Various, though distinct psychiatric disorders, such as Schizophrenia, bipolar disorder or major depression are associated with a dysfunction of the reward system linked to an alteration of dopamine transmission. Furthermore, these pathologies are also accompanied by changes in lipid metabolism and in particular a decrease in the brain content n-3 polyunsaturated fatty acid (PUFA) in the nervous system. However, the implication of brain lipid composition in the etiology of psychiatric endophenotypes has been overlooked. The aim of this study was to investigate a potential causal link between n-3 PUFA deficiency and deficits in reward processing. Using operant conditioning tasks in mice, we showed that developmental n-3 PUFA deficiency leads to a selective motivational deficit at adulthood that is reversed by n-3 PUFA supplementation starting at birth. In parallel, we showed that n-3 PUFA deficiency leads to alterations in electrophysiological properties of medium spiny neurons (MSNs) in the nucleus accumbens, main actors for motivational processes. MSNs from the direct pathway (dMSNs) displayed a decrease in excitability paralleled with an increase of inhibitory input onto these neurons. Using pharmacogenetic and transgenic approaches, we showed that 1) alterations in dMSNs directly results from increased inhibitory input from MSNs of the indirect pathway (iMSNs), called lateral inhibition and 2) rescuing appropriate PUFA levels in D2R-expressing neurons selectively (including iMSNs), was sufficient to reverse both alterations in electrophysiological properties of dMSNs and motivational deficit observed in n-3 PUFA deficient mice.