clozapine and preproenkephalin

Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted metabolic mapping, where DREADD indicates designer receptors exclusively activated by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability.

Topics: Adult; Amygdala; Animals; Clozapine; Corticosterone; Depressive Disorder, Major; Designer Drugs; Enkephalins; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; GTP-Binding Protein alpha Subunits, Gi-Go; Heroin Dependence; Humans; Hungary; Limbic System; Male; Middle Aged; Neuroimaging; Neurons; Positron-Emission Tomography; Protein Precursors; Radiopharmaceuticals; Rats; Rats, Long-Evans; Recombinant Fusion Proteins; RNA, Messenger; United States

The ability to map the functional connectivity of discrete cell types in the intact mammalian brain during behavior is crucial for advancing our understanding of brain function in normal and disease states. We combined designer receptor exclusively activated by designer drug (DREADD) technology and behavioral imaging with μPET and [18F]fluorodeoxyglucose (FDG) to generate whole-brain metabolic maps of cell-specific functional circuits during the awake, freely moving state. We have termed this approach DREADD-assisted metabolic mapping (DREAMM) and documented its ability in rats to map whole-brain functional anatomy. We applied this strategy to evaluating changes in the brain associated with inhibition of prodynorphin-expressing (Pdyn-expressing) and of proenkephalin-expressing (Penk-expressing) medium spiny neurons (MSNs) of the nucleus accumbens shell (NAcSh), which have been implicated in neuropsychiatric disorders. DREAMM revealed discrete behavioral manifestations and concurrent engagement of distinct corticolimbic networks associated with dysregulation of Pdyn and Penk in MSNs of the NAcSh. Furthermore, distinct neuronal networks were recruited in awake versus anesthetized conditions. These data demonstrate that DREAMM is a highly sensitive, molecular, high-resolution quantitative imaging approach.

Topics: Action Potentials; Animals; Brain; Brain Mapping; Clozapine; Designer Drugs; Enkephalins; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Male; Motor Activity; Nerve Net; Neural Pathways; Neuroimaging; Neurons; Nucleus Accumbens; Positron-Emission Tomography; Protein Precursors; Proto-Oncogene Proteins c-fos; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Somatosensory Cortex; Time Factors; Vibrissae; Wakefulness

Typical antipsychotic drugs (i.e. haloperidol) induce extrapyramidal movement disorders while 'atypical' antipsychotics (i.e. clozapine) do not. In situ hybridization histochemistry followed by film autoradiography showed that clozapine treatment (20 mg/kg i.p. daily for 28 days) decreased the level of labelling for preproenkephalin mRNA in the striatum of the rat while haloperidol treatment (1 mg/kg i.p. daily for 28 days) resulted in no change compared with controls. The results suggest that these typical and atypical antipsychotic drugs exert differential effects on the enkephalin-containing striatal projection to the globus pallidus, a pathway critical for the expression of extrapyramidal movement disorders.

Topics: Animals; Basal Ganglia Diseases; Clozapine; Corpus Striatum; Depression, Chemical; Efferent Pathways; Enkephalins; Gene Expression Regulation; Globus Pallidus; Haloperidol; Male; Nucleic Acid Hybridization; Protein Precursors; Rats; Rats, Inbred Strains