BOOK REVIEW

Abstract

THE AMERICAN DRUG SCENE-AN ANTHOLOGY (3rd Edition). James A. Inciardi and Karen McElrath (Eds.). Los Angeles, CA, Roxbury Publishing Co., 2001. Reviewed by Peter L. Myers.     

Oxytocin: The great facilitator of life

Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uterine-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. Only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review.     

Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways

Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3β activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3β at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3β inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3β and activation of CREB.     

AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes

Glutamate plays an important role in the psychotomimetic effects of both channel blocking N-methyl D-aspartate (NMDA) receptor antagonists and hallucinogenic drugs which activate 5-hydroxytryptamine2A (5-HT2A) receptors. Previous work suggested that activation of non-NMDA ionotropic glutamate receptors mediates the effects of 5-HT-induced excitatory post-synaptic potentials/currents (EPSPs/EPSCs) when recording from layer V pyramidal cells in the rat medial pre-frontal cortex (mPFC). However, those effects are mediated by either alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate receptors of the iGluk5 subtype. To test whether activation of AMPA receptors is sufficient to mediate 5-HT-induced EPSCs, a 2,3-benzodiazepine that selectively blocks AMPA receptors was assessed. This selective AMPA receptor antagonist potently suppressed 5-HT-induced EPSCs. Since phenethylamine hallucinogens induce head shakes by activating 5-HT2A receptors in the mPFC and this action is modulated by glutamate, we also examined whether selective blockade of AMPA receptors would suppress DOI-induced head shakes. As predicted, we found that selective blockade of AMPA receptors suppressed DOI-induced head shakes. Given evidence that activation of AMPA receptors is an important downstream effect for both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens, we also tested multiple doses of DOI with a sub-anesthetic dose of MK-801. Synergistic action between these two classes of psychotomimetic drugs was demonstrated by MK-801 enhancing DOI-induced head shakes and locomotor activity. These findings expand the dependence of both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens on enhancing extracellular glutamate.     

Short and long term changes in NMDA receptor binding in mouse brain following chronic phencyclidine treatment

Summary Phencyclidine (PCP) is an antagonist of the NMDA subtype of glutamate receptor. PCP treatment induces psychosis in normal humans, which provides a valuable model of schizophrenia. PCP administration also models some of the symptoms of schizophrenia in experimental animals. NMDA hypofunction has been hypothesized to explain these schizophrenia-like symptoms. Acute or chronic administration of the NMDA receptor antagonist PCP has been shown to induce several short or long-term effects in both humans and experimental animals. In an attempt to clarify the neurochemical substrates of these effects in the present study, we used quantitative autoradiography to examine the effects of chronic (14 days) PCP treatment on NMDA receptor binding in mouse brain following both a short- (1 and 24 h) and long-term (14 days) delay after the last PCP treatment. NMDA receptors were targeted using [³H]MK801. Chronic PCP treatment increased [³H]MK801 binding consistently in the hippocampus in the short-term (p < 0.01). Conversely in the long-term, there were widespread reductions in NMDA receptor binding and this effect was most evident in the hippocampus where a 35% reduction of binding was found (p < 0.001). These results suggest that the hippocampus has a strong involvement in both the short and long-term effects of PCP treatment and that reduced NMDA receptor function might be one of the neurochemical substrates of the long lasting actions of PCP or PCP-induced psychosis. Importantly, this study shows that the long-term delay following chronic PCP treatment more accurately represents a state of NMDA hypofunction than the short-term PCP model.     

Safety and effectiveness of NMDA receptor antagonists for depression: A multidisciplinary review

Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N-methyl-D-aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast-acting NMDA antagonists. To capture the essence of 60 years of peer-reviewed literature, we used a semi-structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult-to-treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence—and lack thereof—for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.     

Schizophrenia‐related endophenotypes in heterozygous neuregulin‐1 ‘knockout’ mice

Neuregulin‐1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N‐methyl‐d ‐aspartate receptor antagonists MK‐801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK‐801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N‐acetylaspartate and GABA were determined using high‐performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor‐activating effects of acute PCP. Subchronic MK‐801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance‐related behaviours observed in vehicle‐treated mutants. No phenotypic differences were demonstrated in N‐acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia‐relevant processes including the effects of psychotomimetic N‐methyl‐d ‐aspartate receptor antagonists.     

Antagonist properties of eliprodil and other NMDA receptor antagonists at rat NR1A/NR2A and NR1A/NR2B receptors expressed in Xenopus oocytes

We have studied the effects of a variety of N-methyl-

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-aspartate (NMDA) antagonists acting at different sites of the NMDA receptor complex on NMDA-induced currents in Xenopus oocytes expressing heteromeric NR1A/NR2A and NR1A/NR2B receptors. The polyamine site antagonists eliprodil (IC₅₀=3.0 μM) and ifenprodil (IC₅₀=0.27 μM) antagonized NMDA responses at NR1A/NR2B receptors but not at NR1A/NR2A receptors (IC₅₀>100 μM). The channel blockers dizocilpine, memantine and phencyclidine (PCP) were equally potent antagonists at both receptor subtypes whereas dextromethorphan was four times more potent at NR1A/NR2A receptors. The glycine site antagonists

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-689,560 and 7-Cl-kynurenate were 10 times more potent at NR1A/NR2A than at NR1A/NR2B receptor subtypes. The selectivity of eliprodil and ifenprodil for the NR1A/NR2B receptor subtype may, at least partially, explain their favorable side effect profile.