properties of the astrocytic NMDA receptors strongly suggest that they have a tri-heteromeric structure composed of GluN1, GluN2C/D and GluN3 subunits. The substantial difference between astroglial and neuronal NMDA receptors in their sensitivity to UBP141 and memantine may enable selective modulation of astrocytic signalling that could be very helpful for elucidating the mechanisms of neuron-glia communications. Our results may also provide the basis for the development of novel therapeutic agents specifically targeting glial signalling.     

Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2

Background and purpose:

We aimed to demonstrate the involvement of 5-HT_1A receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice.

Experimental approach:

Cannabidiol (5 mg·kg⁻¹; i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-α receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT_1A receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT_1A receptor antagonist (0.5 mg·kg⁻¹), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin.

Key results:

Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-α receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT_1A expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT_1A receptor involvement in cannabidiol''s effects. Cannabidiol did not affect the impaired liver function in BDL.

Conclusions and implications:

The behavioural outcomes of BDL result from both 5-HT_1A receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT_1A receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.     

NAc Shell Arc/Arg3.1 Protein Mediates Reconsolidation of Morphine CPP by Increased GluR1 Cell Surface Expression: Activation of ERK-Coupled CREB is Required

Background:

Relapse into drug abuse evoked by reexposure to the drug-associated context has been a primary problem in the treatment of drug addiction. Disrupting the reconsolidation of drug-related context memory would therefore limit the relapse susceptibility.

Methods:

Morphine conditioned place preference (CPP) was used to assess activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and correlative molecule expression in the Nucleus accumbens (NAc) shell during the reconsolidation of morphine CPP. U0126 and Arc/Arg3.1 antisense oligodeoxynucleotide were adapted to evaluate the role and the underlying mechanism of Arc/Arg3.1 during the reconsolidation.

Results:

The retrieval of morphine CPP in rats specifically increased the Arc/Arg3.1 protein level in the NAc shell, accompanied simultaneously by increases in the phosphorylation of extracellular signal-regulated kinase1/2 (pERK1/2), the phosphorylation of Cyclic Adenosine monophosphate (cAMP) response element-binding (pCREB), and the up-regulation of the membrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors GluR1 subunit level. Intra-NAc shell infusion U0126, an inhibitor of the Mitogen-activated protein kinase kinase (MEK), prevented the retrieval-induced up-regulation of pERK1/2, pCREB, Arc/Arg3.1, and membrane GluR1 immediately after retrieval of morphine CPP. The effect of disrupting the reconsolidation of morphine CPP by U0126 could last for at least 14 days, and could not be evoked by a priming injection of morphine. Furthermore, the specific knockdown of Arc/Arg3.1 in the NAc shell decreased the membrane GluR1 level, and impaired both the reconsolidation and the reinstatement of morphine CPP.

Conclusions:

Arc/Arg3.1 in the NAc shell mediates the reconsolidation of morphine-associated context memory via up-regulating the level of membrane of GluR1, for which the local activation of the ERK-CREB signal pathway, as an upstream mechanism of Arc/Arg3.1, is required.     

Effects of hydrocortisone on acute β-adrenoceptor blocker and histamine induced bronchoconstriction

AIMS

β-adrenoceptor blockers are avoided in asthma due to concerns of bronchoconstriction. We investigated the safety of acute exposure to propranolol in asthmatics, sequentially challenged with histamine to mimic an asthma exacerbation and evaluated the role of intravenous hydrocortisone in potentiating salbutamol reversibility.

METHODS

Persistent atopic asthmatics, requiring ≤1000 µg day⁻¹ budesonide, performed a randomized double-blind placebo-controlled crossover study. Following 10 mg or 20 mg of oral propranolol, patients received 400 mg intravenous hydrocortisone or placebo, followed by histamine challenge with nebulized salbutamol 5 mg and ipratropium 500 µg recovery.

RESULTS

Thirteen patients completed per protocol. Hydrocortisone did not potentiate salbutamol recovery post propranolol and histamine challenge vs. placebo (mean difference in FEV₁ 0.04 ml, 95% CI −0.07, 0.15, P = 0.417). β-adrenoceptor blocker induced bronchoconstriction was demonstrated by spirometry and impulse oscillometry. For the placebo visit, FEV₁ fell 4.7% 2 hours post propranolol (95% CI 1.8, 7.5, P = 0.008) whilst total airway resistance (R5%) increased 31.3% (95% CI 15.6, 47.0, P = 0.04). On both visits FEV₁% and R5% returned to baseline after salbutamol post histamine.

CONCLUSION

Nebulized salbutamol and ipratropium produced a full recovery after propranolol and histamine induced bronchoconstriction, independent of hydrocortisone use. Since the greatest risk of β-adrenoceptor blockade is after first dose, our findings offer reassurance to those undertaking further evaluation of chronic β-adrenoceptor blockade as a potential treatment for mild-to-moderate asthma.