Amphetamines are known to enhance alertness, mood, motivation and motor performance. Chronic use of amphetamines is associated with addiction and mental conditions including mood, psychotic, obsessive and compulsive disorders. These known effects of amphetamines may suggest that amphetamine administration alters motivational and cognitive processes that integrate sensory information for action. To study effects of damphetamine on such integrative processes, we employed sensation seeking of unconditioned visual stimuli (VS). Specifically, our procedure required rats to lever-press to obtain a flash of light, which is weakly reinforcing in rats. Because amphetamines effects on drug seeking and mental conditions can be exacerbated by stress, we also examined effects of stress induced by chronic food-restriction and its interaction with amphetamine on VS seeking. We found that in chronically food-restricted (FR) rats (85-90% of their original weights), intraperitoneal (IP) injections of 1 mg/kg amphetamine markedly increased lever-pressing reinforced by VS, while the 0.3-mg/kg dose had no reliable effect, and the 3-mg/kg dose reliably decreased VS seeking. Locomotor activity of FR rats during these tests was affected somewhat differently than VS seeking: The 1-mg/kg dose increased locomotor activity, and the 3-mg/kg dose increased it even more. Unlike FR rats, rats that were given ad libitum (AD) access to food did not reliably increase VS seeking when treated with these doses of amphetamine, while significantly increasing locomotor activity. We also examine effects of the length of food restriction on amphetamine-induced VS seeking. Food deprivation of 24 hours or FR of 3 or 7 days with amphetamine injections (1mg/kg) did not increase VS seeking , while a 2 week FR significantly increased VS seeking, suggesting that chronic food restriction is needed for amphetamine to increase VS seeking. We also examined effects of repeated injections (8 times over 2 weeks) of amphetamine (1 mg/kg, IP) followed by a 3-week incubation. When challenged with 0.1-1 mg/kg amphetamine after incubation, prior amphetamine exposure did not have clear effects on VS seeking in FR or AD rats, but had sensitizing effects on locomotor activity. However, the whole procedure consisting of repeated injections (either saline or amphetamine) followed by a 3-week incubation made FR rats more sensitive to the effects of amphetamine on VS seeking. While FR rats were not different from AD rats in VS seeking without amphetamine, FR rats with prior saline- or amphetamineexposure significantly increased VS seeking with treatments of 0.3 or 1 mg/kg amphetamine. In summary, these results suggest that food restriction is an importnat factor in amphetamine-induced VS seeking, but not in locomotor activity. Neural mechanisms that amphetamine modulates to facilitate VS seeking may be substantially different from those of locomotor activity.

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National Institute on Drug Abuse
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Ikemoto, Satoshi; Bonci, Antonello (2014) Neurocircuitry of drug reward. Neuropharmacology 76 Pt B:329-41
Vollrath-Smith, Fiori R; Shin, Rick; Ikemoto, Satoshi (2012) Synergistic interaction between baclofen administration into the median raphe nucleus and inconsequential visual stimuli on investigatory behavior of rats. Psychopharmacology (Berl) 220:15-25
Webb, Sierra M; Vollrath-Smith, Fiori R; Shin, Rick et al. (2012) Rewarding and incentive motivational effects of excitatory amino acid receptor antagonists into the median raphe and adjacent regions of the rat. Psychopharmacology (Berl) 224:401-12
Jhou, Thomas C; Xu, Sheng-Ping; Lee, Mary R et al. (2012) Mapping of reinforcing and analgesic effects of the mu opioid agonist endomorphin-1 in the ventral midbrain of the rat. Psychopharmacology (Berl) 224:303-12
Cao, Junran; de Lecea, Luis; Ikemoto, Satoshi (2011) Intraventricular administration of neuropeptide S has reward-like effects. Eur J Pharmacol 658:16-21
Shin, Rick; Ikemoto, Satoshi (2010) The GABAB receptor agonist baclofen administered into the median and dorsal raphe nuclei is rewarding as shown by intracranial self-administration and conditioned place preference in rats. Psychopharmacology (Berl) 208:545-54
Shin, Rick; Cao, Junran; Webb, Sierra M et al. (2010) Amphetamine administration into the ventral striatum facilitates behavioral interaction with unconditioned visual signals in rats. PLoS One 5:e8741
Ikemoto, Satoshi (2010) Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 35:129-50
Shin, Rick; Ikemoto, Satoshi (2010) Administration of the GABAA receptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures. Supramammillary picrotoxin and c-Fos expression. BMC Neurosci 11:101
Liu, Zhong-Hua; Shin, Rick; Ikemoto, Satoshi (2008) Dual role of medial A10 dopamine neurons in affective encoding. Neuropsychopharmacology 33:3010-20

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