Elsevier

Neuroscience

Volume 121, Issue 4, 7 November 2003, Pages 991-998
Neuroscience

Neuropharmacology
Dynorphinergic gaba neurons are a target of both typical and atypical antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus and thalamic central medial nucleus

https://doi.org/10.1016/S0306-4522(03)00397-XGet rights and content

Abstract

Administration of typical and atypical antipsychotic drugs leads to activation of cells in the nucleus accumbens shell, central amygdaloid nucleus, and midline thalamic central medial nucleus, implicating important shared effects of these drugs. However, the exact cell types responding to antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus, and midline thalamic central medial nucleus are unclear. We report here that, in a rat model, the results of studies using double immunofluorescence labeling with antibodies directed against markers specific to candidate cell types suggest that the cells responding to haloperidol and clozapine in all three sites are: 1) neurons, rather than astrocytes; 2) inhibitory GABA neurons, but not acetylcholinergic neurons; and 3) dynorphin-containing GABA neurons, but not M-enkephalin-containing GABA neurons.

The present study provides pharmacological evidence, at the cellular level in vivo, that the shared effects of antipsychotic drugs, whether typical and atypical, is activation of dynorphinergic GABA neurons in the nucleus accumbens shell, central amygdaloid nucleus, and midline thalamic central medial nucleus. Alternative ways to modulate dynorphinergic GABA neuronal activity or its target receptors might present an important new avenue for the treatment of schizophrenia and other psychotic disorders.

Section snippets

Animal subjects

Sprague–Dawley rats (Charles River, Wilmington, MA, USA; body weight 320–350 g) were maintained in groups of three to four per cage with food and water ad libitum in a room with a 12-h light/dark cycle. Rats were frequently handled in the days before the study to reduce the effects of stress associated with drug treatment. Our required minimum number of animals were treated in accordance with the provisions of the “Guide for the Care and Use of Laboratory Animals” of the United States

The expression of clozapine- and haloperidol-induced Fos protein is not colocalized with astrocytes in AcbSh, CeA and CM

The location of the double labeled cells in the present study is shown schematically in Fig. 1. The immunoreactive specificity was verified with the control experiment as described in the previous section on experimental procedure. No clozapine-induced Fos-positive cells stained for GFAP, a specific marker for astrocytes, as shown in Fig. 2. Similar results were seen in haloperidol treated rats (Table 1). Thus, clozapine and haloperidol target no astrocytes as their sites of action.

The expression of clozapine- and haloperidol-induced Fos proteins is colocalized with dynorphin-containing GABAergic neurons in AcbSh, CeA and CM

Fos staining

Discussion

In previous studies, we and others have consistently demonstrated that both haloperidol and clozapine are able to induce Fos expression in AcbSh, CeA and CM Deutch et al., 1992, Robertson and Fibiger, 1992, Robertson et al., 1994, Wan et al., 1995, Cohen and Wan, 1996, Sebens et al., 1995, Cohen et al., 1998, Suzuki et al., 1998, Pinna and Morelli, 1999, Cohen et al., 2003. The studies reported here were designed to identify which specific cell types in these regions respond to antipsychotic

Conclusion

In summary, we have examined which cell types in the AcbSh, CeA and CM respond to typical antipsychotic drug haloperidol and atypical antipsychotic agent clozapine. Using double immunofluorescence labeling with antibodies directed against markers specific to candidate cell types, we have demonstrated that both haloperidol and clozapine activate dynorphinergic GABA neurons, but do no appear to activate other cell types examined, including astrocytes, acetylcholinergic neurons and

Acknowledgements

This work was supported by NIH grants (MH31154, NS37483), the Stanley Foundation and the Engelhard Foundation.

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