Although the induction of persistent behavioral alterations by drugs of abuse requires the regulation of gene transcription, the precise intracellular signaling pathways that are involved remain mainly unknown. Extracellular signal-regulated kinase (ERK) is critical for the expression of immediate-early genes in the striatum in response to cocaine and Δ9-tetrahydrocannabinol and for the rewarding properties of these drugs. Here we show that in mice a single injection of cocaine (10 mg/kg) activates mitogen- and stress-activated protein kinase 1 (MSK1) in dorsal striatum and nucleus accumbens. Cocaine-induced phosphorylation of MSK1 threonine 581 and cAMP response element-binding protein (CREB) serine 133 (Ser133) were blocked by SL327, a drug that prevents ERK activation. Cocaine increased the acetylation of histone H4 lysine 5 and phosphorylation of histone H3 Ser10, demonstrating the existence of drug-induced chromatin remodeling in vivo . In MSK1 knock-out (KO) mice CREB and H3 phosphorylation in respon...

Cold allodynia and mechanical hyperalgesia are symptoms most often reported by patients suffering from neuropathic pain. While cold allodynia and mechanical hyperalgesia are both commonly detected in patients and in animal models of neuropathic pain, the two symptoms are not necessarily due to the same pathophysiological events. Using acetone as a cooling stimulus and von Frey hairs as mechanical stimuli, we report that, in the spared tibial nerve (STN) injury model in mice the two evoked symptoms are due to different mechanisms. First, cold allodynia and mechanical hyperalgesia have different pharmacological profile. Drugs that reverse cold allodynia in the STN model are the ones most widely prescribed in the clinic. Indeed, gabapentin (200-1250 mmol/kg, ip) and oxycodone (3-30 mmol/kg, sc) were far more efficacious against cold allodynia than against mechanical hyperalgesia. Other drugs such as delta9-THC (3-30 mmol/kg, sc), amitriptyline (10-25 mmol/kg, ip) and tramadol (20-100 mmol/kg, ip) were equally...

Cannabinoid CB1 receptor antagonists not only block the rewarding effects of delta-9-THC, heroin, nicotine, cocaine, and ethanol, but also prevent relapse to the use of various drugs of abuse, including cocaine, heroin, and methamphetamine (see review by Le Foll and Goldberg, 2005), suggesting a potential use of CB1 receptor antagonists in treatment of drug abuse. However, the neurochemical mechanisms underlying these actions remain poorly understood. Here, we investigated the effects of the novel CB1 receptor antagonist AM 251 on cocaine-induced changes in neurotransmitter release in the nucleus accumbens in rats during reinstatement of drug-seeking behavior. We found that: 1) systemic administration of AM 251 (1, 3, 10 mg/kg i.p., 30 min prior to cocaine injection) significantly attenuates (maximally ~50%) cocaine (10 mg/kg i.p.)-triggered reinstatement of cocaine seeking; 2) acute cocaine (10 mg/kg i.p.) priming injections significantly increase extracellular DA (+160%) and glutamate (+80%), but not GAB...

Soluble Aβ oligomers are neurotoxins in AD, which correlate with its severity. p-JNK is one candidate implicated inβ-amyloid mediated neurodegeneration. Curcumin (curc) is a polyphenolic antioxidant known to be an AP-1 binding inhibitor which affects p-JNK. Curc also has anti-amyloidgenic activity. Therefore, we investigated Aβ oligomer induced p-JNK stimulation, co-localization and neuronal apoptosis. We also investigated the inhibitory effect of curc and its one known metabolite tetrahydrocurcumin (THC) on this Aβ oligomer induced p-JNK activation. We used high molecular weight oligomer (~35 mer) to conduct this study which is neurotoxic to human neuroblastoma cells (SY5Y) at 1μM and increases p-JNK. We also found soluble Aβ oligomer co-localized with p-JNK as determined by A11 and p-JNK antibody in vitro and in vivo. Our results suggest that curc and its metabolite significantly reduced Aβ oligomer induced neuronal toxicity from 1-2.5 μM and blocked p-JNK activation and co-localization through inhibitio...

Motivational deficits characterized by an unwillingness to overcome effortful costs are a common feature of neuropsychiatric and neurologic disorders that are insufficiently understood and treated. Dopamine (DA) signaling in the nucleus accumbens (NAc) facilitates goal-seeking, but how NAc DA release encodes motivationally salient stimuli to influence effortful investment is not clear. Using fast-scan cyclic voltammetry in male and female mice, we find that NAc DA release diametrically responds to cues signaling increasing cost of reward, while DA release to the reward itself is unaffected by its cost. Because endocannabinoid (eCB) signaling facilitates goal seeking and NAc DA release, we further investigated whether repeated augmentation of the eCB 2-arachidonoylglycerol with a low dose of a monoacylglycerol lipase (MAGL) inhibitor facilitates motivation and DA signaling without the development of tolerance. We find that chronic MAGL treatment stably facilitates goal seeking and DA encoding of prior rewar...

Despite exhibiting tau phosphorylation similar to Alzheimer’s disease (AD), the human fetal brain is remarkably resilient to tau aggregation and toxicity. To identify potential mechanisms for this resilience, we used co-immunoprecipitation (co-IP) with mass spectrometry to characterize the tau interactome in human fetal, adult, and Alzheimer’s disease brains. We found significant differences between the tau interactome in fetal and AD brain tissue, with little difference between adult and AD, although these findings are limited by the low throughput and small sample size of these experiments. Differentially interacting proteins were enriched for 14-3-3 domains, and we found that the 14-3-3-β, η, and γ isoforms interacted with phosphorylated tau in Alzheimer’s disease but not the fetal brain. Since long isoform (4R) tau is only seen in the adult brain and this is one of the major differences between fetal and AD tau, we tested the ability of our strongest hit (14-3-3-β) to interact with 3R and 4R tau using ...

Cannabis or marijuana has been used for recreational purposes and as a medicine for many centuries, but its addictive potential and some adverse side effects such as memory impairment, make it become the focus of strong social, legal, and medical controversy over its therapeutic utility. The settlement of this dispute may depend on the clarification of its mechanisms acting on brain. This study was undertaken to examine the effects of cannabinoids on the proliferation of neural stem/progenitor cells in the rat hippocampus both in vitro and in vivo. Using both WST-8 and bromodeoxyuridine (BrdU) ELISA methods, we found that the potent cannabinoid HU210 (10 nM - 500 nM) promoted significantly the proliferation of the cultured neural stem/progenitor cells collected from the rat hippocampus at E17. Using BrdU to label dividing cells in adult Long-Evens, Wistar and Fischer-344 rats, we further found that twice daily i.p. injections of the potent cannabinoid HU210 for 5 days increased significantly the number of ...

Despite significant overlap in the behavioral and physiological roles of the serotonergic and endocannabinoid systems, little is known about the influence each of these systems exerts on the other. This research examined how chronic treatment with the cannabinoid receptor (CB1) agonist HU-210 (7-hydroxy-delta6-tetrahydrocannabinol 1,1-dimethylheptyl) at a dose of 100ìg/kg for 12 days affected the behavioral and physiological responses to 5-HT1A, 2A/2C receptor stimulation. HU-210 induced a sensitization of the wet dog shake response to the 5-HT2A/2C receptor agonist DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; 1 mg/kg IP), and a trend to an increased hyperthermic response to this drug. DOI administration lead to an unanticipated 50% mortality rate in rats pretreated with HU-210 due to apparent symptoms of serotonin syndrome. DOI-induced back muscle contractions were significantly reduced in animals pretreated with HU-210, suggesting that 5-HT2A and 5-HT2C receptors may be differentially regula...

Although 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy‘) is, after marijuana, the second most prevalent illegal drug of abuse in European adolescents, animal experimental evidence of MDMA’s reinforcing effect has remained scarce, particularly in the rodent model, raising questions about the robustness of MDMA’s reinforcing effect under controlled laboratory conditions. In the present rat runway study, male Sprague-Dawley rats were given the opportunity to run for intravenous injections of saline, MDMA, or morphine. Compared to saline (runtime, 50 ± 4 s; N=20), MDMA significantly decreased runtimes to 29 ± 8 s at 0.32 mg/kg MDMA (ANOVA, p<0.001; LSD, p=0.02; N=9) and to 27 ± 9 s at 1 mg/kg MDMA (ANOVA, p<0.001; LSD, p=0.003; N=10), while 0.32 mg/kg morphine (N=10) decreased runtime to 11 ± 6 s (ANOVA, p<0.001; LSD, p<0.001). Thus, MDMA’s reinforcing effect can be demonstrated not only across rat strains, i.e. Sprague-Dawley rats vs. Long Evans rats, but also across operant conditioning paradigms, i.e. l...

Evidence suggests a role in the brain for receptors activated by synthetic cannabinoids (CBs), Δ9-THC, and endogenous agonists known as endocannabinoids. The best characterized physiological role for CB receptors in brain is the presynaptic inhibition of GABA release from axon terminals providing input to GABA-A receptors throughout the CNS. This phenomenon has been observed with the synthetic CB agonist WIN55,212-2 in brain slices containing the ventral tegmental area (VTA), a brain region thought to be essential to the rewarding properties of many commonly abused drugs. Whereas the activation of GABA-A receptors in the VTA is thought to reflect the activity of axon terminals derived from intrinsic neurons, inputs to GABA-B receptors on dopamine (DA) neurons in the VTA are likely derived from GABAergic neurons located in forebrain regions such as the nucleus accumbens. To determine whether cannabinoids could regulate GABAergic input to GABA-B receptors on DA neurons, we performed whole-cell voltage clamp ...