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Acute amphetamine (AMPH) exposure elevates extracellular dopamine by a variety of mechanisms including increasing the rate of internalization of the plasma membrane dopamine transporter (DAT). We report here that AMPH also activates the small GTPases, Rho and Rac. In recombinant expression systems, primary cultures and midbrain slices, activation of Rho and the downstream Rho-kinase (ROCK) triggers endocytosis of DAT. Inhibition of RhoA activity blocks AMPH-induced DAT internalization, while Rac1 inhibition has no significant effect on DAT trafficking. ROCK inhibitors also prevent AMPH-induced DAT internalization. Intriguingly, we found that AMPH must enter the cell to initiate this cascade. Further, intracellular AMPH also increases cAMP, leading to the phosphorylation of Rho by protein kinase A (PKA) that inactivates Rho and serves as a break on DAT internalization, thus demonstrating an important interaction between PKA- and RhoA-dependent signaling in mediating the actions of AMPH. In agreement with o...

There is growing evidence that activation of either protein kinases or protein phosphatases determines the type of plasticity observed after different patterns of hippocampal stimulation. Because activation of the extracellular signal-regulated kinase (ERK) has been shown to be necessary for long-term potentiation, we investigated the regulation of ERK in long-term depression (LTD) in the adult hippocampus in vivo. We found that ERK immunoreactivity was decreased following the induction of LTD and that this decrease required NMDA receptor activation. The LTD-associated decrease in ERK immunoreactivity could be simulated in vitro via incubation of either purified ERK2 or hippocampal homogenates with either protein phosphatase 1 or protein phosphatase 2A. The protein phosphatase-dependent decrease in ERK immunoreactivity was inhibited by microcystin. Intrahippocampal administration of the protein phosphatase inhibitor okadaic acid blocked the LTD-associated decrease in ERK2, but not ERK1, immunoreactivity. Collectively, these data demonstrate that protein phosphatases can decrease ERK immunoreactivity and that such a decrease occurs with ERK2 during LTD. These observations provide the first demonstration of a biochemical alteration of ERK in LTD.

In this study, litters of rat pups and their mothers were continuously video-monitored from Day 14 to Day 35 postpartum in order to describe the behavioral changes that occur during that period. Prior to the onset of solid food intake (Day 18), pups spent most of their active time suckling. During Days 18 to 26, feeding, drinking, grooming, and play-fighting rapidly became frequent daily activities, while suckling gradually began to decline. By Day 28, pups' food and water intake relative to body weight and time allocated to the new behaviors reached asymptote. Pups nevertheless continued to suckle until Day 34. These results suggest that (1) the transition from milk to solid food is embedded in a multitude of behavioral changes; (2) these behavioral changes have distinct temporal characteristics; and (3) the developmental period between Days 14 and 34 can be divided into three phases.