Chronic neuroleptic treatment in rats produces persisting changes in GABAA and dopamine D-2, but not dopamine D-1 receptors

doi:10.1016/0024-3205(89)90600-0

Life Sciences

Volume 44, Issue 3, 1989, Pages 229-236

https://doi.org/10.1016/0024-3205(89)90600-0 Get rights and content

Abstract

The effects of continuous treatment with haloperidol (HAL) or fluphenazine (FLU) for 10 months on dopamine and GABA receptors in the rat brain was examined using in vitro autoradiography. Rats treated with HAL, but not FLU, showed an increase in D-2 receptor binding in the caudate-putamen as revealed by [³H]spiperone. Labeling of D-1 receptors by [³H]SCH23390 revealed no changes in either drug-treated group. Both drug-treated groups, however, exhibited a significant increase in [³H]muscimol binding in substantia nigra, pars reticulata (SNR). These dopaminergic-GABAergic receptor alterations may be related to previously reported changes in oral movement activity seen in these neuroleptic-treated animals.

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Specifically, this method provides greater spatial resolution as compared to in vivo microPET, whilst keeping within a translational framework for comparison to clinical research using the same radioligands, which other techniques such as histology do not allow (Onwordi et al., 2020). Previous QAR studies in naïve adult rats provide evidence that chronic exposure to different antipsychotics influences the binding of both [3H]-muscimol (indexing GABAAR binding) and [3H]-flunitrazepam (indexing BZ-site binding) in a region-specific manner that is also dependent on the duration of drug exposure, the mode of administration and the sex of the animal (Dean et al., 2001; McLeod et al., 2008; See et al., 1990, 1989; Shirakawa and Tamminga, 1994; Skilbeck et al., 2008, 2007; Zink et al., 2004). For example, a 21 day oral exposure to aripiprazole (1 mg/kg), olanzapine (1 mg/kg) or risperidone (03.
Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABA_A receptor (GABA_AR) α subunits, including α5GABA_AR. Positron emission tomography (PET) measures of GABA_AR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABA_AR agonist [³H]-muscimol provide evidence that antipsychotic drugs influence GABA_AR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABA_AR radioligands. To address this, we combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed postmortem using the GABA_AR subunit-selective radioligand [³H]-Ro15-4513 and the non-subunit selective radioligand [³H]-flumazenil. Chronic haloperidol exposure increased [³H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (p<0.01; q<0.01; d=+1.3), which was not dose-dependent. [³H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABA_AR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABA_AR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABA_AR in the context of schizophrenia.
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These data suggest that APD treatment acts to reduce the level of GABAR in the CNS, a finding supported by a number of studies in rats that have reported decreased GABAR after such treatment (Dean et al., 2001; Farnbach-Pralong et al., 1998). However, there are other studies showing APD treatment does not affect (Wong et al., 1996) or increases (Frey et al., 1987, 1989; Huffman and Ticku, 1983; See et al., 1989, 1990; Skilbeck et al., 2007) levels of GABARs. To add to this complex picture there is a limited amount of data from rats that suggest that changes in GABAR after APD treatment are regionally selective (McLeod et al., 2008; Zink et al., 2004) and of a temporal nature, the latter being suggested following the demonstration of an up-regulation of [3H]muscimol binding after acute treatment but an up-regulation of [3H]flunitrazepam binding after chronic treatment with APDs (Skilbeck et al., 2007).
Changes in cortical γ-aminobutyric acid A (GABA_A) receptors and muscarinic receptors have been reported in schizophrenia, a disorder treated with antipsychotic drugs and benzodiazepines. As there is a reported functional relationship between the GABAergic and cholinergic systems in the human central nervous system we have investigated whether there are changes in the GABA_A and muscarinic receptors in the cortex of subjects from APD-treated subjects with schizophrenia and whether changes were different in subjects who had also received benzodiazepine treatment. We failed to show any strong correlations between changes in GABA_A and muscarinic receptors in the CNS of subjects with schizophrenia. We showed that subjects with schizophrenia treated with benzodiazepines had lower levels of muscarinic receptors; which was not the case in rats treated with APDs, benzodiazepines or a combination of both drugs. Further, the benzodiazepine binding site, but not the muscimol binding site, was decreased in the parietal cortex of subjects with schizophrenia independent of benzodiazepine status at death. These data would therefore support our previously stated hypotheses that changes in the cortical cholinergic and GABAergic systems are involved in the pathophysiology of schizophrenia.
Treatment with haloperidol and diazepam alters GABA<inf>A</inf> receptor density in the rat brain
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A significant body of data suggests that GABA_A receptors are altered in the CNS of subjects with schizophrenia. However, subjects with schizophrenia are treated with antipsychotic drugs and, in some cases, antipsychotic drugs and benzodiazepines. It has therefore been suggested that the changes in GABA_A receptors in the CNS of subjects with schizophrenia are due to such drug treatments. Surprisingly, there appear to be no studies to determine the effect of a combined antipsychotic–benzodiazepine treatment on GABA_A receptors. We therefore measured both the GABA binding site ([³H]muscimol) and the benzodiazepine binding site ([³H]flumazenil) in the CNS of rats treated with either haloperidol, diazepam or a combination of the two drugs. The main findings of our study are that treatment with diazepam or the combination of diazepam and haloperidol results in regionally selective increases GABA binding sites but treatment with haloperidol alone decreases the GABA binding site in the thalamus but increases these sites in the hypothalamus. By contrast, treatment with diazepam, haloperidol and a combination of the two drugs resulted in widespread decreases in the number of benzodiazepine binding sites in the rat CNS. The notable exception to this outcome was increased numbers of benzodiazepine binding sites in the frontal cortex of rats that had received diazepam. Our data suggests that there are complex changes in the GABA_A receptor following treatment with haloperidol, diazepam or a combination of these drugs. This outcome may be relevant to the therapeutic benefits of using both drugs in conjunction early in the treatment of a psychotic episode.
Alterations in striatal neuropeptide Y system activity of rats with haloperidol-induced behavioral supersensitivity
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The study was conducted to determine whether the expression of behavioral supersensitivity induced by haloperidol (HAL) administered once daily (2 mg/kg i.p.) for 14 days is associated with the alterations in activity of neuropeptide Y (NPY) system in the striatum (caudate-putamen) and nucleus accumbens. Dopamine supersensitivity was tested by measurement of locomotor activity and stereotyped behavior after administration of the dopamine D₂/D₃ receptor agonist quinpirole (1 mg/kg i.p.) on day 1, 3 and 7 after HAL withdrawal. Neuropeptide Y-like immunoreactivity (NPY-LI) was determined in the striatum and nucleus accumbens isolated 6 h after quinpirole injection on day 1, 3 and 7 after the end of HAL treatment. NPY mRNA was quantified in these structures on day 7 after HAL withdrawal. HAL increased spontaneous locomotor activity and prevalence of rearing, grooming and head-down sniffing. At the same time, striatal NPY-LI increased progressively from the reduced level found on day 1 of haloperidol withdrawal. NPY mRNA remained unchanged. In saline-treated rats, quinpirole enhanced locomotion, rearing, and induced intense head-down sniffing and oral activity. These behavioral effects were accompanied by a decrease in striatal NPY-LI. NPY mRNA was slightly increased. HAL treatment altered response to quinpirole, namely it increased locomotion, intensified oral activity and reduced rearing and head-down sniffing. The second and the third quinpirole injection decreased NPY-LI levels. NPY mRNA was unchanged. In the nucleus accumbens, apart from a decrease in NPY-LI on day 1 after the last haloperidol dose, the level of NPY-LI and NPY mRNA in any experimental group did not differ from the control value. The presented results suggest that the alterations in the activity of the striatal but not nucleus accumbens NPY system contribute to adaptive changes induced by long-term haloperidol treatment and may be of significance to the motor hyperactivity induced by intermittent stimulation of postsynaptic dopamine D₂ receptors.
Measurement of dopamine D<inf>2</inf>-like receptors in postmortem CNS and pituitary: Differential regional changes in schizophrenia
2004, Life Sciences
In situ radioligand binding with autoradiography and anti-human dopamine D₂ receptor antibodies with Western blots have been used to measure the density of dopamine D₂-like receptors in the caudate-putamen and pituitary from schizophrenic subjects who did or did not have residual antipsychotic drugs in their tissue at death. There was a significant decrease in the Ki for haloperidol displaceable [¹²⁵I]iodosulpride binding in the pituitary (p < 0.01) and caudate-putamen (p < 0.05) from subjects with schizophrenia with residual drugs in their tissue. There was a significant decrease in the density of [¹²⁵I]iodosulpride in the pituitary (p < 0.001) and a strong trend to a decrease in binding in the caudate-putamen (p = 0.055) from subjects with schizophrenia. By contrast, [³H]spiperone binding was decreased in the caudate-putamen (p < 0.05) with a trend to decreased binding in the pituitary (p = 0.07) from subjects with schizophrenia. There was no difference in the density of dopamine D₂ receptors in the caudate-putamen from subjects with schizophrenia (p = 0.31). All the findings on receptor densities were independent of drug status. [¹²⁵I]iodosulpride binds to the dopamine D_2&3 receptors. We have shown that there is no change in the dopamine D₂ receptor in the caudate-putamen from subjects with schizophrenia and therefore, these data would be consistent with there being a decrease in the dopamine D₃ in the caudate-putamen from subjects with schizophrenia. Since dopamine D₃ receptors are absent or present at low concentrations in the pituitary, our data would suggest the dopamine D₂ receptor is decreased in that tissue from schizophrenic subjects.
Oral dyskinesias and histopathological alterations in substantia nigra after long-term haloperidol treatment of old rats
2003, Neuroscience
The pathophysiologic basis of tardive dyskinesia remains unclear, but several lines of evidence suggest that persistent neuronal changes in the basal ganglia produced by oxidative stress or glutamate toxicity may play a role, especially in the elderly. In the present study we examined whether histopathological alterations in substantia nigra are related to oral dyskinesia in a rodent model of tardive dyskinesia. Haloperidol decanoate (38 mg/kg/4 weeks) was administered to young (8 weeks) and old (38 weeks) rats for a total period of 28 weeks, and the development of vacuous chewing movements (VCM) was observed. Rats with high and low levels of VCM and saline-treated controls were analyzed for histopathological alterations. Reduced nerve cell number and atrophic neurons were prominent features in the substantia nigra of old rats with high levels of VCM. Some alterations were also present in the substantia nigra of the old rats with low levels of VCM and young rats with high VCM levels, but these were significantly less affected than the high VCM rats. These results show that the development of haloperidol-induced oral dyskinesias in old rats is associated with histopathological alterations in the substantia nigra. This suggests that nigral degeneration induced by neuroleptics may contribute to the development of persistent VCM in rats and possibly irreversible tardive dyskinesia in humans.

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Chronic neuroleptic treatment in rats produces persisting changes in GABAA and dopamine D-2, but not dopamine D-1 receptors

Abstract

Eur. J. Pharmacol.

Pharm. Biochem. Behav.

Life Sci.

Pharm. Biochem. Behav.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Life Sci.

Eur. J. Pharmacol.

Neuropharmacology

Psychiat. Res.

Pharm. Biochem. Behav.

Dyskinesia - Research and Treatment

Science

psychopharmacology

Psychopharmacology

Trends in Neurosci.

Nature (London)

Psychopharmacology

Arch. Gen. Psychiat.

Chronic neuroleptic treatment in rats produces persisting changes in GABA_A and dopamine D-2, but not dopamine D-1 receptors