The principal features and mechanisms of dopamine modulation in the prefrontal cortex

Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein Most rodent models have behavioural phenotype changes that resemble ‘positive-like’ symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed

LINKED ARTICLES
This article is part of a themed issue on Translational Neuropharmacology To view the other articles in this issue visit http://dxdoiorg/101111/bph2011164issue-4

/pdf/animal-models-of-schizophrenia-3x9e66fdpk.pdf

Animal models of schizophrenia

These guidelines from the British Association for Psychopharmacology address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting, involving experts in schizophrenia and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from the participants and interested parties, and cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. The practice recommendations presented are based on the available evidence to date, and seek to clarify which interventions are of proven benefit. It is hoped that the recommendations will help to inform clinical decision making for practitioners, and perhaps also serve as a source of information for patients and carers. They are accompanied by a more detailed qualitative review of the available evidence. The strength of supporting evidence for each recommendation is rated.

https://journals.sagepub.com/doi/pdf/10.1177/0269881119889296

Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology:

Dopamine regulates the activity of neural networks in the prefrontal cortex that process working memory information, but its precise biophysical actions are poorly understood. The present study characterized the effects of dopamine on GABAergic inputs to prefrontal pyramidal neurons using whole-cell patch-clamp recordings in vitro. In most pyramidal cells, dopamine had a temporally biphasic effect on evoked IPSCs, producing an initial abrupt decrease in amplitude followed by a delayed increase in IPSC amplitude. Using receptor subtype-specific agonists and antagonists, we found that the initial abrupt reduction was D2 receptor-mediated, whereas the late, slower developing enhancement was D1 receptor-mediated. Linearly combining the effects of the two agonists could reproduce the biphasic dopamine effect. Because D1 agonists enhanced spontaneous (sIPSCs) but did not affect miniature (mIPSCs) IPSCs, it appears that D1 agonists caused larger evoked IPSCs by increasing the intrinsic excitability of interneurons and their axons. In contrast, D2 agonists had no effects on sIPSCs but did produce a significant reduction in mIPSCs, suggestive of a decrease in GABA release probability. In addition, D2 agonists reduced the postsynaptic response to a GABA(A) agonist. D1 and D2 receptors therefore regulated GABAergic activity in opposite manners and through different mechanisms in prefrontal cortex (PFC) pyramidal cells. This bidirectional modulation could have important implications for the computational properties of active PFC networks.

/pdf/bidirectional-dopamine-modulation-of-gabaergic-inhibition-in-3su72i0day.pdf

Bidirectional Dopamine Modulation of GABAergic Inhibition in Prefrontal Cortical Pyramidal Neurons

This review presents an overview about pharmaceutical and cosmetic topical products containing polymeric nanoparticles (nanospheres and nanocapsules), reporting the main preparation and characterization methods and the studies of penetration and transport of substances through the skin. The penetration and transport extent of those systems through the skin depends on the ingredients chemical composition, on the encapsulation mechanism influencing the drug release, on the size of nanoparticles and on the viscosity of the formulations. The polymeric nanoparticles are able to modify the activity of drugs, delay and control the drug release, and increase the drug adhesivity or its time of permanence in the skin. Briefly, the nanoparticles can be useful as reservoirs of lipophilic drugs to deliver them in the stratum corneum becoming an important strategy to control their permeation into the skin.

https://journals.sagepub.com/doi/pdf/10.1177/117739280700200002

Polymeric Nanoparticles, Nanospheres and Nanocapsules, for Cutaneous Applications

Behavioural sensitization to psychostimulants may develop context-dependently in certain circumstances. Animals given a stimulant repeatedly in a test cage but not in other environments may show enhanced drug-induced behaviour in the test cage. Conditioning mechanisms have been claimed to be responsible for these phenomena. However, several recent findings are not properly accounted for by conditioning. In addition, growing evidence supports the hypothesis that behavioural sensitization reflects neural changes induced by repeated exposure to psychostimulants (the pharmacological hypothesis). However, the pharmacological hypothesis itself fails to account for environmental influences. In this paper, we propose a hypothesis on the role of environment that is complementary to the pharmacological hypothesis. According to our hypothesis, environment does not have a causal role in the development of sensitization, but it modifies the mode of expression of the sensitized behaviour. Sensitization primarily reflects a neuroadaptive change induced by repeated exposure of the neural system to psychostimulants. However, psychostimulants are known to induce different behaviours in different environments. Therefore, repeated administration of a psychostimulant in different environments would result in augmentation of different behaviours. Our hypothesis potentially accommodates various previous observations. We briefly review the literature and present our hypothesis.

Context determines the type of sensitized behaviour: a brief review and a hypothesis on the role of environment in behavioural sensitization.

In spite of numerous reports on a 1 to 2 year maintenance neuroleptic treatment of schizophrenia, there is little systematic information on decade-long maintenance therapy. We conducted a retrospective study in fifty outpatients with paranoid schizophrenia who have been seen at our clinic for a duration of 15 years or more since their first psychotic episodes. Relapse rate within 2, 5, 10, and 15 years from remission of the first psychotic episode were 52, 60, 86, and 90%, respectively. However, the incidence of relapse decreased with time. This decrease was accounted for by the decrease of relapse observed when off drug. Conversely, the incidence of relapse occurred on drug remained unchanged. The average maintenance dose 15 years after remission of the first psychotic episode was 5.41 ± 7.28 mg/d (haloperidol equivalents: mean ± SD). The maintenance dose correlated significantly with the number of relapses and total duration of psychotic episodes. These results suggest that maintenance treatment remained effective for decades, although it did not ameliorate the liability to relapse itself. Repeated relapse may be associated with requirement for a higher neuroleptic dose for relapse prevention.

Psychotic relapse and maintenance therapy in paranoid schizophrenia: a 15 year follow up.

Rationale: Repeated administration of phencyclidine (PCP) produces behavioral sensitization to PCP. Although the precise mechanism is unknown, glutamatergic neurotransmission seems to play an important role in the development of sensitization. Objectives: The present study examined whether a novel compound, MS-153 ((R)-(–)-5-methyl-1-nicotinyl-2-pyrazoline), which has an ability to enhance glutamate uptake and inhibit glutamate release, would block the development of behavioral sensitization to PCP. Methods: For studying effects of MS-153, locomotor activity was measured by an infrared sensor and ataxia was measured by a rating scale. Results: MS-153 (10 and 100 mg/kg) enhanced locomotion and ataxia induced by a single injection of PCP (7.5 mg/kg). Repeated administration of PCP (20 mg/kg, once in every day, for 5 days) developed sensitization to locomotion- and ataxia-inducing effects of PCP (7.5 mg/kg). MS-153 given 60 min and 120 min later of every PCP treatment blocked the development of behavioral sensitization to both locomotion- and ataxia-inducing effects of PCP. Co-administration of MS-153 with repeated saline treatment did not produce hypersensitivity to PCP. Conclusions: These results suggest that the attenuation of glutamatergic neural transmission enhances acute effects of PCP, in contrast, blocks the behavioral sensitization developed by repeated PCP treatment. Therefore, glutamatergic neural transmission plays an important role in the development of behavioral sensitization to PCP.

Effect of MS-153 on the development of behavioral sensitization to locomotion- and ataxia-inducing effects of phencyclidine.

Effect of MS-153 on the development of behavioral sensitization to stereotypy-inducing effect of phencyclidine

The toxic dose of methamphetamine (METH) (5 mg/kg, sc, x4, 2 hr intervals) decreased contents of dopamine, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in striatum, and decreased contents of serotonin (5-HT) in both striatum and nucleus accumbens Administration of low doses of a non-selective endothelial and neuronal nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) (5 and 10 mg/kg, ip, x1) intensified the METH-induced decreases in contents of dopamine and its metabolites in striatum NO substrate, L-arginine (500 mg/kg, ip, x4) reversed these effects of L-NAME on the METH-neurotoxicity L-NAME did not change the METH-induced hyperthermia These findings, which are contrary to our previous study with a high dose of L-NAME, suggest that the inhibition of endothelial or neuronal NOS-mediated NO production by low doses of L-NAME enhanced the METH-induced neurotoxicity The finding that L-NAME can have opposite effects on the METH-neurotoxicity according to the dosing is important, however, additional experiments should be performed to clarify which type of NOS is related to these effects

Effect of low doses of L-NAME on methamphetamine-induced dopaminergic depletion in the rat striatum

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