Background Reelin (RELN) is a glycoprotein secreted preferentially by cortical γ-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD) 67 , but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. Methods Reelin, GAD 65 , GAD 67 , DAB1, and neuron-specific–enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. Results Prefrontal cortex and cerebellar expression of RELN mRNA, GAD 67 protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD 65 and neuron-specific–enolase expression implying that RELN and GAD 67 down-regulations were unrelated to neuronal damage. Reelin and GAD 67 were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. Conclusions The selective down-regulation of RELN and GAD 67 in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/481668/yoa9104.pdf

Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: A postmortem brain study

Extracellular single unit recording techniques were used to study the effects of both acute and repeated oral neuroleptic administration on the in vivo activity of rat A9 and A10 dopaminergic (DA) neurons. All antipsychotic drugs examined acutely (haloperidol, l-sulpiride, chlorpromazine, and clozapine) increased the number of spontaneously firing DA neurons in both A9 and A10 compared to controls. Repeated (21 day) treatment with haloperidol, l-sulpiride, and chlorpromazine (antipsychotic drugs which can cause extrapyramidal side effects) markedly reduced the number of active DA cells below control levels in both regions. The "silent" DA neurons were in an apparent state of tonic depolarization inactivation since they could be induced to discharge by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid, but not the excitatory amino acid glutamate. The depolarization inactivation observed may be specific for antipsychotic drugs since a non-neuroleptic phenothiazine (promethazine), the inactive isomer of sulpiride (d-sulpiride), and a tricyclic antidepressant (desmethylimipramine) neither increased DA activity when given acutely nor induced depolarization inactivation when administered repeatedly. In contrast to the other drugs tested, repeated treatment with clozapine (an effective antipsychotic drug which does not produce extrapyramidal side effects) resulted in the depolarization inactivation of A10 neurons but not A9 cells. These data suggest that neuroleptics which can induce extrapyramidal side effects produce depolarization inactivation of both A9 and A10 neurons whereas antipsychotic drugs which lack this property inactivate only A10 neurons. It is suggested that the time-dependent development of A9 DA neuron inactivation induced by repeated neuroleptic treatment may provide a mechanism for understanding the delayed onset of extrapyramidal side effects often observed with these drugs.

https://www.jneurosci.org/content/jneuro/3/8/1607.full.pdf

Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons

Prolonged treatment with classical antipsychotic drugs decreased the number of spontaneously active dopamine neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) of the rat brain. In contrast, treatment with atypical antipsychotic drugs selectively decreased the number of A10 dopamine neurons. Related drugs lacking antipsychotic efficacy failed to decrease dopamine activity. These findings suggest that the inability of atypical antipsychotic drugs to decrease A9 dopamine neuronal activity may be related to their lower potential for causing tardive dyskinesia and that the inactivation of A10 neurons may be involved in the delayed onset of therapeutic effects during treatment.

https://science.sciencemag.org/content/sci/221/4615/1054.full.pdf

Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons

The striatal cholinergic interneuron: synaptic target of dopaminergic terminals?

BIOCHEMICAL1,2 and neurophysiological3–5 evidence has suggested that benzodiazepines may relieve anxiety facilitating the synaptic action of γ-aminobutyric acid (GABA), an important neurotransmitter in the brain of mammals, including man. As benzodiazepines fail to increase the turnover of GABA stored presynaptically as would be expected if they were to act as indirect GABA agonists, and since it has been difficult to demonstrate a direct agonistic action of the benzodiazepines on GABA postsynaptic receptors5–7 in vitro, the molecular mechanism whereby benzodiazepines facilitate GABAergic transmission is still unknown. Independent investigators8–10 have recently reported the presence of a high affinity, saturable, stereospecific binding site for benzodiazepines in synaptic membrane preparations obtained from brain of different animal species, including man. This high affinity binding is now used to determine the therapeutic potency and to study the mode of action of benzodiazepines in anxiety.

An endogenous protein modulates the affinity of GABA and benzodiazepine receptors in rat brain.

Turnover times of gamma-aminobutyric acid and acetylcholine in nucleus caudatus, nucleus accumbens, globus pallidus and substantia nigra: effects of repeated administration of haloperidol

SEVERAL lines of indirect evidence indicate that the nigrostriatal and mesolimbic dopaminergic systems interact with acetylcholine (ACh)1,2,3 and γ-aminobutyric acid4 (GABA)-secreting neurones. The reciprocal relationships among these neurones have not, however, been established with precision. Nucleus caudatus and nucleus accumbens are innervated by dopaminergic axons which have their cell bodies located in substantia nigra and ventral tegmental area5, respectively. These nuclei contain high concentrations of ACh6 and GABA7 and a high activity of cholineacetyltransferase (CAT)6 and glutamic acid decarboxylase7 (GAD). The nucleus accumbens and nucleus caudatus are connected with globus pallidus and substantia nigra which also contain GABA7, ACh6 and their synthesising enzymes. Antipsychotics, including chlorpromazine, clozapine and haloperidol increase the turnover rate of dopamine (DA) in the nucleus caudatus and nucleus accumbens8. Clozapine, a non-cataleptogenic antipsychotic, preferentially increases the DA turnover in the nucleus accumbens whereas chlorpromazine and haloperidol, two cataleptogenic antipsychotics show a preferential effect on the nucleus caudatus8.

The effects of antipsychotics on the turnover rate of GABA and acetylcholine in rat brain nuclei.

The turnover rate of gamma-aminobutyric acid in the nuclei of telencephalon: implications in the pharmacology of antipsychotics and of a minor tranquilizer.

Turnover rates of γ-aminobutyric acid in substantia nigra, N. caudatus, globus pallidus and N. accumbens of rats injected with cataleptogenic and non-cataleptogenic antipsychotics

GABA turnover was estimated mass fragmentographically in brain nuclei of rats infused with 1 3 C labeled glucose. Haloperidol and clozapine, enhance GABA turnover in globus pallidus and N. accumbens. Haloperidol reduces GABA turnover in caudate but does not affect that of substantia nigra, whereas clozapine increases the turnover in both caudate and substantia nigra. Two GABA mimetics, muscimol and diazepam, reduce GABA turnover in caudate, N. accumbens and substantia nigra but not in globus pallidus. Assuming that turnover rates of GABA reflect of activity in GABA terminals. Regulation of GABA neurons by GABA receptors and the interaction between GABAergic and dopaminergic neurons are discussed.

E. Marco

Papers

Turnover times of gamma-aminobutyric acid and acetylcholine in nucleus caudatus, nucleus accumbens, globus pallidus and substantia nigra: effects of repeated administration of haloperidol

The effects of antipsychotics on the turnover rate of GABA and acetylcholine in rat brain nuclei.

The turnover rate of gamma-aminobutyric acid in the nuclei of telencephalon: implications in the pharmacology of antipsychotics and of a minor tranquilizer.

Turnover rates of γ-aminobutyric acid in substantia nigra, N. caudatus, globus pallidus and N. accumbens of rats injected with cataleptogenic and non-cataleptogenic antipsychotics

The turnover rate of gaba in brain nuclei of rats injected with da receptor antagonists and gaba receptor agonists