Modulation of the neurotoxic effects of methamphetamine by the selective kappa-opioid receptor agonist U69593

Kappa-opioid receptor agonists prevent alterations in dopamine neurotransmission that occur in response to repeated cocaine administration. The present microdialysis study examined whether administration of the selective kappa-opioid receptor agonist U69593 with methamphetamine prevents alterations in dopamine levels produced by neurotoxic doses of methamphetamine. Swiss Webster mice were injected intraperitoneally with methamphetamine (10.0 mg/kg) or saline, four times in 1 day, at 2-h intervals. Prior to the first and third injection, they received U69593 (0.32 mg/kg s.c.) or vehicle. Microdialysis was conducted 3, 7, or 21 days later. Basal and K+-evoked (60 and 100 mM) dopamine overflow were reduced 3 days after methamphetamine administration. These effects were long-lasting in that they were still apparent 7 and 21 days after methamphetamine treatment. Intrastriatal (5.0 and 50 microM) or systemic (1.0-10.0 mg/kg) administration of methamphetamine increased dopamine concentrations in control animals. In mice preexposed to methamphetamine, methamphetamine-evoked dopamine overflow was reduced. In animals that had received methamphetamine with U69593, basal dopamine levels did not differ from those of vehicle-treated controls. U69593 treatment attenuated the decrease in K+-evoked dopamine produced by prior methamphetamine exposure. The reduction in methamphetamine-evoked dopamine levels was also attenuated. The administration of U69593 alone did not modify basal or stimulus-evoked dopamine levels. These data demonstrate that repeated methamphetamine administration reduces presynaptic dopamine neuronal function in mouse striatum and that co-administration of a selective kappa-opioid receptor agonist with methamphetamine attenuates these effects. U69593 treatment did not modify the hyperthermic effects of methamphetamine, indicating that this kappa-opioid receptor agonist selectively attenuates methamphetamine-induced alterations in dopamine neurotransmission.     

Serotonin 5-HT(2) receptor stimulation of dopamine release in the posterior but not anterior nucleus accumbens of the rat

The objective of the present study was to examine the involvement of serotonin 5-HT(2) receptors within the rat nucleus accumbens (Acc) in the regulation of dopamine (DA) release using in vivo microdialysis. Perfusion with the 5-HT(2) agonist (+)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), at concentrations of 25-250 microM, through microdialysis probes located in the posterior Acc increased extracellular DA levels to a maximum of 200% of baseline. DOI-induced increases in the extracellular levels of DA were Ca(2+) dependent and were inhibited by co-perfusion with the 5-HT(2) antagonist LY-53,857. DOI enhancement of the extracellular concentrations of DA was observed when probes were implanted in the Acc core and shell regions posterior to anteroposterior +1.2 mm from bregma, whereas a small reduction in the extracellular levels of DA was observed in the anterior Acc. There were no differences between core and shell subdivisions within either the anterior or the posterior Acc. These results suggest that activation of 5-HT(2) receptors within the posterior, but not anterior, Acc stimulates DA release, indicating rostral-caudal differences in the interactions of 5-HT with DA systems in the Acc.     

Behavioral sensitization to amphetamine is not accompanied by changes in glutamate receptor surface expression in the rat nucleus accumbens

We examined whether behavioral sensitization to amphetamine is associated with redistribution of glutamate receptors (GluR) in the rat nucleus accumbens (NAc) or dorsolateral striatum (DLSTR). Following repeated amphetamine treatment and 21 days of withdrawal, surface and intracellular levels of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or NMDA receptor subunits were determined using a protein cross-linking assay. In contrast to our previous results in cocaine-sensitized rats, we did not observe redistribution of GluR1 or GluR2 to the cell surface in the NAc after amphetamine withdrawal, although a small increase in total GluR1 was found in the shell subregion. Nor did we observe activation of signaling pathways associated with cocaine-induced AMPA receptor trafficking or changes in NMDA receptor subunits. No significant changes were observed in the DLSTR. We also investigated the effect of administering a challenge injection of amphetamine to amphetamine-sensitized rats 24 h prior to biochemical analysis based on prior studies showing that cocaine challenge decreases AMPA receptor surface expression in the NAc of cocaine-sensitized rats. GluR1 and GluR2 were not significantly altered in either NAc or DLSTR, although a modest effect on GluR3 cannot be ruled out. Our results suggest that glutamate transmission in the NAc is dramatically different in rats sensitized to amphetamine versus cocaine.     

Dopamine D1 receptor activation of adenylyl cyclase, not phospholipase C, in the nucleus accumbens promotes maternal behavior onset in rats

A body of evidence supports the idea that the mesolimbic dopamine (DA) system modulates the natural increase in responsiveness female rats show toward offspring (biological or foster) at birth. In the absence of the full hormonal changes associated with pregnancy and birth, female rats do not show immediate responsiveness toward foster offspring. Activation of the mesolimbic DA system can produce an immediate onset of maternal behavior in these females. For example, female rats that are hysterectomized and ovariectomized on day 15 of pregnancy (15HO) and presented with pups 48 hours later normally show maternal behavior after 2-3 days of pup exposure, but will show maternal behavior on day 0 of testing after microinjection of the DA D₁ receptor agonist, SKF 38393, into the nucleus accumbens (NA) at the time of pup presentation. DA D₁ receptor stimulation is known to activate cAMP intracellular signaling cascades via its stimulation of adenylyl cyclase (AC). However, some DA D₁ receptors are also linked to phospholipase C (PLC) and are capable of activating phosphatidylinositol signaling cascades. SKF 38393 stimulates both types of D₁ receptors. Here we provide evidence that the facilitatory effects of DA D₁ receptor stimulation in the NA on maternal behavior are mediated by AC-linked DA D₁ receptors. By examining the effects of intra-NA application of SKF 83822, a drug which selectively binds DA D₁-AC receptors, or SKF 83959, a drug which selectively activates D₁-PLC-linked receptors, we find that only SKF 83822 facilitates maternal behavior onset.