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A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition.
Lawson, Kate A; Ruiz, Christina M; Mahler, Stephen V.
Affiliation
  • Lawson KA; Department of Neurobiology and Behavior, University of California Irvine, 1132 McGaugh Hall, Irvine, CA, 92697, USA. lawsonk1@uci.edu.
  • Ruiz CM; Department of Neurobiology and Behavior, University of California Irvine, 1132 McGaugh Hall, Irvine, CA, 92697, USA.
  • Mahler SV; Department of Neurobiology and Behavior, University of California Irvine, 1132 McGaugh Hall, Irvine, CA, 92697, USA.
Psychopharmacology (Berl) ; 240(10): 2101-2110, 2023 Oct.
Article in En | MEDLINE | ID: mdl-37530882
ABSTRACT
RATIONALE Designer receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist.

OBJECTIVES:

Second-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit.

METHODS:

Male and female THCre + rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons of THCre + rats. All rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in counterbalanced order.

RESULTS:

All three CNO doses reduced operant rewards earned in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest J60 dose tested significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in THCre + rats were correlated and were present in both sexes.

CONCLUSIONS:

Findings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Designer Drugs / Clozapine Limits: Animals Language: En Journal: Psychopharmacology (Berl) Year: 2023 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Designer Drugs / Clozapine Limits: Animals Language: En Journal: Psychopharmacology (Berl) Year: 2023 Document type: Article Affiliation country: