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Director's Report to the National Advisory Council on Drug Abuse - February, 2004

Research Findings - Basic Research

Amphetamine, LSD and PCP Act through a Common Signaling Pathway

It has been established that drugs of abuse affect the regulation of DARPP-32 (32 kD dopamine and cAMP-regulated phosphoprotein) phosphorylation. In this publication, the researchers examined the molecular effects of D-amphetamine, LSD and PCP on phosphorylation of DARPP-32 and three of its downstream effector molecules. The researchers created three strains of mutant mice, each with a DARPP-32 phosphorylation site that had been mutated to an alanine, which prevented phosphorylation at key sites, threonine (Thr) 34, Thr 75 and Serine (Ser) 130. In the Thr 34 and Ser 130 mutant animals, they found psychotomimetic-induced increases of downstream effector molecules, were reduced in frontal cortex and striatum compared to wild-type and the ability of the psychotomimetics to increase c-fos mRNA in cingulated cortex and in the paraventricular region of striatum was reduced in the Thr 34 and Ser 130 mutant animals. Looking at the effects of amphetamine, LSD and PCP on prepulse inhibition (PPI) and repetitive movements, researchers observed attenuation of both behavioral parameters with each drug in the Thr 34 mutant animals. Both behaviors were also attenuated in the Ser 130 mutant animals except for PCP/PPI effect. By eliminating single phosphorylation sites on DARPP-32, these researchers were able to demonstrate a decrease in behavioral effects of psychotomimetics, revealing the critical role that this molecule has in both molecular and behavioral drug response. Svenningsson, P., Tzavara, E.T., Carruthers, R., Rachleff, I., Wattler, S., Nehls, M., McKinzie, D.L., Fienberg, A.A., Nomikos, G.G. and Greengard, P. Diverse Psychotomimetics Act Through a Common Signaling Pathway. Science. 302(5649), pp. 1412-1415, November 21, 2003.

Marijuana and Pregnancy

Earlier studies from Dr. S.K. Dey's laboratory has shown that in a mouse model, anandamide, an endogenous cannabinoid ligand, and its receptors play an important regulatory role in the establishment of normal pregnancy and these effects are dose and stage-specific as lower levels of endocannabinoids and CB receptors were found to be beneficial for implantation while higher concentrations were detrimental to this process. In a recent paper, they demonstrate that anandamide within a very narrow range regulates blastocyst function and implantation by differentially modulating mitogen-activated protein kinase (MAPK) signaling and Ca++ channel activity via CB1 receptors. Anandamide at a low concentration induces extracellular regulated kinase (ERK) phosphorylation and nuclear translocation in trophectoderm cells without influencing Ca++ channels, and renders the blastocyst competent for implantation in the receptive uterus. In contrast, anandamide at a higher concentration inhibits Ca++ channel activity and blastocyst competency for implantation without influencing MAPK signaling. These studies utilized genetic, pharmacological and physiological approaches to uncovering a potentially important regulatory mechanism for synchronizing blastocyst and uterine competency to implantation. This observation in addition to advancing our basic knowledge has high clinical relevance as elevated levels of anandamide could induce spontaneous early pregnancy losses in women who smoke marijuana. Wang, H., Matsumoto, H., Guo, Y., Paria, B.C., Roberts, R.L. and Dey, S.K. Differential G-protein Coupled Cannabinoid Receptor Signaling by Anandamide Directs Blastocyst Activation for Implantation. Proc Natl Acad Sci., pp. 14914-14919, 2003.

Extended Access to Nicotine Self-administration in Rats Does Not Lead to Gradual Escalationin Intake

Researchers at the Scripps Research Institute in La Jolla previously reported that groups of rats given extended access to self-administer cocaine or heroin showed a gradual escalation in drug intake compared to groups of animals that had a more restricted access to these drugs. Dr. Athina Markou and her colleagues sought to broaden these findings to the study of nicotine self-administration in rats. Using the same experimental design of the earlier studies, groups of rats were given access to nicotine one hour a day for five days a week, one hour a day seven days a week, or six hours a day seven days a week. A fourth group of animals had no access to the experimental chamber. All animals were observed for somatic signs of nicotine withdrawal on day 25 of nicotine self-administration, 17 hours after the end of the previous session. On day 31 of nicotine access, the animals were challenged with the nicotinic receptor antagonist mecamylamine for somatic signs of withdrawal and subsequently for effects on nicotine self-administration. The investigators found that extended access to nicotine self-administration resulted in the development of nicotine dependence for periods lasting up to four weeks, but did not lead to higher rates of drug intake; these results differed from the earlier findings for cocaine and heroin. The authors propose that these results parallel those in humans, where nicotine addicts show long-lasting stable rates of intake following an initial increase in intake during the acquisition phase of dependence and cocaine addicts who have a propensity to escalate drug intake. Patterson, N.E. and Markou, A. Prolonged Nicotine Dependence Associated with Extended Access to Nicotine Self-administration in Rats. Psychopharmacology OnLine, Jan. 8, 2004.

Placebo Effects of Tobacco Smoking and Other Nicotine Intake

In this review, Perkins et al. discuss common terms and methods of placebo research, especially the balanced-placebo design. Also included was discussion of the limited research directly assessing placebo effects of smoking and other nicotine intake, namely studies that manipulated instructions to subjects about the drug content of an ingested substance. Finally, other studies relevant to gauging the likely magnitude of placebo smoking effects were examined. In an effort to encourage more research on these placebo effects, substantial attention is paid to future directions. Among recommendations are testing the utility of the balanced-placebo design and other rigorously controlled designs, and including multiple measures of placebo effects in addition to self-report. Future research also should explore the moderating influences of the environmental context and of individual difference factors on placebo effects of smoking and other nicotine intake. Perkins, K.A., Sayette, M., Conklin, C. and Cagguila, A.R. Nicotine & Tobacco Research 5(5), pp. 695-709, 2003.

Altered Integration between Dopamine, Glutamate and Norepinephrine in Midbrain Dopamine Neurons May Account for Individuals' Tendency to Seek Psychostimulants

In a majority of the midbrain dopamine neurons, the afferent signaling that activates the glutamate receptor shifts the regular spontaneous discharge pattern of activity to burst firing, represented by a transient pause of the discharge due to the metabotropic glutamate-induced hyperpolarization. The burst firing results in a phasic release of dopamine and may be important in the neural processing of reward, including both natural rewards and those signaled by conditioned visual and auditory cues. Dr. John Williams showed that spontaneous bursting activity could not be detected in slices of midbrain because they lacked afferent input. Similarly, bursting activity occurred In vivo in dopamine-deficient animals only in the presence of the dopamine precursor, L-dopa. This work suggests that the integrity of the endogenous dopamine system, regulated by network feedback mechanisms, is critical in the generation of the burst firing pattern of the dopamine neurons. He also showed that amphetamine enhanced the burst firing rate of these neurons by shortening the pause phase of the discharges (reduction of the mGlu receptor-mediated hyperpolarizing outward current). This effect occurred through activation of the alpha-1 adrenergic receptors as the effect of amphetamine was mimicked by an adrenergic agonist and was attenuated by an antagonist. In addition, the enhancement of burst firing in these dopamine neurons normally induced by alpha-1 receptor activation was reduced in animals that actively sought cocaine (self-administering) but not in the yoked controls. The consequences of this adaptation would be a lower burst discharge and a reduced dopamine release at target loci. It suggests that individuals' tendency to seek psychostimulants may involve impaired integration among dopamine, glutamate and norepinephrine in midbrain dopamine neurons. The altered burst discharge may underlie changes in synaptic plasticity and could encode information for reward-related learning. Paladini, C. A., Robinson, S., Morikawa, H., Williams, J. T. & Palmiter, R. Dopamine Controls the Firing Pattern of Dopamine Neurons Via a Network Feedback Mechanism. Proc Natl Acad. Sci. 100, pp. 2866-2871, 2003; Morikawa, H., Khodakhah, K. and Williams, J.T. Two Intracellular Pathways Mediate Metabotropic Glutamate Receptor-Induced Calcium Mobilization in Dopamine Neurons. J. Neurosci. 23, pp. 149-157, 2003.

Simulation of Neuronal Encoding for Memory Task as a Simple Model for Assessment of Drugs' Effect on Behavior Performance

The firing pattern of a single neuron or ensembles of neurons varies in response to changing external or internal environments of the organism. What information does it encode and what is its functional significance? In many labs, interpretations of the electrophysiological data are at the level of altered excitation/inhibition of neurons or in brain circuits. Dr. Deadwyler's group employs a simple model to assess the "behavioral effect" on functionally relevant synaptic events and records neuronal activity in the memory circuits of the hippocampus. Their study is unique in that activity in the hippocampal cells was evoked with trains of electrical pulses that mimicked firing patterns of these neurons recorded In vivo when animals traversed place fields or when they were performing a short-term memory task. The simulation of neuronal encoding of a particular behavior task provides a simple experimental model that facilitated assessment of behavioral impact in a brain circuit of interest and assessed how cognitive encoding or consequences may be affected when homeostasis of the brain is altered, such as under the influence of drugs. The model allowed Dr. Deadwyler to conclude that under normal synaptic feedback control mechanisms, the phenomenon of depolarization-induced suppression of inhibition (disinhibition) mediated by the endocannabinoid system in the hippocampus, was not involved in the short-term memory process. Hampson, R.E., Zhuang, S-Y., Weiner, J.L. and Deadwyler, S.A. J. Neurophysiol., 90, pp. 55-64, 2003.

5-Butylthevinone: Sterochemistry of the Diels-Alder Reaction of 5-butylthebaine with 3-buten-2-one

In this paper the authors have reported on the X-ray analysis of 5-butylthevinone (7∀-acetyl-4,5-∀-epoxy-3,6-dimethoxy-5-∃-butyl-17-methyl-6∀,14∀-ethenoisomermorphinan), C27H35NO4. This compound belongs to an important class of opioids, known as orvinols (highly potent analgesics), and is the sole product of a Diels Alder reaction of 5-butylthebaine with 3-buten-2-one, through attack of the dienophile on the ∃-face of diene, even though it has been suggested that the introduction of 5∃-substituents tends to hinder attack from the ∃face, and leads to the production of exo-etheno adducts through attack from the ∀-face. Chen, W., Metcalf, M.D., Coop, A., Flippen-Anderson, J.L. and Deschamps, J.R. Acta Cryst. E59, 0114-0016, 2003.

Nicotinic Ligand Transport

There is a continuing research interest in developing chemical agents with a structural similarity to nicotine, which could be therapeutically delivered as smoking-cessation agents, without the identified risks associated with smoking cigarettes. One such class of compounds, developed by Dr. Linda Dwoskin and her collaborators, are known as N-alkylnicotinium analogs, which chemically consist of the nicotine molecule alkylated on the pyridine ring nitrogen by alkyl groups of varying length. The resulting compounds have been shown capable of inhibiting the release of dopamine which nicotine induces, particularly for alkyl groups of carbon length seven to twelve. The inhibition produced can be in the low micromolar to nanomolar range, in terms of IC50 inhibitory values. One of the most promising of these compounds is NONI, or N-octyl nicotinium iodide, which appears to function as a competitive antagonist with nicotine, as judged by its ability to inhibit nicotine binding, and its potent inhibition of dopamine overflow from rat striatal slices preloaded with tritiated dopamine, using Scatchard analysis of the results. NONI shows moderate binding to the neuronal nicotinic receptor subtypes containing the beta 2 subunit (i.e., alpha4beta2 and alpha3beta2), but not the alpha7 subunit. Because NONI is a salt carrying a cationic positive charge on the nicotine moiety, it would be expected to exhibit low permeability across the brain brain barrier (BBB), and present an inherent drug delivery problem. However, in a recent in-situ rat brain infusion study, Dr. Dwoskin has reported that tritiated NONI has a permeability comparable to that of tritiated choline. Furthermore, NONI has a Ki of 49 microM in inhibiting the transport of of tritiated choline, whereas nicotine was largely ineffective in this regard. Because both choline (5000 microM) and NONI (250 microM) could significantly inhibit the uptake of tritiated choline, it was concluded that NONI is transferred across the BBB at least in part by active transport by the choline transporter. This work suggests the utilization of the choline transporter as a delivery system for charged nicotinic ligands. Allen, D.D., Lockman, P.R., Roder, K.E., Dwoskin, L.P., and Crooks, P.A. The Journal of Pharmacology and Experimental Therapeutics, 304(3), pp. 1268-1274, 2003.

Syntaxin 1A Interacts Directly with the GABA Transporter to Inhibit GABA Efflux and Exchange in Rat Brain

GABA is the primary inhibitory transmitter in the brain. GABA transporters control the extracellular levels of GABA by coupling transmitter uptake to the sodium and chloride cotransport. These GABA transporter (GAT1), in turn, are regulated by interactions with syntaxin 1A, a protein involved in vesicle docking and in the regulation of ion channels and transporters. Dr. Quick and his group had previously shown that syntaxin 1A decreases the transport of GABA and its associated ions through interactions with the aspartic acid residue in the N-terminal tail of the transporter. However, the reduction in uptake could be the result of many steps in the transport cycle, including substrate binding, substrate flux or efflux, or reorientation of transporters that did not bind GABA. Dr. Quick's group mutated the aspartic acid residues of the transporter and showed that the syntaxin 1A-mediated reduction in GABA flux and efflux was mimicked by mutations in GAT1 at the syntaxin 1A binding site. This suggested that syntaxin 1A exerts its effects through interactions with GAT1's N-terminal tail and that the inhibition occurs after substrate binding and involves both unidirectional transport and transmitter exchange. Wang, D., Decken, S.L., Whitworth, T.L. and Quick, M.W. Molecular Pharmacology, 64, pp. 905-913, 2003.

A Spatial Focusing Model for G Protein Signals: Regulator of G protein Signaling (RGS) Protein-Mediated Kinetic Scaffolding

Regulators of G protein signaling (RGS) are GTPase-accelerating proteins (GAPs), which can inhibit heterotrimeric G protein pathways. In this study, Drs. Neubig and Traynor and their colleagues at the University of Michigan provide experimental and theoretical evidence that high concentrations of receptors (as at a synapse) can lead to saturation of GDP-GTP exchange making GTP hydrolysis rate-limiting. This results in local depletion of inactive heterotrimeric G-GDP, which is reversed by RGS GAP activity. Thus, RGS enhances receptor-mediated G protein activation even as it deactivates the G protein. Evidence supporting this model includes a GTP-dependent enhancement of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding to G(i) by RGS. The RGS domain of RGS4 is sufficient for this, not requiring the NH(2)- or COOH-terminal extensions. Furthermore, a kinetic model including only the GAP activity of RGS replicates the GTP-dependent enhancement of GTPgammaS binding observed experimentally. Finally in a Monte Carlo model, this mechanism results in a dramatic "spatial focusing" of active G protein. Near the receptor, G protein activity is maintained even with RGS due to the ability of RGS to reduce depletion of local Galpha-GDP levels permitting rapid recoupling to receptor and maintained G protein activation near the receptor. In contrast, distant signals are suppressed by the RGS, since Galpha-GDP is not depleted there. Thus, a novel RGS-mediated "kinetic scaffolding" mechanism is proposed which narrows the spatial range of active G protein around a cluster of receptors limiting the spill-over of G protein signals to more distant effector molecules, thus enhancing the specificity of G(i) protein signals. Zhong, H., Wade, S.M., Woolf, P.J., Linderman, J.J., Traynor, J.R. and Neubig, R.R. A Spatial Focusing Model for G protein Signals. Regulator of G Protein Signaling (RGS) Protein-Mediated Kinetic Scaffolding. J Biol Chem. 278(9), pp. 7278-7284, February 28, 2003. Epub November 21, 2002.

The Role of GABAB Receptors in the Discriminative Stimulus Effects of Gamma-Hydroxybutyrate in Rats: Time Course and Antagonism Studies

Gamma-Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug of abuse, although its mechanism of action is poorly understood. Dr. Charles France and his research team at the University of Texas Health Science Center characterized the role of GABA(A), GABA(B), and other receptors in the discriminative stimulus effects of GHB. Eight rats reliably discriminated 200 mg/kg GHB from saline after a median of 35 (range: 23-41) training sessions. GHB, a metabolic precursor 1,4-butanediol (1,4-BDL), and the GABA(B) agonist (+/-)baclofen all occasioned greater than 83% responding on the GHB lever. The onset of action was similar for GHB and 1,4-BDL; however, 1,4-BDL exhibited a longer duration of action than GHB. The GHB precursor gamma-butyrolactone, the benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist morphine, and the N-methyl-d-aspartate antagonist ketamine elicited substantial GHB-appropriate responding, although none occasioned greater than 66% drug-lever responding. The barbiturate pentobarbital and the GABA(A) receptor agonist muscimol did not occasion greater than 17% drug-lever responding at any dose tested. The benzodiazepine antagonist flumazenil attenuated GHB-lever responding occasioned by diazepam, but not GHB. The GABA(B) receptor antagonist CGP 35348 antagonized GHB-lever responding occasioned by baclofen or GHB. Small doses of the purported GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) attenuated partially the effects of GHB, whereas larger doses of NCS-382 alone occasioned partial GHB-lever responding. These results implicate GABA(B) mechanisms in the discriminative stimulus effects of GHB and further suggest that the effects of 1,4-BDL under these conditions result from its conversion to GHB. That NCS-382 shares effects with GHB could explain the lack of antagonism reported for NCS-382 in some studies. Carter, L.P., Flores, L.R., Wu, H., Chen, W., Unzeitig, A.W., Coop, A. and France, C.P. The Role of GABAB Receptors in the Discriminative Stimulus Effects of Gamma-Hydroxybutyrate in Rats: Time Course and Antagonism Studies. J Pharmacol Exp Ther., 305(2), pp. 668-674, May 2003. Epub February 11, 2003.

Immunity and Drugs of Abuse: Opioids and Immunity

Various opioids have been shown to inhibit immune function. Dr. Loh has shown the cooperativity of the delta and mu systems. There is even a negative cooperativity in which the absence of the mu system reduces the effects of delta agonists. They focus on the inhibition of phagocytosis by macrophages. Studies with selective opioid agonists show that mu- and delta(2)-opioid receptors, but not kappa, are involved in opioid inhibition of phagocytosis in elicited murine macrophages. All mu and delta(2) agonists tested had similar maximal effects on phagocytosis, and all dose-response curves suggest positive cooperativity. In addition, mu and delta antagonists antagonized the effect of both mu and delta agonists. Furthermore, in mu-opioid receptor knockout mice (MORKO), Dr. Loh observed a decrease in potency and maximal effect for a delta agonist. These data suggest that mu and delta receptors are not only involved in the modulation of phagocytosis in macrophages, but they also affect each other's activity by an unknown cooperative mechanism. Tomassini, N., Renaud, F.L., Roy, S. and Loh, H.H. Mu and Delta Receptors Mediate Morphine Effects on Phagocytosis by Murine Peritoneal Macrophages. J Neuroimmun., 136, pp. 9-16, 2003.

Opioid Mechanisms of Immune Modulation

Dr. Sharp and his group have probed the biochemical and molecular pathways whereby DORs (delta opioid receptors) affect the activation of phosphotidylinositol-3 kinase (PI3 kinase) and thereby modulate T-cell IL-2 gene expression and protein production in thymocytes. In addition to these upstream signaling studies, they measured the effects of these signaling pathways on the activation of transcription factors involved in IL-2 gene transcription. These basic studies are providing a clearer understanding of how opioids effect immune modulation. Opioid receptors (DORs) modulate thymocyte (TCR) signaling through the mitogen-activated protein kinases (MAPKs), ERKs 1 and 2. These studies determined whether a DOR agonist alone ([D-Ala(2)-D-Leu(5)]enkephalin; DADLE) affects phosphorylation of the activating transcription factor (ATF-2) and its interaction with the MAPK, c-Jun NH2-terminal kinase (JNK). DOR expression was induced on murine splenocytes by anti-CD3 and then quiescent cells were treated with DADLE. DADLE, itself, dose-dependently induced maximal phosphorylation of ATF-2 within 5-10 min; naltrindole, a specific antagonist, abolished this. Anti-ATF-2 immunoprecipitates from control and DADLE-treated splenocytes showed a dominant 59 kDa phosphorylated band and a 71 kDa band. DADLE stimulated phosphorylation of both bands, although the 71 kDa band was selectively immunoprecipitated by anti-JNK. Thus, DADLE stimulated phosphorylation of 71kDa ATF-2 and its association with JNK, suggesting that JNK is activated through DORs. Along with previous observations, these studies suggest that lymphocyte DORs can affect the activation of MAPKs by TCR-independent stimulation (e.g., JNK) or indirectly by modulating TCR-dependent stimulation (e.g., ERK). Shahabi, N.A., McAllen, K. and Sharp, B.M. Phosphorylation of Activating Transcription Factor in Murine Splenocytes through Delta Opioid Receptors. Cell Immunol., 221, pp. 121-127, 2003.

Morphine Enhances HCV Replication

There is currently little information related to opioids' actions on hepatitis C virus (HCV) infections. Recently, morphine was demonstrated to increase the replication of HCV in liver cells. Thus, as with HIV, morphine causes enhanced infectivity by this virus and may be of concern in individuals with hepatitis. Little information is available regarding whether substance abuse enhances hepatitis C virus (HCV) replication and promotes HCV disease progression. Dr. Wenzhe Ho investigated whether morphine alters HCV mRNA expression in HCV replicon-containing liver cells. Morphine significantly increased HCV mRNA expression, an effect which could be abolished by either of the opioid receptor antagonists, naltrexone or beta-funaltrexamine. Investigation of the mechanism responsible for this enhancement of HCV replicon expression demonstrated that morphine activated NF-KB promoter and that caffeic acid phenethyl ester, a specific inhibitor of the activation of NF-kappaB, blocked morphine-activated HCV RNA expression. In addition, morphine compromised the anti-HCV effect of interferon alpha (IFN-alpha). Dr. Ho's in vitro data indicate that morphine may play an important role as a positive regulator of HCV replication in human hepatic cells and may compromise IFN-alpha therapy. Li, Y., Zhang, T., Douglas, S.D., Lai, J.P., Xiao, W.D., Pleasure, D.E. and Ho, W.Z. Morphine Enhances Hepatitis C Virus (HCV) Replicon Expression. Amer J Path., 163, pp. 1167-1175, 2003.

Cannabinoids and Immunity

Most studies have shown that an opioid or cannabinoid receptor mediates the immune modulation by different drugs. Dr. Norbert Kaminski has shown that the calcium ionophore (PMA/Io)-stimulated interleukin-2 production was blocked but the cannabinoid-induced inhibition of PMA/Io-stimulated interleukin-2 was not blocked by cannabiniod type 1 or type 2 antagonists. This shows that there are apparently two different systems at work in lymphocytes. Cannabinoids exhibit immunosuppressive actions that include inhibition of interleukin-2 production in response to a variety of T cell activation stimuli. Traditionally, the effects of these compounds have been attributed to cannabinoid receptors CB1 and CB2, both of which are expressed in mouse splenocytes. Therefore, a CB1 antagonist and a CB2 antagonist were used to investigate the role of cannabinoid receptors in the cannabinoid-induced inhibition of phorbol ester plus calcium ionophore (PMA/Io)-stimulated interleukin-2 production by mouse splenocytes. PMA/Io-stimulated interleukin-2 production was inhibited by cannabinol, cannabidiol, and both WIN 55212-2. Cannabinoid-induced inhibition of PMA/Io-stimulated interleukin-2 was not attenuated by the presence of both SR144528 and SR141716A. Using pertussis toxin to address the role of G protein-coupled receptors in this response, it was determined that pertussis toxin treatment did not attenuate cannabinol-induced inhibition of PMA/Io-stimulated interleukin-2. With the demonstration that cannabinoid-induced inhibition of PMA/Iostimulated interleukin-2 was not mediated via CB1 or CB2, alternative targets of cannabinoids in T cells were examined. Specifically, it was demonstrated that cannabinoids elevated intracellular calcium concentration in resting splenocytes and that the cannabinol-induced elevation in intracellular calcium concentration was attenuated by treatment with both SR144528 and SR141716A. Interestingly, pretreatment of splenocytes with agents that elevate intracellular calcium concentration inhibited PMA/Io-stimulated interleukin-2 production, suggesting that an elevation in intracellular calcium concentration might be involved in the mechanism of interleukin-2 inhibition. These studies suggest that immune modulation produced by cannabinoids involves multiple mechanisms, which might be both cannabinoid receptor-dependent and-independent. Kaplan, B.L.F., Rockwell, C.E. and Kaminski, N.E. Evidence for Cannabinoid Receptor-Dependent and-Independent Mechanisms of Action in Leukocytes. J Pharm Exper Ther., 306, pp. 1077-1085, 2003.

Atrophin 2 Recruits Histone Deacetylase and is Required for the Function of Multiple Signaling Centers During Mouse Embryogenesis

This research identified a new transcription factor required for early forebrain development. By performing a genetic screen in mice, the Peterson group isolated a number of mutants, including open minded (OM). OM mice fail to close the anterior neural tube, and fuse the telencephalic with the optic vesicles by 9.5 days gestation. The gene mutated in OM mice has now been identified and characterized: it is Atrophin 2 (ATR2) and it is a transcriptional repressor that interacts with histone deacytlase 1. Its loss leads to the dysfunction of two important signaling centers in the forebrain: the anterior neural ridge and the prechordal mesoderm. This dysregulation is also apparent by the misexpression or loss of expression of the genes encoding the essential secreted proteins FGF8 and sonic hedgehog, respectively. This study provides essential insight into the molecular mechanism by which many forebrain regions are formed, including the cortex and the basal ganglia. Zoltewicz, J.S., Stewart, N.J., Leung, R. and Peterson, A.S. Development, 131, pp. 3-14. 2004.


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