Shifts in the neurobiological mechanisms motivating cocaine use with the development of an addiction-like phenotype in male rats

• Published in: Psychopharmacology 2021-03, Vol.238 (3), p.811-823
• Main Authors: Lynch, Wendy J., Bakhti-Suroosh, Anousheh, Abel, Jean M., Davis, Camilla
• Format: Article
• Language: English
• Subjects: Addictions; Analysis; Animals; Behavior, Addictive - psychology; Benzazepines - pharmacology; Biomedical and Life Sciences; Biomedicine; Cocaine; Cocaine - administration & dosage; Cocaine - toxicity; Cocaine abuse; Cocaine-Related Disorders - metabolism; Cocaine-Related Disorders - psychology; Dopamine; Dopamine - metabolism; Dopamine Antagonists - pharmacology; Dopamine D1 receptors; Dopamine D2 receptors; Drug therapy; Gene expression; Genotype & phenotype; Glutamic Acid - metabolism; Male; Motivation; Motivation (Psychology); Motivation - drug effects; Neurobiology; Neurosciences; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Original Investigation; Pharmacology/Toxicology; Phenotype; Phenotypes; Psychiatry; Psychological aspects; Rats; Receptors, AMPA - metabolism; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Salicylamides - pharmacology; Self Administration; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-020-05732-4

Rationale The development of addiction is accompanied by a shift in the mechanisms motivating cocaine use from nucleus accumbens (NAc) dopamine D 1 receptor (D 1 R) signaling to glutamate AMPA-kainate receptor (AMPA-R) signaling. Objective Here, we determined whether similar shifts occur for NAc-D 2 R signaling and following systemic manipulation of D 1 R, D 2 R, and AMPA-R signaling. Methods Male rats were given short-access (20 infusions/day) or extended-access to cocaine (24 h/day, 96 infusions/day, 10 days). Motivation for cocaine was assessed following 14 days of abstinence using a progressive-ratio schedule. Once responding stabilized, the effects of NAc-D 2 R antagonism (eticlopride; 0–10.0 μg/side) and systemic D 1 R (SCH-23390; 0–1.0 mg/kg), D 2 R (eticlopride; 0–0.1 mg/kg), and AMPA-R (CNQX; 0–1.5 mg/kg) antagonism, and NAc-dopamine-R gene expression ( Drd1/2/3 ) were examined. Results Motivation for cocaine was markedly higher in the extended- versus short-access group confirming the development of an addiction-like phenotype in the extended-access group. NAc-infused eticlopride decreased motivation for cocaine in both the short- and extended-access groups although low doses (0.1–0.3 μg) were more effective in the short-access group and high doses (3–10 μg/side) tended to be more effective in the extended-access group. Systemic administration of eticlopride (0.1 mg/kg) was more effective in the extended-access group, and systemic administration of CNQX was effective in the extended- but not short-access group. NAc- Drd2 expression was decreased in both the short- and extended-access groups. Conclusion These findings indicate that in contrast to NAc-D 1 R, D 2 R remain critical for motivating cocaine use with the development of an addiction-like phenotype. These findings also indicate that shifts in the mechanisms motivating cocaine use impact the response to both site-specific and systemic pharmacological treatment.