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Aripiprazole is a second-generation antipsychotic that is increasingly being prescribed to children and adolescents. Despite this trend, little preclinical research has been done on the neural and behavioral actions of aripiprazole during early development. In the present study, young male and female Sprague-Dawley rats were pretreated with vehicle, haloperidol (1 mg/kg), or aripiprazole (10 mg/kg) once daily on postnatal days (PD) 10–20. After 1, 4, or 8 days (i.e. on PD 21, PD 24, or PD 28), amphetamine-induced locomotor activity and stereotypy, as well as dorsal striatal D2 receptor levels, were measured in separate groups of rats. Pretreating young rats with aripiprazole or haloperidol increased D2 binding sites in the dorsal striatum. Consistent with these results, dopamine supersensitivity was apparent when aripiprazole- and haloperidol-pretreated rats were given a test day injection of amphetamine (2 or 4 mg/kg). Increased D2 receptor levels and altered behavioral responding persisted for at least 8 days after conclusion of the pretreatment regimen. Contrary to what has been reported in adults, repeated aripiprazole treatment caused D2 receptor up-regulation and persistent alterations of amphetamine-induced behavior in young rats. These findings are consistent with human clinical studies showing that children and adolescents are more prone than adults to aripiprazole-induced side effects, including extrapyramidal symptoms. [ABSTRACT FROM AUTHOR]

Abstract: The early ontogeny of D-amphetamine-induced one-trial behavioral sensitization was characterized using male and female preweanling and preadolescent rats. In Experiment 1, rats were injected with saline or D-amphetamine (1, 4, or 8mg/kg) in activity chambers or the home cage on postnatal day (PD) 12, PD 16, PD 20, or PD 24. One day later, rats were challenged with either 0.5 or 2mg/kg D-amphetamine and distance traveled was measured in activity chambers for 120min. In Experiment 2, saline or D-amphetamine was administered in activity chambers on PD 24, while a challenge injection of D-amphetamine (0.25–4mg/kg) was given on PD 25. At younger ages (PD 13 and PD 17), a strong sensitized response was evident on the test day regardless of whether rats were pretreated with D-amphetamine (4 or 8mg/kg) before being placed in the activity chamber or 30min after being returned to the home cage. Rats did not display D-amphetamine-induced behavioral sensitization on PD 21, nor was context-dependent sensitization apparent on PD 25 even when a broad dose range of D-amphetamine was used. When low doses of D-amphetamine were administered on the pretreatment and test days (1 and 0.5mg/kg, respectively), sensitized responding was not evident at any age. In summary, D-amphetamine-induced one-trial behavioral sensitization was only apparent within a narrow developmental window during early ontogeny. This ontogenetic pattern of sensitized responding is similar to the one produced by methamphetamine and distinct from the pattern produced by cocaine. The unique sensitization profiles resulting from repeated D-amphetamine and cocaine treatment may be a consequence of their different mechanisms of action. [Copyright &y& Elsevier]

The article presents the conducted study to determine the effect of postnatal manganese (Mn) chloride exposure on the D2 long (D2L) and D2 short (D2S) receptor isoforms of the brain. In the study, Sprague-Dawley male rats were given daily oral supplements of Mn chloride. Based on the results, postnatal Mn exposure affects the functioning of postsynaptic dopamine (DA) receptors.

Rationale: Treating children and adolescents with partial D2-like agonists is becoming increasingly common, although few developmental animal studies have assessed the psychopharmacology of this class of drug. Contrary to results from adult rat studies, it has been reported that partial D2-like agonists may not induce agonist-like behavioral effects in preweanling rats during states of low dopaminergic tone. Objective: The purpose of the present study was to determine whether a partial D2- like agonist would act as an agonist in preweanling rats after a 5-day regimen of the dopamine-depleting agent reserpine or the tyrosine hydroxylase inhibitor α-methyl- DL-p-tyrosine (AMPT). Methods: Sprague--Dawley rats were pretreated with reserpine (1 mg/kg per day) or AMPT (3x200 mg/kg per day) on postnatal day (PD) 16--PD 20. Either 2 h (AMPT) or 5 h (reserpine) after the last pretreatment injection, rats were treated with saline, the partial D2-like agonist terguride, or the full D2-like agonist R(-)-propylnorapomorphine (NPA). Distance traveled and repetitive motor movements were measured for 60 min. Results: After repeated reserpine treatment, both terguride and NPA increased the distance-traveled scores of preweanling rats; however, only NPA, but not terguride, increased distance-traveled scores after a 5-day regimen of AMPT or an acute injection of reserpine. Conclusions: It is now apparent that partial D2-like agonists are capable of inducing agonist-like behavioral effects in preweanling rats during a state of low dopaminergic tone. For agonistic actions to be observed, the pretreatment regimen must result in substantial and prolonged dopamine depletion. [ABSTRACT FROM AUTHOR]

Rationale: Repeated exposure to psychostimulant drugs results in conditioned activity and behavioral sensitization. Nonassociative cellular changes are necessary for behavioral sensitization, while associative processes appear to modify the sensitized response. Objective: The purpose of the present study was to determine whether the absence of the D1 receptor would disrupt associative processes modulating sensitization and conditioned activity. Methods: Wild-type and D1 receptor knockout mice (i.e., D1-deficient mice) were injected with amphetamine (AMPH; 8 mg/kg, IP) before being placed in a previously novel test chamber (AMPH-Test group) or before being returned to the home cage (AMPH-Home group). Separate groups of mice were injected with saline (SAL) at the same time points. Distance traveled was measured 60 min each day, with the preexposure phase lasting 1 or 7 days. Sensitization was subsequently assessed after an injection of AMPH (1 mg/kg, IP), while conditioned activity was assessed after an injection of SAL. Results: After a 1-day preexposure phase, wild-type and D1-deficient mice exhibited similar patterns of sensitization and conditioned activity. After a 7-day preexposure phase, (1) D1-deficient mice exhibited more robust context-specific sensitization than wild-type mice, (2) only D1-deficient mice showed context-independent sensitization, and (3) only D1-deficient mice showed conditioned activity. Conclusions: Repeatedly treating D1-deficient mice with AMPH appears to cause a general increase in responsivity. The reason for this hyper-responsivity is uncertain, but it is possible that cues from the testing environment were unable to inhibit responding (i.e., associative processes were disrupted). Alternatively, compensatory mechanisms (e.g., increases in D2-like receptors) may affect processes underlying sensitization and conditioned activity. [ABSTRACT FROM AUTHOR]

Rationale: In adult rats, the partial D2-like agonist terguride acts as an antagonist at normosensitive D2-like post-synaptic receptors, while it acts as an agonist at the same receptors during states of low dopaminergic tone. Objective: The purpose of the present study was to determine whether partial D2-like agonists exhibit both antagonistic and agonistic actions during the preweanling period. Methods: In experiments 1 and 2 (examining the agonistic actions of terguride), preweanling rats were either given an escalating regimen of amphetamine to induce a state of amphetamine withdrawal or pretreated with the tyrosine hydroxylase inhibitor AMPT. Distance traveled was measured after rats were injected with saline, terguride (0.4-1.6 mg/kg), or the full D2-like receptor agonist NPA (0.01 mg/kg). In experiment 3 (examining the antagonistic actions of terguride), preweanling rats were pretreated with terguride 30 min before they were tested with saline, NPA (0.05 mg/kg), or amphetamine (1.5 mg/kg). Results: NPA had an exaggerated locomotor activating effect when tested under conditions of amphetamine withdrawal, while the partial D2-like agonist did not enhance distance traveled under any circumstance. Similarly, NPA increased and terguride did not affect the distance-traveled scores of AMPT-pretreated rats. In experiment 3, terguride pretreatment significantly reduced the distance traveled of amphetamine-treated and NPA-treated rats. Conclusions: The behavioral evidence indicates that, during the preweanling period, terguride antagonizes D2-like post-synaptic receptors in a state of high dopaminergic tone; however, there is no evidence that terguride is capable of stimulating D2-like post-synaptic receptors during states of low dopaminergic tone. [ABSTRACT FROM AUTHOR]

κ-Opioid receptor agonists (e.g., enadoline or U-50,488) increase the locomotor activity of preweanling rats, while the same drugs depress the locomotor activity of adults. Curiously, direct stimulation of dopamine (DA) D[sub 2] -like receptors fully attenuates the U-50,488-induced locomotor activity of preweanling rats. The purpose of the present study was to determine whether indirect DA agonists (i.e., cocaine, methylphenidate, and amphetamine) would also attenuate U-50,488's behavioral effects. In two experiments, 17-day-old rats were injected with saline or U-50,488 (5 mg/kg, sc) and locomotor activity and stereotyped sniffing were assessed. After 20 min, the saline- and U-50,488-pretreated rats were injected with saline, cocaine (5, 10, or 20 mg/kg, ip), methylphenidate (10 or 20 mg/kg, ip), amphetamine (2.5 or 5 mg/kg, ip), or the direct D[sub 2] -like receptor agonist NPA (1 mg/kg, ip). As expected, U-50,488 dramatically enhanced the locomotor activity of 17-day-old rats, while attenuating the stereotyped sniffing caused by indirect and direct DA agonists. All three indirect DA agonists augmented U-50,488's locomotor activating effects across the initial 10 min of testing and then activity declined to U-50,488 control values. Direct stimulation of DA receptors produced nearly opposite effects because NPA attenuated U-50,488-induced locomotor activity across the entire testing session. It is uncertain why direct and indirect DA agonists affected U-50,488-induced locomotor activity differently, but the relative amount of DA D[sub 1] -like receptor activation is probably not responsible. © 1999 John Wiley & Sons, Inc. Dev Psychobiol 34: 183–193, 1999 [ABSTRACT FROM AUTHOR]

In three experiments, the effects of augmenting or blocking dopamine (DA) D-2-receptor activity on the ontogeny of response suppression learning of preweanling rat pups were determined. In the initial experiment, rat pups were trained to traverse a straight alley for nipple attachment to an anesthetized dam. When footshock (0.2 mA, 0.5 sec) was made contingent on responding, younger (11- and 13-day-olds) rat pups were deficient to older (17- and 19-day-olds) pups at withholding punished responding. In the subsequent experiments, response suppression learning was assessed after injecting 11- and 17-day-old rat pups with the specific DA D-2 agonist, LY 171555 (0.005-, 0.01-, and 0.1-mg/kg, i.p.), or the specific DA D-2 antagonist, sulpiride (5.0-, 15.0-, and 50.0-mg/kg, i.p.). LY 171555 enhanced the punished responding of both the 11- and 17-day-old rat pups; whereas, sulpiride increased the punished responding of the 17-, btu not the 11-day-olds. In four additional experiments, the effects of LY 171555 and sulpiride on the locomotor activity, nociception, and reinforcement processes of 17-day-old rat pups was assessed. Rat pups given LY 171555 (0.01 mg/kg, i.p.) exhibited enhanced locomotor activity and a trend towards hyperanalgesia using a hot plate task. Sulpiride (15.0 mg/kg, i.p.) completely antagonized LY 171555's activity enhancing effects and had hyperalgesic properties. In two experiments, sulpiride did not affect the nonpunished appetitive responding of the 17-day-olds; whereas, haloperidol-treated pups responded on fewer reinforced trials than did saline-treated pups. Therefore, these results indicate that the response suppression learning of 17-day-old rat pups is mediated, at least partially, by a DAD-2 receptor system, and that D-2 receptors are also involved in the locomotor activity and nociceptive responses of young rat pups. [ABSTRACT FROM AUTHOR]