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1.
Neuropharmacology ; 213: 109079, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35561792

ABSTRACT

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.


Subject(s)
Dizocilpine Maleate , Psychotic Disorders , Animals , Dizocilpine Maleate/pharmacology , GABAergic Neurons/metabolism , Mice , Mice, Knockout , N-Methylaspartate , Phencyclidine/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism
2.
Front Neuroanat ; 11: 87, 2017.
Article in English | MEDLINE | ID: mdl-29033796

ABSTRACT

The prefrontal cortex (PFC) is deeply involved in higher brain functions, many of which are altered in psychiatric conditions. The PFC exerts a top-down control of most cortical and subcortical areas through descending pathways and is densely innervated by axons emerging from the brainstem monoamine cell groups, namely, the dorsal and median raphe nuclei (DR and MnR, respectively), the ventral tegmental area and the locus coeruleus (LC). In turn, the activity of these cell groups is tightly controlled by afferent pathways arising from layer V PFC pyramidal neurons. The reciprocal connectivity between PFC and monoamine cell groups is of interest to study the pathophysiology and treatment of severe psychiatric disorders, such as major depression and schizophrenia, inasmuch as antidepressant and antipsychotic drugs target monoamine receptors/transporters expressed in these areas. Here we review previous reports examining the presence of monoamine receptors in pyramidal and GABAergic neurons of the PFC using double in situ hybridization. Additionally, we present new data on the quantitative layer distribution (layers I, II-III, V, and VI) of monoamine receptor-expressing cells in the cingulate (Cg), prelimbic (PrL) and infralimbic (IL) subfields of the medial PFC (mPFC). The receptors examined include serotonin 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3, dopamine D1 and D2 receptors, and α1A-, α1B-, and α1D-adrenoceptors. With the exception of 5-HT3 receptors, selectively expressed by layers I-III GABA interneurons, the rest of monoamine receptors are widely expressed by pyramidal and GABAergic neurons in intermediate and deep layers of mPFC (5-HT2C receptors are also expressed in layer I). This complex distribution suggests that monoamines may modulate the communications between PFC and cortical/subcortical areas through the activation of receptors expressed by neurons in intermediate (e.g., 5-HT1A, 5-HT2A, α1D-adrenoceptors, dopamine D1 receptors) and deep layers (e.g., 5-HT1A, 5-HT2A, α1A-adrenoceptors, dopamine D2 receptors), respectively. Overall, these data provide a detailed framework to better understand the role of monoamines in the processing of cognitive and emotional signals by the PFC. Likewise, they may be helpful to characterize brain circuits relevant for the therapeutic action of antidepressant and antipsychotic drugs and to improve their therapeutic action, overcoming the limitations of current drugs.

3.
J Psychiatry Neurosci ; 42(1): 48-58, 2017 01.
Article in English | MEDLINE | ID: mdl-27391101

ABSTRACT

BACKGROUND: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. METHODS: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. RESULTS: We found elevated postpubertal N-methyl-D-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. LIMITATIONS: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology. CONCLUSION: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.


Subject(s)
Aging/physiology , DiGeorge Syndrome/physiopathology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Sensory Gating/physiology , 3,4-Dihydroxyphenylacetic Acid/metabolism , Aging/drug effects , Animals , Auditory Perception/physiology , Corpus Striatum/metabolism , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem , Excitatory Amino Acid Antagonists/pharmacology , Male , Mice, Inbred C57BL , Motor Activity/drug effects , Prefrontal Cortex/metabolism , Receptors, AMPA/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Reflex, Startle/physiology
4.
Nat Rev Drug Discov ; 16(1): 1-2, 2017 01.
Article in English | MEDLINE | ID: mdl-27811930

ABSTRACT

Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.


Subject(s)
Antidepressive Agents/pharmacology , Antipsychotic Agents/pharmacology , Mental Disorders/physiopathology , Neural Pathways/physiopathology , Antidepressive Agents/therapeutic use , Antipsychotic Agents/therapeutic use , Depressive Disorder/drug therapy , Depressive Disorder/physiopathology , Drug Industry , Humans , Schizophrenia/drug therapy , Schizophrenia/physiopathology
5.
Cereb Cortex ; 27(6): 3125-3139, 2017 06 01.
Article in English | MEDLINE | ID: mdl-27252352

ABSTRACT

The prefrontal cortex (PFC) is enriched in several serotonin receptors, including 5-HT1A-R, 5-HT2A-R, and 5-HT3-R. These receptors modulate PFC activity due to their expression in large neuronal populations (5-HT1A-R, 5-HT2A-R) or in selected GABAergic populations (5-HT3-R). They are also relevant for antidepressant and antipsychotic drug action. Less is known about the localization of 5-HT2C-R, for which atypical antipsychotics show high affinity. Here, we report on the cellular distribution of 5-HT2C-R in rat PFC and striatum, using double in situ hybridization histochemistry. In PFC, 5-HT2C-R are expressed in pyramidal (VGLUT1-positive) and GABAergic (GAD-positive) neurons, including parvalbumin-positive neurons. There is a marked dorso-ventral gradient in the proportion of VGLUT1-positive cells expressing 5-HT2C-R (9% in the cingulate cortex, 61% in the tenia tecta and 66% in the piriform cortex), less marked for GABAergic neurons (13-27%). There is also a laminar gradient, with more cells expressing 5-HT2C-R in deep (V-VI) than in intermediate (II-III) layers. In common with 5-HT3-R, layer I GABAergic cells express 5-HT2C-R. The proportion of 5-HT2C-R-expressing striatal neurons was 23% (dorsolateral caudate-putamen), 37% (ventromedial caudate-putamen), 53% (nucleus accumbens-core), and 49% (nucleus accumbens-shell). These results help to better understand the serotonergic modulation of PFC-based networks, including basal ganglia circuits, and atypical antipsychotic drug action.


Subject(s)
Corpus Striatum/cytology , GABAergic Neurons/metabolism , Prefrontal Cortex/cytology , Pyramidal Cells/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Analysis of Variance , Animals , Brain Mapping , Glutamate Decarboxylase/metabolism , Male , Parvalbumins/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2C/genetics , Vesicular Glutamate Transport Protein 1/metabolism
6.
Psychopharmacology (Berl) ; 233(11): 2151-2163, 2016 06.
Article in English | MEDLINE | ID: mdl-26983414

ABSTRACT

RATIONALE: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. OBJECTIVES: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. METHOD: Experiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAA receptor antagonism. Experiments 4-6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. RESULTS: In experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial α7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12. CONCLUSION: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.


Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/physiopathology , Gene Deletion , Prefrontal Cortex/physiopathology , Schizophrenia/genetics , Schizophrenia/physiopathology , Schizophrenic Psychology , Animals , Attention Deficit Disorder with Hyperactivity/psychology , Behavior, Animal/drug effects , Chromosome Deletion , Chromosome Disorders/genetics , Chromosomes, Human, Pair 15/genetics , Disease Models, Animal , Evoked Potentials, Auditory/drug effects , Extinction, Psychological/drug effects , GABA Antagonists/pharmacology , Humans , Intellectual Disability/genetics , Interneurons/drug effects , Male , Mice , Mice, Inbred C57BL , Pyramidal Cells/drug effects , Pyridazines/pharmacology , Reaction Time/drug effects , Receptors, GABA-A/drug effects , Reversal Learning/drug effects , Seizures/genetics
7.
Psychopharmacology (Berl) ; 232(21-22): 4085-97, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25943167

ABSTRACT

RATIONALE: N-methyl-D-aspartate receptor (NMDA-R) hypofunction has been proposed to account for the pathophysiology of schizophrenia. Thus, NMDA-R blockade has been used to model schizophrenia in experimental animals. Acute and repeated treatments have been successfully tested; however, long-term exposure to NMDA-R antagonists more likely resembles the core symptoms of the illness. OBJECTIVES: To explore whether schizophrenia-related behaviors are differentially induced by acute and subchronic phencyclidine (PCP) treatment in mice and to examine the neurobiological bases of these differences. RESULTS: Subchronic PCP induced a sensitization of acute locomotor effects. Spontaneous alternation in a T-maze and novel object recognition performance were impaired after subchronic but not acute PCP, suggesting a deficit in working memory. On the contrary, reversal learning and immobility in the tail suspension test were unaffected. Subchronic PCP significantly reduced basal dopamine but not serotonin output in medial prefrontal cortex (mPFC) and markedly decreased the expression of tyrosine hydroxylase in the ventral tegmental area. Finally, acute and subchronic PCP treatments evoked a different pattern of c-fos expression. At 1 h post-treatment, acute PCP increased c-fos expression in many cortical regions, striatum, thalamus, hippocampus, and dorsal raphe. However, the increased c-fos expression produced by subchronic PCP was restricted to the retrosplenial cortex, thalamus, hippocampus, and supramammillary nucleus. Four days after the last PCP injection, c-fos expression was still increased in the hippocampus of subchronic PCP-treated mice. CONCLUSIONS: Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects.


Subject(s)
Behavior, Animal/drug effects , Disease Models, Animal , Motor Activity/drug effects , Phencyclidine , Schizophrenia/physiopathology , Animals , Dopamine/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Memory, Short-Term/drug effects , Mice , Neostriatum/drug effects , Neostriatum/metabolism , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Reversal Learning/drug effects , Schizophrenia/chemically induced , Schizophrenia/metabolism
8.
Biol Psychiatry ; 76(12): 937-45, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25038984

ABSTRACT

BACKGROUND: The neurobiological basis of action of noncompetitive N-methyl-D-aspartate acid receptor (NMDA-R) antagonists is poorly understood. Electrophysiological studies indicate that phencyclidine (PCP) markedly disrupts neuronal activity with an overall excitatory effect and reduces the power of low-frequency oscillations (LFO; <4 Hz) in thalamocortical networks. Because the reticular nucleus of the thalamus (RtN) provides tonic feed-forward inhibition to the rest of the thalamic nuclei, we examined the effect of PCP on RtN activity, under the working hypothesis that NMDA-R blockade in RtN would disinhibit thalamocortical networks. METHODS: Drug effects (PCP followed by clozapine) on the activity of RtN (single unit and local field potential recordings) and prefrontal cortex (PFC; electrocorticogram) in anesthetized rats were assessed. RESULTS: PCP (.25-.5 mg/kg, intravenous) reduced the discharge rate of 19 of 21 RtN neurons to 37% of baseline (p < .000001) and the power of LFO in RtN and PFC to ~20% of baseline (p < .001). PCP also reduced the coherence between PFC and RtN in the LFO range. A low clozapine dose (1 mg/kg intravenous) significantly countered the effect of PCP on LFO in PFC but not in RtN and further reduced the discharge rate of RtN neurons. However, clozapine administration partly antagonized the fall in coherence and phase-locking values produced by PCP. CONCLUSIONS: PCP activates thalamocortical circuits in a bottom-up manner by reducing the activity of RtN neurons, which tonically inhibit thalamic relay neurons. However, clozapine reversal of PCP effects is not driven by restoring RtN activity and may involve a cortical action.


Subject(s)
GABAergic Neurons/drug effects , Hallucinogens/pharmacology , Phencyclidine/pharmacology , Thalamus/cytology , Action Potentials/drug effects , Analysis of Variance , Animals , Clozapine/pharmacology , GABA Antagonists/pharmacology , Male , Neural Pathways/drug effects , Neural Pathways/physiology , Parvalbumins/metabolism , Prefrontal Cortex/cytology , Rats , Rats, Wistar
9.
Psychopharmacology (Berl) ; 225(1): 61-74, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22820867

ABSTRACT

RATIONALE: Identifying the etiological factors in anxiety and depression is critical to develop more efficacious therapies. The inhibitory serotonin(1A) receptors (5-HT(1A)R) located on 5-HT neurons (autoreceptors) limit antidepressant responses and their expression may be increased in treatment-resistant depressed patients. OBJECTIVES: Recently, we reported that intranasal administration of modified small interference RNA (siRNA) molecules targeting 5-HT(1A)R in serotonergic neurons evoked antidepressant-like effects. Here we extended this finding using marketed siRNAs against 5-HT(1A)R (1A-siRNA) to reduce directly the 5-HT(1A) autoreceptor expression and evaluate its biological consequences under basal conditions and in response to stressful situations. METHODS: Adult mice were locally infused with vehicle, nonsense siRNA, and 1A-siRNA into dorsal raphe nucleus (DR). 5-HT(1A)R knockout mice (1A-KO) were also used. Histological approaches, in vivo microdialysis, and stress-related behaviors were performed to assess the effects of 5-HT(1A) autoreceptor knockdown. RESULTS: Intra-DR 1A-siRNA infusion selectively reduced 5-HT(1A)R mRNA and binding levels and canceled 8-OH-DPAT-induced hypothermia. Basal extracellular 5-HT in medial prefrontal cortex (mPFC) did not differ among treatments. However, 1A-siRNA-treated mice displayed less immobility in the tail suspension and forced swim tests, as did 1A-KO mice. This was accompanied by a greater increase in prefrontal 5-HT release during tail suspension test. Moreover, intra-DR 1A-siRNA infusion augmented the increase of extracellular 5-HT in mPFC evoked by fluoxetine, up to the level in 1A-KO mice. CONCLUSION: Together with our previous report, the present results indicate that acute suppression of 5-HT(1A) autoreceptor expression evokes robust antidepressant-like effects, likely mediated by an increased capacity of serotonergic neurons to release 5-HT in stressful conditions.


Subject(s)
Fluoxetine/pharmacology , Receptor, Serotonin, 5-HT1A/genetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , 8-Hydroxy-2-(di-n-propylamino)tetralin/toxicity , Animals , Autoreceptors/genetics , Behavior, Animal/drug effects , Disease Models, Animal , Gene Knockdown Techniques , Hypothermia/chemically induced , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microdialysis , Prefrontal Cortex/metabolism , RNA, Messenger/metabolism , RNA, Small Interfering/administration & dosage , Raphe Nuclei , Stress, Psychological/therapy
10.
Int J Neuropsychopharmacol ; 16(5): 1139-51, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23195622

ABSTRACT

The prefrontal cortex (PFC) is involved in behavioural control and cognitive processes that are altered in schizophrenia. The brainstem monoaminergic systems control PFC function, yet the cells/networks involved are not fully known. Serotonin (5-HT) and norepinephrine (NE) increase PFC neuronal activity through the activation of α(1)-adrenergic receptors (α(1)ARs) and 5-HT(2A) receptors (5-HT(2A)Rs), respectively. Neurochemical and behavioural interactions between these receptors have been reported. Further, classical and atypical antipsychotic drugs share nm in vitro affinity for α(1)ARs while having preferential affinity for D(2) and 5-HT(2A)Rs, respectively. Using double in situ hybridization we examined the cellular expression of α(1)ARs in pyramidal (vGluT1-positive) and GABAergic (GAD(65/67)-positive) neurons in rat PFC and their co-localization with 5-HT(2A)Rs. α(1)ARs are expressed by a high proportion of pyramidal (59-85%) and GABAergic (52-79%) neurons. The expression in pyramidal neurons exhibited a dorsoventral gradient, with a lower percentage of α(1)AR-positive neurons in infralimbic cortex compared to anterior cingulate and prelimbic cortex. The expression of α(1A), α(1B) and α(1D) adrenergic receptors was segregated in different layers and subdivisions. In all them there is a high co-expression with 5-HT(2A)Rs (∼80%). These observations indicate that NE controls the activity of most PFC pyramidal neurons via α(1)ARs, either directly or indirectly, via GABAergic interneurons. Antipsychotic drugs can thus modulate the activity of PFC via α(1)AR blockade. The high co-expression with 5-HT(2A)Rs indicates a convergence of excitatory serotonergic and noradrenergic inputs onto the same neuronal populations. Moreover, atypical antipsychotics may exert a more powerful control of PFC function through the simultaneous blockade of α(1)ARs and 5-HT(2A)Rs.


Subject(s)
Neurons/metabolism , Prefrontal Cortex/cytology , Prefrontal Cortex/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Analysis of Variance , Animals , Gene Expression/physiology , Glucose Transporter Type 1/metabolism , Glutamate Decarboxylase/metabolism , Male , Neurons/cytology , Norepinephrine/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptors, Adrenergic, alpha-1/genetics
11.
Neuropharmacology ; 63(4): 675-84, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22652058

ABSTRACT

Most antidepressant treatments, based on serotonin (5-HT) and/or norepinephrine (NE) transporter blockade, show limited efficacy and slow onset of action, requiring the use of augmentation strategies. Here we report on a novel antidepressant strategy to selectively increase DA function in prefrontal cortex (PFC) without the potential tolerance problems associated to DA transporter blockade. This approach is based on previous observations indicating that extracellular DA in rat medial PFC (mPFC) - but not in nucleus accumbens (NAc) - arises from noradrenergic terminals and is sensitive to noradrenergic drugs. A low dose of reboxetine (3 mg/kg i.p.; NE reuptake inhibitor) non-significantly increased extracellular DA in mPFC. Interestingly, its combined administration with 5 mg/kg s.c. mirtazapine (non-selective α2-adrenoceptor antagonist) increased extracellular DA in mPFC (264 ± 28%), but not in NAc. Extracellular NE (but not 5-HT) in mPFC was also enhanced by the combined treatment (472 ± 70%). Repeated (×3) reboxetine + mirtazapine administration produced a moderate additional increase in mPFC DA and markedly reduced the immobility time (-51%) in the forced-swim test. Neurochemical and behavioral effects of the reboxetine + mirtazapine combination persisted in rats pretreated with citalopram (3 mg/kg, s.c.), suggesting its potential usefulness to augment SSRI effects. In situ hybridization c-fos studies were performed to examine the brain areas involved in the above antidepressant-like effects, showing changes in c-fos expression in hippocampal and cortical areas. BDNF expression was also increased in the hippocampal formation. Overall, these results indicate a synergistic effect of the reboxetine + mirtazapine combination to increase DA and NE function in mPFC and to evoke robust antidepressant-like responses.


Subject(s)
Adrenergic Uptake Inhibitors/therapeutic use , Adrenergic alpha-2 Receptor Antagonists/therapeutic use , Antidepressive Agents/therapeutic use , Depression/drug therapy , Dopamine/metabolism , Prefrontal Cortex/drug effects , Animals , Behavior, Animal/drug effects , Brain Chemistry/drug effects , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Depression/metabolism , Depression/pathology , Drug Synergism , Drug Therapy, Combination , Extracellular Fluid/metabolism , Gene Expression Regulation/drug effects , Male , Mianserin/analogs & derivatives , Mianserin/therapeutic use , Mirtazapine , Morpholines/therapeutic use , Organ Specificity , Prefrontal Cortex/metabolism , Prefrontal Cortex/pathology , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reboxetine
12.
Curr Top Med Chem ; 12(21): 2357-74, 2012.
Article in English | MEDLINE | ID: mdl-23279176

ABSTRACT

Schizophrenia has been historically characterized by the presence of positive symptomatology, however, decades of research highlight the importance of cognitive deficits in this disorder. At present, cognitive impairments remain one of the most important unmet therapeutic needs in schizophrenia. The prefrontal cortex (PFC) controls a large number of higher brain functions altered in a variety of psychiatric disorders, including schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of current atypical antipsychotics. Functional studies also show that these medications act at PFC level to increase dopamine neurotransmission in the mesocortical pathway. Here we focus on monoaminergic molecular targets that are actively being explored as potential therapeutic agents in the basic and clinical cognitive neuroscience research, to support the development of co-treatments used in conjunction with antipsychotic medications. These targets include dopamine and serotonin receptors in the prefrontal cortex, as well as elements of the noradrenergic system.


Subject(s)
Antipsychotic Agents/pharmacology , Dopamine/metabolism , Drug Design , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Synaptic Transmission/drug effects , Antipsychotic Agents/therapeutic use , Cognition Disorders/drug therapy , Humans , Prefrontal Cortex/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D3/metabolism , Schizophrenic Psychology , Synaptic Transmission/physiology
13.
Cereb Cortex ; 22(7): 1487-97, 2012 Jul.
Article in English | MEDLINE | ID: mdl-21893679

ABSTRACT

5-HT(1A) receptors (5-HT1AR) are expressed by pyramidal and γ-aminobutyric acidergic (GABAergic) neurons in medial prefrontal cortex (mPFC). Endogenous serotonin inhibits mPFC pyramidal neurons via 5-HT1AR while 5-HT1AR agonists, given systemically, paradoxically excite ventral tegmental area-projecting pyramidal neurons. This enhances mesocortical dopamine function, a process involved in the superior efficacy of atypical antipsychotic drugs on negative and cognitive symptoms of schizophrenia. Moreover, the 5-HT1AR-induced increase of pyramidal discharge may also contribute to the maintenance of activity patterns required for working memory, impaired in schizophrenia. Given the importance of these processes, we examined the neurobiological basis of pyramidal activation through 5-HT1AR using the prototypical agent 8-OH-DPAT. (±)8-OH-DPAT (7.5 µg/kg i.v.) increased discharge rate and c-fos expression in rat mPFC pyramidal neurons. Local blockade of GABA(A) inputs with gabazine (SR-95531) avoided (±)8-OH-DPAT-induced excitations of pyramidal neurons. Moreover, (±)8-OH-DPAT administration reduced the discharge rate of mPFC fast-spiking GABAergic interneurons at doses exciting pyramidal neurons. Activation of other 5-HT1AR subpopulations (raphe nuclei or hippocampus) does not appear to contribute to pyramidal excitations. Overall, the present data suggest a preferential action of (±)8-OH-DPAT on 5-HT1AR in GABAergic interneurons. This results in pyramidal disinhibition and subsequent downstream excitations of subcortical structures reciprocally connected with PFC, such as midbrain dopaminergic neurons.


Subject(s)
Action Potentials/physiology , Interneurons/physiology , Neural Pathways/physiology , Prefrontal Cortex/physiology , Pyramidal Cells/physiology , Serotonin 5-HT1 Receptor Agonists/pharmacology , gamma-Aminobutyric Acid/metabolism , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Action Potentials/drug effects , Animals , Male , Neural Pathways/drug effects , Rats , Rats, Wistar
14.
Biol Psychiatry ; 69(10): 918-27, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21251645

ABSTRACT

BACKGROUND: Noncompetitive N-methyl-D-aspartate receptor antagonists are widely used as pharmacological models of schizophrenia. Their neurobiological actions are still poorly understood, although the prefrontal cortex (PFC) appears as a key target area. METHODS: We examined the effect of phencyclidine (PCP) on neuronal activity of the mediodorsal (MD) and centromedial (CM) thalamic nuclei, reciprocally connected with the PFC, using extracellular recordings (n = 50 neurons from 35 Wistar rats) and c-fos expression. RESULTS: Phencyclidine (.25 mg/kg intravenous [IV]) markedly disorganized the activity of MD/CM neurons, increasing (424%) and decreasing (41%) the activity of 57% and 20% of the recorded neurons, respectively (23% remained unaffected). Phencyclidine reduced delta oscillations (.15-4 Hz) as assessed by recording local field potentials. The subsequent clozapine administration (1 mg/kg IV) reversed PCP effects on neuronal discharge and delta oscillations. Double in situ hybridization experiments revealed that PCP (10 mg/kg intraperitoneal [IP]) markedly increased c-fos expression in glutamatergic neurons of several cortical areas (prefrontal, somatosensory, retrosplenial, entorhinal) and in thalamic nuclei, including MD/CM. Phencyclidine also increased c-fos expression in the amygdala; yet, it had a small effect in the hippocampus. Phencyclidine did not increase c-fos expression in gamma-aminobutyric acidergic cells except in hippocampus, amygdala, somatosensory, and retrosplenial cortices. Clozapine (5 mg/kg IP) had no effect by itself but significantly prevented PCP-induced c-fos expression. CONCLUSIONS: Phencyclidine likely exerts its psychotomimetic action by increasing excitatory neurotransmission in thalamo-cortico-thalamic networks involving, among others, PFC, retrosplenial, and somatosensory cortices. The antipsychotic action of clozapine includes, among other actions, an attenuation of the neuronal hyperactivity in thalamocortical networks.


Subject(s)
Antipsychotic Agents/pharmacology , Cerebral Cortex/drug effects , Clozapine/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Phencyclidine/pharmacology , Thalamus/drug effects , Action Potentials/drug effects , Animals , Brain Mapping , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Drug Interactions , Evoked Potentials/drug effects , Gene Expression Regulation/drug effects , Male , Neural Pathways/drug effects , Neural Pathways/physiology , Neurons/drug effects , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/metabolism , Rats , Thalamus/cytology , Thalamus/metabolism , Vesicular Glutamate Transport Protein 1/genetics , Vesicular Glutamate Transport Protein 1/metabolism
15.
Cereb Cortex ; 19(4): 849-60, 2009 Apr.
Article in English | MEDLINE | ID: mdl-18689859

ABSTRACT

Mesocortical dopamine (DA) is a key neurotransmitter in cognitive processes and is involved in schizophrenia and antipsychotic drug action. DA exerts a highly complex modulation of network activity in prefrontal cortex (PFC), possibly due to the recruitment of multiple signaling pathways and to specialized cellular localizations of DA receptors in cortical microcircuits. Using double in situ hybridization, we quantitatively assessed the expression of D(1) and D(2) receptor messenger RNAs (mRNAs) in pyramidal and gamma-aminobutyric acidergic (GABAergic) neurons of rat PFC. The proportion of pyramidal and GABA cells expressing these transcripts shows great regional variability in PFC, with little overlap (layer V). More pyramidal and GABA cells express D(1) than D(2) receptors. D(1) receptors are expressed by a greater proportion of GABA than pyramidal neurons, yet the number of D(1)-positive pyramidal cells outnumbers D(1)-positive interneurons due to the greater abundance of pyramidal neurons. Occasional PFC cells show high levels of mRNA, similar to those in striatal neurons. Finally, pyramidal and GABAergic cells expressing the same transcript were almost never found in close apposition, yet D(2)-containing pyramidal neurons were often found close to non-D(2) GABA neurons. Thus, cellular and network DA actions in PFC are region and layer specific and may depend on precise cellular interactions.


Subject(s)
Prefrontal Cortex/metabolism , Pyramidal Cells/metabolism , Receptors, Dopamine D1/biosynthesis , Receptors, Dopamine D2/biosynthesis , gamma-Aminobutyric Acid/biosynthesis , Animals , Gene Expression Regulation/physiology , Male , Neurons/cytology , Neurons/metabolism , Prefrontal Cortex/cytology , Pyramidal Cells/cytology , Rats , Rats, Wistar , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/genetics
16.
Neurotox Res ; 14(2-3): 129-40, 2008 Oct.
Article in English | MEDLINE | ID: mdl-19073421

ABSTRACT

Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. Schizophrenic patients show a reduced performance in tasks engaging the PFC and a reduction of markers of cellular integrity and function. Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to exacerbate schizophrenia symptoms in patients and to elicit psychotomimetic actions in healthy volunteers. Also, these drugs evoke behavioral alterations in experimental animals that resemble schizophrenia symptoms. The PFC seems to be a key target area for these agents. However, the cellular and network elements involved are poorly known. Cognitive deficits are of particular interest since an early antipsychotic-induced improvement in cognitive performance predicts a better long-term clinical outcome. Here we report that the non-competitive NMDA receptor antagonist phencyclidine (PCP) induces a marked disruption of the activity of PFC. PCP administration increased the activity of a substantial proportion of pyramidal neurons, as evidenced by an increase in discharge rate and in c-fos expression. Examination of the effects of PCP on other brain areas revealed an increased c-fos expression in a number of cortical and subcortical areas, but notably in thalamic nuclei projecting to the PFC. The administration of classical (haloperidol) and/or atypical (clozapine) antipsychotic drugs reversed PCP effects. These results indicate that PCP induces a marked disruption of the network activity in PFC and that antipsychotic drugs may partly exert their therapeutic effect by normalizing hyperactive cortico-thalamocortical circuits.


Subject(s)
Antipsychotic Agents/pharmacology , Phencyclidine/pharmacology , Prefrontal Cortex/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Thalamic Nuclei/drug effects , Animals , Cerebral Cortex/metabolism , Clozapine/pharmacology , Haloperidol/pharmacology , Male , Neural Pathways , Phencyclidine/antagonists & inhibitors , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiology , Proto-Oncogene Proteins c-fos/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Pyramidal Cells/physiology , Rats , Rats, Wistar , Somatosensory Cortex/metabolism , Thalamic Nuclei/metabolism
17.
Proc Natl Acad Sci U S A ; 104(37): 14843-8, 2007 Sep 11.
Article in English | MEDLINE | ID: mdl-17785415

ABSTRACT

NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models because of their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. These deficits are of particular interest because an early improvement in cognitive performance predicts a better long-term clinical outcome. Here, we examined the effect of the noncompetitive NMDA-R antagonist phencyclidine (PCP) on PFC function to understand the cellular and network elements involved in its schizomimetic actions. PCP induces a marked disruption of the activity of the PFC in the rat, increasing and decreasing the activity of 45% and 33% of the pyramidal neurons recorded, respectively (22% of the neurons were unaffected). Concurrently, PCP markedly reduced cortical synchrony in the delta frequency range (0.3-4 Hz) as assessed by recording local field potentials. The subsequent administration of the antipsychotic drugs haloperidol and clozapine reversed PCP effects on pyramidal cell firing and cortical synchronization. PCP increased c-fos expression in PFC pyramidal neurons, an effect prevented by the administration of clozapine. PCP also enhanced c-fos expression in the centromedial and mediodorsal (but not reticular) nuclei of the thalamus, suggesting the participation of enhanced thalamocortical excitatory inputs. These results shed light on the involvement of PFC in the schizomimetic action of NMDA-R antagonists and show that antipsychotic drugs may partly exert their therapeutic effect by normalizing a disrupted PFC activity, an effect that may add to subcortical dopamine receptor blockade.


Subject(s)
Antipsychotic Agents/pharmacology , Clozapine/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Haloperidol/pharmacology , Phencyclidine/pharmacology , Prefrontal Cortex/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Animals , Histocytochemistry , In Situ Hybridization , Male , Patch-Clamp Techniques , Prefrontal Cortex/cytology , Prefrontal Cortex/metabolism , Pyramidal Cells/drug effects , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
18.
Cereb Cortex ; 14(12): 1365-75, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15166106

ABSTRACT

Serotonin (5-hydroxytryptamine, 5-HT) controls pyramidal cell activity in prefrontal cortex (PFC) through various receptors, in particular, 5-HT1A and 5-HT2A receptors. Here we report that the physiological stimulation of the raphe nuclei excites local, putatively GABAergic neurons in the prelimbic and cingulate areas of the rat PFC in vivo. These excitations had a latency of 36 +/- 4 ms and a duration of 69 +/- 9 ms and were blocked by the i.v. administration of the 5-HT3 receptor antagonists ondansetron and tropisetron. The latency and duration were shorter than those elicited through 5-HT2A receptors in pyramidal neurons of the same areas. Double in situ hybridization histochemistry showed the presence of GABAergic neurons expressing 5-HT3 receptor mRNA in PFC. These cells were more abundant in the cingulate, prelimbic and infralimbic areas, particularly in superficial layers. The percentages of GAD mRNA-positive neurons expressing 5-HT3 receptor mRNA in prelimbic cortex were 40, 18, 6 and 8% in layers I, II-III, V and VI, respectively, a distribution complementary to that of cells expressing 5-HT2A receptors. Overall, these results support an important role of 5-HT in the control of the excitability of apical dendrites of pyramidal neurons in the medial PFC through the activation of 5-HT3 receptors in GABAergic interneurons.


Subject(s)
Interneurons/physiology , Prefrontal Cortex/physiology , Receptors, Serotonin, 5-HT3/physiology , gamma-Aminobutyric Acid/physiology , Animals , Electric Stimulation/methods , Interneurons/drug effects , Male , Prefrontal Cortex/drug effects , Rats , Rats, Wistar , Serotonin 5-HT3 Receptor Antagonists , Serotonin Antagonists/pharmacology
19.
Cereb Cortex ; 14(10): 1100-9, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15115744

ABSTRACT

Serotonergic 5-HT1A and 5-HT2A receptors are abundantly expressed in prefrontal cortex (PFC) and are targets of atypical antipsychotic drugs. They mediate, respectively, inhibitory and excitatory actions of 5-HT. The transcripts for both receptors are largely (approximately 80%) colocalized in rat and mouse PFC, yet their quantitative distribution in pyramidal and GABAergic interneurons is unknown. We used double in situ hybridization histochemistry to estimate the proportion of pyramidal and GABAergic neurons expressing these receptor transcripts in rat PFC. The number of GABAergic interneurons (expressing GAD mRNA) was a 22% of glutamatergic neurons (expressing vGluT1 mRNA, considered as putative pyramidal neurons). 5-HT2A receptor mRNA was present in a large percentage of pyramidal neurons (from 55% in prelimbic cortex to 88% in tenia tecta), except in layer VI, where it was localized only in 30% of those neurons. 5-HT2A receptor mRNA was present in approximately 25% of GAD-containing cells except in layer VI (10%). Likewise, approximately 60% of glutamatergic cells contained the 5-HT1A receptor transcript. We also found that approximately 25% of GAD-expressing cells contained the 5-HT1A receptor mRNA. These data help to clarify the role of 5-HT in prefrontal circuits and shed new light to the cellular elements involved in the action of atypical antipsychotics.


Subject(s)
Prefrontal Cortex/metabolism , Pyramidal Cells/metabolism , Receptor, Serotonin, 5-HT1A/biosynthesis , Receptor, Serotonin, 5-HT2A/biosynthesis , gamma-Aminobutyric Acid/metabolism , Animals , Gene Expression Regulation , Male , Neurons/chemistry , Neurons/metabolism , Prefrontal Cortex/chemistry , Pyramidal Cells/chemistry , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT1A/physiology , Receptor, Serotonin, 5-HT2A/physiology , gamma-Aminobutyric Acid/physiology
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