Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in the adult rat. Protein kinase A (PKA) and adenylyl cyclase (basal and DA-stimulated) activity in the dorsal striatum (i.e., caudate-putamen) were measured to determine whether MPH-induced alterations in these enzymes correlate with the occurrence of behavioral sensitization. In two experiments, adult rats were injected (i.p.) on 5 consecutive pre-exposure days with saline or MPH (5, 10, 15, or 20 mg/kg). Sensitization was tested after a single abstinence day, with rats receiving a challenge injection of MPH prior to either a 40- or 150-min testing session (additional control groups received saline on the test day). Immediately after the 40-min testing session, rats were killed and tissue from the dorsal striatum was dissected for later analysis of PKA and adenylyl cyclase activity. Results showed that repeated MPH treatment sensitized the stereotyped sniffing, but not the locomotor activity, of adult rats. PKA activity was significantly depressed in rats treated with MPH (10 or 20 mg/kg) during both the pre-exposure and test day phases. DA-stimulated adenylyl cyclase activity was reduced after chronic MPH treatment, while basal adenylyl cyclase values were enhanced. Thus, the present study showed that MPH was able to sensitize the stereotyped behaviors of adult rats, an action that corresponded with drug-induced changes in dorsal striatal DA signal transduction mechanisms.

Kappa opioid mediated locomotor activity in the preweanling rat: role of pre- and postsynaptic dopamine receptors.

Treatment with a non-selective DA receptor agonist (i.e., NPA) has previously been shown to attenuate the kappa opioid mediated locomotor activity of preweanling rats. The purpose of the present study was to determine whether stimulation of D1-like or D2-like receptors is responsible for this behavioral effect and whether the critical DA receptors are located pre- or postsynaptically. To assess these questions, 17-day-old rats were injected with saline, the D2/D3 agonist quinpirole (0.1, 0.3, or 1.0 mg/kg, i.p.), or the D1 agonist SKF 38393 (7.5, 15, or 30 mg/kg, i.p.), 20 min after receiving the kappa opioid agonist U-50,488 (5 mg/kg, s.c.) or saline. Results showed that the locomotor activating effects of U-50,488 were blocked by the D2/D3, but not the D1, receptor agonist. To dissociate the effects of DA autoreceptors and postsynaptic receptors, 17-day-old rats were given alpha-methyl-DL-p-tyrosine (AMPT reduces endogenous DA stores) prior to U-50,488 or amphetamine (1.5 mg/kg, s.c.) treatment. Interestingly, AMPT (which reduced DA levels by more than 80%) fully attenuated amphetamine-induced locomotor activity, while having little effect on U-50,488-induced locomotion. In addition, quinpirole blocked the locomotor activating effects of U-50,488 in rats acutely depleted of DA. When considered together, these results indicate that kappa opioid stimulation enhances locomotor activity regardless of presynaptic DA levels. Similarly, quinpirole appears to attenuate U-50,488-induced locomotor activity by stimulating postsynaptic D2-like receptors, since the D2/D3 agonist inhibited kappa opioid mediated behavior independent of endogenous DA levels.

Paradoxical effects of kappa-opioid stimulation on the locomotor activity and Fos immunoreactivity of the preweanling rat: role of dopamine receptors.

The kappa-opioid agonist U-50,488 increases the locomotor activity of preweanling rats. The authors attempted to determine whether this effect was modulated by dopamine (DA) system functioning. Surprisingly, U-50,488's locomotor activating effects were attenuated by both the DA receptor antagonist flupenthixol and the DA receptor agonist R(-)-propylnorapomorphine (NPA). In order to determine those brain areas stimulated by U-50,488, Fos immunoreactivity was assessed in 17- and 80-day-old rats. U-50,488 not only enhanced the locomotor activity of the younger rats, but it also enhanced Fos expression in various brain areas, including the nucleus accumbens and medial striatum. NPA blocked U-50,488-induced Fos expression in the latter region. When considered together, these results indicate that U-50,488 does not increase locomotion by stimulating a DA mechanism. Instead, either agonizing or antagonizing DA receptors is sufficient to disrupt U-50,488's locomotor activating effects in the preweanling rat.