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.     

Effects of asenapine on prefrontal N‐methyl‐D‐aspartate receptor‐mediated transmission: Involvement of dopamine D1 receptors

Asenapine is a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder. Like clozapine, asenapine facilitates cortical dopaminergic and N‐methyl‐D ‐aspartate (NMDA) receptor‐mediated transmission in rats. The facilitation of NMDA‐induced currents in cortical pyramidal cells by clozapine is dependent on dopamine and D₁ receptor activation. Moreover, previous results show that clozapine prevents and reverses the blockade of NMDA‐induced currents and firing activity in the pyramidal cells by the noncompetitive NMDA receptor antagonist phencyclidine (PCP). Here, we investigated the effects of asenapine in these regards using intracellular electrophysiological recording in vitro. Asenapine (5 nM) significantly facilitated NMDA‐induced currents (162 ± 15% of control) in pyramidal cells of the medial prefrontal cortex (mPFC). The asenapine‐induced facilitation was blocked by the D₁ receptor antagonist SCH23390 (1 μM). Furthermore, the PCP‐induced blockade of cortical NMDA‐induced currents was effectively reversed by 5 nM asenapine. Our results demonstrate a clozapine‐like facilitation of cortical NMDA‐induced currents by asenapine that involves prefrontal dopamine and activation of D₁ receptors. Asenapine and clozapine also share the ability to reverse functional PCP‐induced hypoactivity of cortical NMDA receptors. The ability of asenapine to increase both cortical dopaminergic and NMDA receptor‐mediated glutamatergic transmission suggests that this drug may have an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms. Synapse 64:870–874, 2010. © 2010 Wiley‐Liss, Inc.     

Phencyclidine (PCP)-Induced Disruption in Cognitive Performance is Gender-Specific and Associated with a Reduction in Brain-Derived Neurotrophic Factor (BDNF) in Specific Regions of the Female Rat Brain

Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n = 8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p < 0.05), motor cortex (p < 0.01), orbital cortex (p < 0.01), olfactory bulb (p < 0.05), retrosplenial cortex (p < 0.001), frontal cortex (p < 0.01), parietal cortex (p < 0.01), CA1 (p < 0.05) and polymorphic layer of dentate gyrus (p < 0.05) of the hippocampus and the central (p < 0.01), lateral (p < 0.05) and basolateral (p < 0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p < 0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.     

D1 dopamine and NMDA receptors interactions in the medial prefrontal cortex: Modulation of spatial working memory in rats

Dopamine (DA) and N-methyl-d-aspartate (NMDA) receptors seem to be critically involved in working memory processing in the medial prefrontal cortex (mPFC). Effects of NMDA receptors blockade on dopamine D₁ receptors activation in the mPFC on spatial working memory was investigated. Adult male Wistar rats, well trained in an eight-arm radial maze and bilaterally cannulated in the mPFC, received intracortical administrations of saline (SAL) or SKF-38393 (DA D₁ receptor agonist) followed, 10 min later, by MK-801 (non-competitive NMDA receptor antagonist). They were tested in 1 h delayed tasks after 5 min of the second administration. SKF-38393 (0.56 and 1.8 μg) was disruptive to working memory, increasing significantly the number of errors in the 1 h post-delay performance when administered into the mPFC. MK-801, at doses with no significant effects alone (0.32 or 1.0 μg), reduced significantly the disruptive effect of 0.56 μg SKF-38393. These results showed that the disruptive effect of DA D₁ receptors activation in the mPFC on working memory was significantly reduced by an open-channel NMDA receptor blockade, suggesting that the processing of working memory in the mPFC involving DA D₁ receptors depend, at least in part, of NMDA receptors activity in this cortical area.     

Neonatal exposure to MK‐801 reduces mRNA expression of mGlu3 receptors in the medial prefrontal cortex of adolescent rats

Schizophrenia is considered as a “neurodegenerative” and “neurodevelopmental” disorder, the pathophysiology of which may include hypofunction of the N‐methyl‐d ‐aspartate receptor (NMDA‐R) or subsequent pathways. Accordingly, administration of NMDA‐R antagonists to rodents during the perinatal period may emulate some core pathophysiological aspects of schizophrenia. The effect of 4‐day (postnatal day; PD 7–10) administration of MK‐801, a selective NMDA‐R antagonist, on gene expression in the medial prefrontal cortex (mPFC), hippocampus, and amygdala was evaluated using quantitative polymerase chain reaction methods. Specifically, we sought to determine whether genes related to Glu transmissions, for example those encoding for NMDA‐Rs, metabotropic Glu receptors (mGluRs), or Glu transporters, were altered by neonatal treatment with MK‐801. Model rats showed downregulation of the mGluR3 subtype in the mPFC around puberty, especially at PD 35 in response to MK‐801 or during ontogenesis without pharmacological manipulations. Genes encoding for other mGluRs subtypes, that is NMDA‐Rs and Glu transporters, were not affected by the neonatal insult. These results suggest that NMDA‐R antagonism in the early course of development modulates the expression of mGluR3 in mPFC around puberty. Thus, mGluR3 may serve as a potential target to prevent the onset and progression of schizophrenia. Synapse 68:202–208, 2014 . © 2014 Wiley Periodicals, Inc.     

Subchronic treatment with phencyclidine in adolescence leads to impaired exploratory behavior in adult rats without altering social interaction or N‐methyl‐D‐aspartate receptor binding levels

Although both the onset of schizophrenia and human phencyclidine (PCP) abuse typically present within the interval from adolescence to early adulthood, the majority of preclinical research employing the PCP model of schizophrenia has been conducted on neonatal or adult animals. The present study was designed to evaluate the behavioral and neurochemical sequelae of subchronic exposure to PCP in adolescence. Male 35–42‐day‐old Sprague Dawley rats were subcutaneously administered either saline (10 ml · kg^?1) or PCP hydrochloride (10 mg · kg^?1) once daily for a period of 14 days (n = 6/group). The animals were allowed to withdraw from treatment for 2 weeks, and their social and exploratory behaviors were subsequently assessed in adulthood by using the social interaction test. To examine the effects of adolescent PCP administration on the regulation of N‐methyl‐D‐aspartate receptors (NMDARs), quantitative autoradiography was performed on brain sections of adult, control and PCP‐withdrawn rats by using 20 nM ³H‐MK‐801. Prior subchronic exposure to PCP in adolescence had no enduring effects on the reciprocal contact and noncontact social behavior of adult rats. Spontaneous rearing in response to the novel testing arena and time spent investigating its walls and floor were reduced in PCP‐withdrawn animals compared with control. The long‐term behavioral effects of PCP occurred in the absence of persistent deficits in spontaneous locomotion or self‐grooming activity and were not mediated by altered NMDAR density. Our results document differential effects of adolescent PCP administration on the social and exploratory behaviors of adult rats, suggesting that distinct neurobiological mechanisms are involved in mediating these behaviors. © 2014 Wiley Periodicals, Inc.     

Chronic phencyclidine induces behavioral sensitization and apoptotic cell death in the olfactory and piriform cortex

In this study, we tested the hypothesis that chronic administration of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist, would cause a long-lasting behavioral sensitization associated with neuronal toxicity. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once a day for 5 days, withdrawn for 72 hr, placed in locomotor activity chambers, and challenged with 3.2 mg/kg PCP. Following assessment of locomotor activity, the rats were killed and their brains processed for analysis of apoptosis by either electron microscopy or terminal dUTP nick-end labeling (TUNEL). In study I, PCP challenge produced a much more robust and long-lasting increase in locomotor activity in rats chronically treated with PCP than in those chronically treated with saline. In study II, clozapine pretreatment blunted the degree of sensitization caused by PCP. In study I, a marked increase in TUNEL-positive neurons was found in layer II of the olfactory tubercle and piriform cortex of rats chronically treated with PCP. Many of these neurons had crescent-shaped nuclei consistent with apoptotic condensation and margination of nuclear chromatin under the nuclear membrane. Acute PCP had no effect. Electron microscopy revealed that PCP caused nuclear condensation and neuronal degeneration consistent with apoptosis. Cell counts in layer II of the piriform cortex revealed that chronic PCP treatment resulted in the loss of almost 25% of the cells in this region. However, an increase in glial fibrillary acidic protein (GFAP)-positive cells in the molecular layer suggests that this neurotoxicity also may involve necrosis. In study II, the PCP-induced neuronal degeneration was essentially completely abolished by clozapine pretreatment. This pattern of degeneration was found to coincide with the distribution of the mRNA of the NR1 subunit of the NMDA receptor. The relevance of these data to a PCP model of chronic NMDA receptor hypofunction is discussed. J. Neurosci. Res. 52:709–722, 1998. © 1998 Wiley-Liss, Inc.     

Effects of the serotonin2A/2C receptor agonist and antagonist on phencyclidine-induced dopamine release in rat medial prefrontal cortex

1. Systemic administration of PCP (7.5 mg/kg, i.p.) produced a greater increase in extracellular DA levels in the mPFC than in the STR and NAC, as determined by in vivo microdialysis of awake, freely moving rats. Preferential activation by PCP of prefrontal DA neurons may be, at least in part, the basis for the pathophysiology of PCP-induced psychosis as well as schizophrenia. 2. Recent studies suggest a possible involvement of 5-HT2A receptors in the pathophysiology and treatment of schizophrenia. This study was designed to examine whether and how 5-HT2A receptors modulate PCP-induced DA release in the mPFC. 3. The 5-HT2A/2C receptor agonist (+/-)-DOI (2.5 mg/kg, but not 0.75 mg/kg, i.p.), administered 60 min prior to PCP, significantly attenuated the PCP-induced increase in extracellular DA levels. Pretreatment of the 5-HT2A/2C receptor antagonist ritanserin (1.0 and 5.0 mg/kg, i.p.), administered 60 min prior to PCP, did not influence the PCP-induced increase. When administered alone, neither DOI (2.5 mg/kg) nor ritanserin (1.0 mg/kg) affected basal extracellular DA levels in the mPFC. 4. The NMDA receptor antagonist MK-801 (1.0 mg/kg, i.p.) also increased extracellular DA levels in the mPFC, but this effect was unaffected by pretreatment with DOI (2.5 mg/kg). 5. These results suggest that the stimulation of 5-HT2A/2C receptors may inhibit DA release in the mPFC when it is facilitated by PCP. Other than the NMDA receptor-mediated mechanism may also be involved in the neurochemical interaction between 5-HT2A receptors and PCP in the mPFC.     

PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats

Persistent suppression of N-methyl-d-aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that chronic NMDA receptor antagonism in animals may represent a useful model of neurobiological and related cognitive deficits in schizophrenia. Schizophrenia is associated with impairments in frontal lobe-dependent cognitive functions, including working memory and attentional shifting. Deficits in attention and executive function have not been well characterized in animal models of schizophrenia using chronic NMDA receptor antagonist administration. We investigated whether subchronic systemic administration of the NMDA receptor antagonist phencyclidine (PCP) to rats followed by a drug washout period would produce enduring cognitive deficits on an attentional set-shifting task. The task is functionally analogous to a sensitive test of frontal function in humans and non-human primates. Subchronic PCP administration selectively impaired extradimensional shift learning without affecting other discrimination or reversal tasks. Moreover, acute treatment with the PDE10A inhibitor papaverine immediately prior to testing attenuated the PCP-induced deficits in extradimensional shift learning across a range of doses. These data suggest that subchronic PCP administration may model effectively some of the cognitive deficits that are observed in schizophrenia, and that PDE10A inhibition may be an effective therapeutic route to improve executive function deficits associated with schizophrenia.     

Alpha and beta noradrenergic mediation of NMDA glutamatergic effects on lordosis behaviour and plasmatic LH concentrations in the primed female rat

In previous studies we have found that blockade of NMDA (N-Methyl-d-Aspartic-Acid)-type glutamatergic receptor with intracerebroventricular (ICV) selective drugs induces an inhibition of lordosis in ovariectomized (OVX) estrogen primed rats receiving progesterone or luteinizing hormone releasing hormone (LHRH). By the opposite way, stimulation with NMDA in OVX estrogen primed rats induced a significant increase of lordosis. In the present study the action of an α1-noradrenergic antagonist, HEAT (BE 2254/2-beta-4-Hydroxyphenyl-Ethyl-Aminomethyl-1-Tetralone), and Metoprolol, a β-noradrenergic antagonist, were studied injecting them ICV previously to NMDA administration in treated OVX estrogen primed rats. In experiment 1, the enhancing effect on lordosis induced by NMDA at high dose (1 μg) was abolished by HEAT administration (P < 0.001 for 3 and 6 μg), and the LH plasma levels were decreased only with the higher dose (P < 0.05), suggesting that behavioral effects are quite more sensitive to the α-blockade than hormonal effects. In experiment 2, enhancing effects on lordosis behavior were not observed with neither the NMDA at low dose (0.5 μg) nor the metoprolol alone (5.71 μg), but a synergism was observed when both were simultaneously administered (P < 0.001). The LH plasma levels were increased by Metoprolol alone (P < 0.05), and powered by the combination with NMDA at low dose (P < 0.01 vs. SAL and NMDA alone); no differences were observed with Metoprolol. LH increase was observed with Metoprolol even without behavioural modifications. These findings strongly suggest that facilitatory and inhibitory effects of NMDA in this model are mediated by α- and β-adrenergic transmission in both, behavioral and hormonal effects.     

Evaluation of the antipsychotic effect of bi-acetylated l-stepholidine (l-SPD-A), a novel dopamine and serotonin receptor dual ligand

Bi-acetylated l-stepholidine (l-SPD-A), a novel derivate of l-stepholidine (l-SPD), possesses a pharmacological profile of D₁/5-HT_1A agonism and D₂ antagonism. In the present study, we examined the potential antipsychotic effect of l-SPD-A in a phencyclidine (PCP)-induced rat model of schizophrenia. Pretreatment with l-SPD-A blocked acute PCP-induced hyperlocomotion and reversed prepulse inhibition (PPI) deficits. Chronic l-SPD-A administration (i.p., 10 mg/kg/day for 14 days) improved social interaction and novel object recognition impairments in rats that were pretreated with PCP (i.p., 5 mg/kg/day for 14 days). Moreover, in a conditioned avoidance response (CAR) test, l-SPD-A, with either i.p. or oral administration, significantly decreased active avoidance without affecting the escape response of rats. Importantly, compared to that of the parent compound l-SPD, l-SPD-A showed stronger suppression of CARs. Lastly, using a [³⁵S]GTPγS binding assay, we demonstrated that l-SPD-A improved impaired dopamine D₁ receptor function in the prefrontal cortex (PFC) in chronic PCP-treated rats. Taken together, these results indicate that l-SPD-A was not only effective against the hyperactivity, but also improved the sensorimotor gating deficit, social withdrawal and cognitive impairment in an animal model of schizophrenia. The present data suggest that l-SPD-A, a potential neurotransmitter stabilizer, is a promising novel candidate drug for the treatment of schizophrenia.     

High‐frequency stimulation of the medial prefrontal cortex decreases cellular firing in the dorsal raphe

High‐frequency deep brain stimulation (HFS‐DBS) of the subcallosal cingulate (SCC) region has been investigated as a treatment for refractory forms of depression with a ~50% remission rate in open label studies. However, the therapeutic mechanisms of DBS are still largely unknown. Using anaesthetized Sprague Dawley rats, we recorded neuronal spiking activity in 102 neurons of the dorsal raphe (DR) before, during and after the induction of a 5‐min HFS train in the infralimbic region (IL) of the medial prefrontal cortex (mPFC), the rodent homologue of the human SCC. The majority of DR cells (82%) significantly decreased firing rate during HFS (P < 0.01, 55.7 ± 4.5% of baseline, 35 rats). To assess whether mPFC‐HFS mediates inhibition of DR cellular firing by stimulating local GABAergic interneurons, the GABA_A antagonist bicuculline (Bic, 100 μm ) was injected directly into the DR during HFS. Neurons inhibited by HFS recovered their firing rate during Bic+HFS (P < 0.01, n = 15, seven rats) to levels not different from baseline. Cells that were not affected by HFS did not change firing rate during Bic+HFS (P = 0.968, n = 7, three rats). These results indicate that blocking GABA_A reverses HFS‐mediated inhibition of DR neurons. As the cells that were not inhibited by HFS were also unaffected by HFS+Bic, they are probably not innervated by local GABA. Taken together, our results suggest that mPFC‐HFS may exert a preferential effect on DR neurons with GABA_A receptors.     

Behavioral effects of non-viral mediated RNA interference of synapsin II in the medial prefrontal cortex of the rat

Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Researchers have demonstrated reductions in synapsin II mRNA and protein in post-mortem prefrontal cortex and hippocampus samples from patients with schizophrenia. Synapsin II protein expression has been shown to be regulated by dopamine D(1) and D(2) receptor activation. Furthermore, behavioral testing of the synapsin II knockout mouse has revealed a schizophrenic-like behavioral phenotype in this mutant strain, suggesting a relationship between dysregulated and/or reduced synapsin II and schizophrenia. However, it remains unknown the specific regions of the brain of which perturbations in synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with a selective knock-down of synapsin II in the medial prefrontal cortex through the use of siRNA technology. Two weeks after continuous infusion of synapsin II siRNAs, animals were examined for the presence of a schizophrenic-like behavioral phenotype. Our results reveal that rats with selective reductions in medial prefrontal cortical synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), hyperlocomotion, and reduced social behavior. These results implicate a role for decreased medial prefrontal cortical synapsin II levels in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that increasing synapsin II levels in the medial prefrontal cortex may potentially serve as a novel therapeutic target for this devastating disorder.     

Chronic phencyclidine treatment increases dendritic spine density in prefrontal cortex and nucleus accumbens neurons

We examined whether repeated exposure to the noncompetitive NMDA receptor antagonist phencyclidine (PCP) produces enduring changes in dendritic structure in a manner similar to the stimulants cocaine and amphetamine. Adult rats were treated with i.p. injections of PCP (5 mg/kg) or saline, twice a day, for 5 consecutive days, for a total of 4 weeks. One month after the last injection, their brains were removed and processed for Golgi-Cox staining. Prior exposure to PCP increased dendritic spine density in the mPFC and NAcc core, but not in the parietal cortex. These findings, which are similar to those observed after chronic treatment with cocaine and amphetamine, raise the possibility that, despite differences in their mechanisms of action, PCP and stimulant drugs may induce some of their enduring effects via common processes.     

A primate model of schizophrenia using chronic PCP treatment

To establish a primate animal model of schizophrenia with negative symptoms, the behavioral effects of chronic phencyclidine (PCP) and additional acute methamphetamine (MAP) administration were investigated in six monkeys. The results indicate that chronic PCP treatment induced a significant decrease in all categories of social behaviors, and that the chronic PCP monkeys also spent less time in proximity to other monkeys than the control monkeys. Acute MAP injection to the chronic PCP monkeys exacerbated the behavioral effects of PCP. The results suggest that these monkeys can be used as a primate model of schizophrenia with negative symptoms.     

Influence of Chronic Nicotine Administration on Cerebral Type 1 Cannabinoid Receptor Binding: An In Vivo Micro-PET Study in the Rat Using [<Superscript>18</Superscript>F]MK-9470

Several lines of evidence suggest a functional interaction between central nicotinic and endocannabinoid systems. Furthermore, type 1 cannabinoid receptor (CB1R) antagonism is evaluated as antismoking therapy, and nicotine usage can be an important confound in positron emission tomography (PET) imaging studies of the CB1R. We evaluated CB1R binding in the rat brain using the PET radioligand [¹⁸F]MK-9470 after chronic administration of nicotine. Twelve female Wistar rats were scanned at baseline and after chronic administration of either nicotine (1 mg/kg; 2 weeks daily intraperitoneal (IP)) or saline as control. In vivo micro-PET images of CB1R binding were anatomically standardized and analyzed by voxel-based statistical parametric mapping and a predefined volume-of-interest approach. We did not observe changes in [¹⁸F]MK-9470 binding (p _height < 0.001 level; uncorrected) on a group basis in either condition. Only at a less stringent threshold of p _height < 0.005 (uncorrected) was a modest increase observed in tracer binding in the cerebellum for nicotine (peak voxel value + 6.8%, p _cluster = 0.002 corrected). In conclusion, chronic IP administration of nicotine does not produce major cerebral changes in CB1R binding of [¹⁸F]MK-9470 in the rat. These results also suggest that chronic nicotine usage is unlikely to interfere with human PET imaging using this radioligand.     

Neurochemical and behavioural effects of acute and chronic memantine administration in rats: Further support for NMDA as a new pharmacological target for the treatment of depression?

A growing body of evidence has pointed to the NMDA receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the acute and chronic treatment with memantine and imipramine in rats. To this aim, rats were acutely or chronically for 14 days once a day treated with memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. The acute treatment with memantine at all doses and imipramine at doses (20 and 30 mg/kg) reduced immobility time of rats compared to the saline group (p < 0.05), without affecting spontaneous locomotor activity and chronic treatment with memantine and imipramine, at all doses tested, reduced immobility time of rats compared to the saline group (p < 0.05), without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine- and memantine-treated rats by ELISA sandwich assay. Interesting enough, acute administration, but not chronic administration of memantine at higher dose (20 mg/kg) increased BDNF protein levels in the rat hippocampus (p < 0.05). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of depression.     

Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-Methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex.

BACKGROUND: Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC). METHODS: In freely moving rats, we measured the effects of the positive modulator of mGlu5 receptor 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) alone or in combination with the NMDA antagonist MK801 on 1) spontaneous firing and bursting of medial PFC (mPFC) neurons, and 2) dopamine release as measured by microdialysis in the mPFC and nucleus accumbens (NAc). RESULTS: The predominant effect of CDPPB on mPFC neurons was excitatory, leading to an overall excitatory population response. Pretreatment with CDPPB prevented MK801-induced excessive firing and reduced spontaneous bursting. In contrast, CDPPB had no significant effect on basal dopamine release as compared with control rats and did not alter MK801-induced activation of dopamine release in the mPFC and NAc. CONCLUSIONS: These results show that positive modulation of mGlu5 receptors reverses the effects of noncompetitive NMDA antagonists on cortical neuronal firing without affecting dopamine neurotransmission. Thus, these compounds may be effective in ameliorating PFC mediated behavioral abnormalities that results from NMDA receptor hypofunction.     

C-FOS ANTISENSE OLIGODEOXYNUCLEOTIDE OFFSETS BEHAVIORAL NOCICEPTIVE RESPONSES AND BOTH UP-REGULATIONS OF C-FOS PROTEIN AND DYNORPHIN A (1-8) IN DORSAL HORN: A STUDY USING THE FORMALIN TEST IN RATS

The formalin test was used to elicit acute and chronic pain in rats, and antisense oligodeoxynucleotide (AS-ODN) was used as a tool to modulate the expression of nociceptive behavioral and neurochemical responses. AS-ODN complementary to c-Fos mRNA was administered intrathecally (i.t.) 4 h before formalin injection in the experimental group. Normal saline or reverse AS-ODN was pre-administered i.t. at the same time in two control groups (saline and reverse AS-ODN). The results showed that the acute phase of nociceptive behavior showed no change by AS-ODN administration, whereas the tonic phase of nociceptive licking and biting behavior was significantly suppressed by AS-ODN as compared with the saline or the reverse AS-ODN group, respectively (p < .05 and p < .01). At the same time, both Fos-like immunoreactive (FLI) neurons and density of dynorphin-like immunoreactivities (DLI) were decreased significantly (p < .05 and p < .01) in the AS-ODN group as compared with that in two control groups. The results indicate that the long-lasting nociceptive responses elicited by sustained noxious inputs are based on the up-regulation of c-Fos gene expression, which in turn induces the upregulation of Dyn A production. It is proposed that intensified Dyn A production in the dorsal horn may be pivotal for the appearance of chronic pain.     

Mapping Brain Regions in Which Deep Brain Stimulation Affects Schizophrenia-Like Behavior in Two Rat Models of Schizophrenia

Background and ObjectivesThe development of more efficient treatment remains a major unmet need in the realm of schizophrenia disease. Using the maternal immune stimulation and the pubertal cannabinoid administration rat model of schizophrenia, the present study aimed at testing the hypothesis that deep brain stimulation (DBS) serves as a novel therapeutic technique for this disorder.MethodsAdult offspring of dams, treated with the immune activating agent poly I:C (4 mg/kg, n = 50) or saline (n = 50), underwent bilateral stereotactic electrode implantation into one of the following brain regions: subthalamic nucleus (STN, n = 12/10), entopeduncularis nucleus (EP, n = 10/11), globus pallidus (GP, n = 10/10), medial prefrontal cortex (mPFC, n = 8/8), or dorsomedial thalamus (DM, n = 10/11). Adult rats treated with the CB1 receptor agonist WIN 55,212-2 (WIN, n = 16) or saline (n = 12) during puberty were bilaterally implanted with electrodes into either the mPFC (n = 8/6) or the DM (n = 8/6). After a post-operative recovery period of one week, all rats were tested on a well-established cross-species phenomenon that is disrupted in schizophrenia, the pre-pulse inhibition (PPI) of the acoustic startle reflex (ASR) under different DBS conditions.ResultsPoly I:C induced deficits in PPI of the ASR were normalized upon DBS. DBS effects depended on both stimulation target and stimulation parameters. Most prominent effects were found under DBS at high frequencies in the mPFC and DM. These effects were replicated in the pubertal WIN administration rat model of schizophrenia.ConclusionsBrain regions, in which DBS normalized PPI deficits, might be of therapeutic relevance to the treatment of schizophrenia. Results imply that DBS could be considered a plausible therapeutic technique in the realm of schizophrenia disease.