Receptors In Ventral Striatum Research Articles

Dopamine depletion shifts behavior from activity based reinforcers to more sedentary ones and adenosine receptor antagonism reverses that shift: Relation to ventral striatum DARPP32 phosphorylation patterns

The mesolimbic dopamine (DA) system plays a critical role in behavioral activation and effort-based decision-making. DA depletion produces anergia (shifts to low effort options) in animals tested on effort-based decision-making tasks. Caffeine, the most consumed stimulant in the world, acts as an adenosine A1/A2A receptor antagonist, and in striatal areas DA D1 and D2 receptors are co-localized with adenosine A1 and A2A receptors respectively. In the present work, we evaluated the effect of caffeine on anergia induced by the VMAT-2 inhibitor tetrabenazine (TBZ), which depletes DA. Anergia was evaluated in a three-chamber T-maze task in which animals can chose between running on a wheel (RW) vs. sedentary activities such as consuming sucrose or sniffing a neutral odor. TBZ-caffeine interactions in ventral striatum were evaluated using DARPP-32 phosphorylation patterns as an intracellular marker of DA-adenosine receptor interaction. In the T-maze, control mice spent more time running and much less consuming sucrose or sniffing. TBZ (4.0 mg/kg) reduced ventral striatal DA tissue levels as measured by HPLC, and also shifted preferences in the T-maze, reducing selection of the reinforcer that involved vigorous activity (RW), but increasing consumption of a reinforcer that required little effort (sucrose), at doses that had no effect on independent measures of appetite or locomotion in a RW. Caffeine at doses that had no effect on their own reversed the effects of TBZ on T-maze performance, and also suppressed TBZ-induced pDARPP-32(Thr34) expression as measured by western blot, suggesting a role for D2-A2A interactions. These results support the idea that DA depletion produces anergia, but does not affect the primary motivational effects of sucrose. Caffeine, possibly by acting on A2A receptors in ventral striatum, reversed the DA depletion effects. It is possible that caffeine, like selective adenosine A2A antagonists, could have some therapeutic benefit for treating effort-related symptoms.

Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [(11)C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([(11)C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [(11)C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

Reductions in binding and functions of D 2 dopamine receptors in the rat ventral striatum during amphetamine sensitization

Rats receiving amphetamine (5 mg kg , i.p. once daily) for 14 continuous days develop behavioral sensitization to a subsequent amphetamine challenge (1 mg kg ) at withdrawal days 8 to 10. The present study was aimed at investigating whether there are changes in binding or functions of striatal D 2 dopamine receptors in amphetamine-sensitized rats. The results indicated that the Bmax value of D 2 receptors in the ventral striatum decreased 40% and 52% 7 and 10 days after amphetamine withdrawal, respectively, without changes in their binding affinities ( Kd). During this withdrawal period, the D 2 3 receptor agonist-induced (a) locomotor activation (bromocriptine, 5 mg kg , i.p. or quinpirole, 1 mg kg , i.p.) and (b) inhibition of forskolin-enhanced adenylyl cyclase activity (bromocriptine, 50 or 150 μM) in the ventral striatum were both suppressed as compared with saline controls. The decreases in D 2 receptor function were unrelated to the coupled G-proteins, since none of the Gαi-3, Gαo or Gαq in the ventral striatum exhibited quantitative differences between control and amphetamine sensitized rats. Collectively, these results demonstrate that intermittent amphetamine administration for a period of 14 days leads to diminished D 2 receptor expression and functions in the ventral striatum at late withdrawal periods. The decrease of D 2 receptors might reflect cellular mechanisms underlying the expression of amphetamine sensitization.