Omega-3 fatty acid deficiency impairs frontostriatal recruitment following repeated amphetamine treatment in rats: A 7 Tesla in vivo phMRI study

Abstract

Although attention deficit hyperactivity disorder is associated with deficits in docosahexaenoic acid (DHA), an omega-3 fatty acid implicated in dopamine and glutamate synaptic plasticity, its role in neuroplastic brain changes that occur following repeated amphetamine (AMPH) treatment are not known. This study used pharmacological magnetic resonance imaging to investigate the impact of repeated AMPH exposure and alterations in brain DHA levels on AMPH-induced brain activation patterns. Male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (n = 20) from P21 to P90. During adolescence (P40–60), one-half of each diet group received daily AMPH injections escalated weekly (0.5, 1.0, 2.5, 5.0 mg/kg/d) or drug vehicle. Following a 30-d abstinence period blood oxygen level dependent (BOLD) responses were determined in a 7 T Bruker Biospec system following an AMPH challenge (7.5 mg/kg, i.v). Postmortem erythrocyte and forebrain DHA composition were determined by gas chromatography. Compared with control rats, forebrain and erythrocyte DHA levels were significantly lower in DEF rats and significantly higher in FO rats. Across AMPH doses DEF rats exhibited greater locomotor activity compared to control and FO rats. In AMPH-naïve rats, the AMPH challenge increased BOLD activity in the substantia nigra and basal forebrain and no diet group differences were observed. In AMPH-pretreated control and FO rats, the AMPH challenge similarly increased BOLD activation in the bilateral caudate putamen, thalamus, and motor and cingulate cortices. In contrast, BOLD activation in AMPH-pretreated DEF rats was similar to AMPH-naïve DEF animals, and AMPH-pretreated DEF rats exhibited attenuated frontostriatal BOLD activation compared with AMPH-pretreated control and FO rats. These findings demonstrate that chronic escalating AMPH treatment induces enduring frontostriatal recruitment and that peri-adolescent deficits in brain DHA accrual impair this response.

Keywords:

• Omega-3 fatty acids
• Docosahexaenoic acid (DHA)
• Sensitization
• Magnetic resonance imaging
• Amphetamine
• Rat

Acknowledgements

The NIH did not have any role in the design, implementation, analysis or interpretation of the research.

Disclaimer statements

Contributors None.

Conflicts of interest R.K.M. was a member of the IRF scientific advisory board, and served as a paid consultant for VAYA Pharma Inc., and Vifor Pharma Inc.

Ethics approval All experimental procedures were approved on 2012-present by the University of Cincinnati and Children’s Hospital Institutional Animal Care and Use Committees, and adhere to the guidelines set by the National Institutes of Health.

ORCID

Jennifer D. Schurdak http://orcid.org/0000-0002-6570-9083

Additional information

Funding

R.K.M. has received research support from NARSAD, Martek Biosciences Corporation, Ortho-McNeil Janssen, AstraZeneca, Eli Lilly and Company, Kyowa Hakko Bio Co., LTD, Royal DSM Nutritional Products, LLC, and the Inflammation Research Foundation (IRF). This work was supported in part by National Institute of Health grants MH107378, DK097599, MH097818, and NCRR UL1 RR026314 to R.K.M.