dizocilpine-maleate and gabazine

Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-D-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABA(A) receptors.. The present study used a rodent model to compare the inhibition of NMDA and GABA(A) receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing.. Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats.. Reducing GABA(A) receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC.. These data demonstrate that, while tonic stimulation of NMDA and GABA(A) receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.

Topics: 3-Mercaptopropionic Acid; Animals; Attention; Carbolines; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; GABA Antagonists; Glutamate Decarboxylase; Gyrus Cinguli; Male; Pyridazines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Cortical motor maps are the basis of voluntary movement, but they have proven difficult to understand in the context of their underlying neuronal circuits. We applied light-based motor mapping of Channelrhodopsin-2 mice to reveal a functional subdivision of the forelimb motor cortex based on the direction of movement evoked by brief (10 ms) pulses. Prolonged trains of electrical or optogenetic stimulation (100-500 ms) targeted to anterior or posterior subregions of motor cortex evoked reproducible complex movements of the forelimb to distinct positions in space. Blocking excitatory cortical synaptic transmission did not abolish basic motor map topography, but the site-specific expression of complex movements was lost. Our data suggest that the topography of movement maps arises from their segregated output projections, whereas complex movements evoked by prolonged stimulation require intracortical synaptic transmission.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Bacterial Proteins; Biophysics; Brain Mapping; Central Nervous System Stimulants; Channelrhodopsins; Dizocilpine Maleate; Electric Stimulation; Electromyography; Evoked Potentials, Motor; Excitatory Amino Acid Antagonists; Forelimb; GABA Antagonists; Green Fluorescent Proteins; Light; Luminescent Proteins; Mice; Mice, Transgenic; Motor Cortex; Movement; Nerve Net; Neural Pathways; Optics and Photonics; Picrotoxin; Pyridazines; Reaction Time; Synaptic Transmission; Thy-1 Antigens; Transduction, Genetic; Video Recording; Wakefulness

Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund's adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hypersensitivity. Intrathecal pretreatment or post-treatment of a 5-HT3 receptor antagonist (Y-25130 or ondansetron) blocked the SP-induced hyperalgesia. The SP-induced hyperalgesia was both GABA(A) and NMDA receptor-dependent after pre- and post-treatment with selective antagonists at the spinal level. A microinjection of SP into the RVM also led to increased NMDA NR1 receptor subunit phosphorylation in spinal cord tissue. The GABA(A) receptor-mediated hyperalgesia involved a shift in the anionic gradient in dorsal horn nociceptive neurons and an increase in phosphorylated NKCC1 protein (isoform of the Na-K-Cl cotransporter). Following a low dose of SP infused into the RVM, intrathecal muscimol (GABA(A) agonist) increased SP-induced thermal hyperalgesia, phosphorylated NKCC1 protein expression, and NMDA NR1 subunit phosphorylation in the spinal cord. The thermal hyperalgesia was blocked by intrathecal gabazine, the GABA(A) receptor antagonist, and MK-801, the NMDA receptor channel blocker. These findings indicate that NK-1 receptors in the RVM are involved in SP-induced thermal hyperalgesia, this hyperalgesia is 5-HT3-receptor dependent at the spinal level, and involves the functional interaction of spinal GABA(A) and NMDA receptors.

Topics: Animals; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Freund's Adjuvant; GABA Agents; Hyperalgesia; In Vitro Techniques; Inflammation; Male; Medulla Oblongata; Membrane Potentials; Microinjections; Muscimol; Ondansetron; Oxazines; Pain Measurement; Pain Threshold; Posterior Horn Cells; Pyridazines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Neurokinin-1; Serotonin Antagonists; Spinal Cord; Substance P; Tryptophan; Up-Regulation

The Spontaneously Hypertensive rat (SHR) has been previously shown to have a host of neurochemical differences compared with their normotensive counterpart, the Wistar-Kyoto (WKY) rat. Using quantitative receptor autoradiography, the density of GABA(A) and NMDA receptors and [3H]cGMP binding within the locus coeruleus (LC) and central pontine grey (CGPn) were compared in the SHR and WKY rat using the radioligands [3H]SR95531, [3H]MK-801 and [3H]cGMP respectively. It was found that [3H]SR95531 binding was significantly greater in both the LC and CGPn of the SHR compared with the WKY rat (unpaired t test; P < 0.05). Greater binding densities of [3H]MK-801 and [3H]cGMP were also observed in the LC of the SHR compared with the WKY rat; however, no differences in the binding density of these two ligands were observed in the CGPn. It is suggested that these neurochemical differences within the LC of the SHR may relate to phenotypic differences between SHR and WKY rats that have previously been reported.

Topics: Animals; Autoradiography; Brain Stem; Cyclic GMP; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; GABA Antagonists; Male; Pyridazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, GABA-A; Species Specificity

To investigate the modulatory roles of central gamma-aminobutyric acid (GABA)A and GABAB receptors in the regulation of basal and stress-induced plasma interleukin-6 (IL-6) levels, we examined the effects of i.c.v. injection of GABA receptor agonists and antagonists on basal and restraint stress-induced plasma IL-6 levels in mice. Muscimol (20-200 ng), a GABAA receptor agonist, and baclofen (5-20 ng), a GABAB receptor agonist, injected i.c.v. did not affect the basal levels of plasma IL-6. In the restraint-stressed animals, muscimol and baclofen inhibited the stress-induced plasma IL-6 levels from the dose of 50 and 15 ng, respectively. 2-(3-Carboxyl)-3-amino-6-(4-methoxyphenyl)-pyridazinium bromide (SR-95,531; 0.3-10 ng), a GABAA receptor antagonist, and 2-hydroxysaclofen (1-10 microgram), a GABAB receptor antagonist, injected i.c.v. increased both the basal and the restraint stress-induced plasma IL-6 levels. The i.p. pretreatment of animals with 6-hydroxydopamine (100 mg/kg) for 3 days significantly inhibited SR-95,531 (3 ng i.c.v.)- but not 2-hydroxysaclofen (10 microg i.c.v.)-induced increase in the basal plasma IL-6 levels. These data suggest that central GABAA and GABAB receptors are involved in the suppressive modulation of basal and restraint stress-induced plasma IL-6 levels in mice.

Topics: Animals; Baclofen; Brain; Dizocilpine Maleate; GABA Modulators; Injections, Intraventricular; Interleukin-6; Male; Mice; Mice, Inbred ICR; Muscimol; Oxidopamine; Pyridazines; Receptors, GABA-A; Receptors, GABA-B; Stress, Physiological