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Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0–360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity. [ABSTRACT FROM AUTHOR]

The behavioral manifestations of psychostimulant-induced sensitization vary markedly between young and adult rats, suggesting that the neural mechanisms mediating this phenomenon differ across ontogeny. In this project we examined the importance of D1 and D2 receptors for the induction and expression of cocaine-induced behavioral sensitization during the preweanling period. In the behavioral experiments, rats were injected with reversible D1 and/or D2 antagonists (SCH23390 and/or raclopride) or an irreversible receptor antagonist (EEDQ) either before cocaine administration on the pretreatment day (induction) or before cocaine challenge on the test day (expression). In the EEDQ experiments, receptor specificity was assessed by using selective dopamine antagonists to protect D1 and/or D2 receptors from inactivation. Receptor binding assays showed that EEDQ caused substantial reductions in dorsal striatal D1 and D2 binding sites, while SCH23390 and raclopride fully protected D1 and D2 receptors from EEDQ-induced alkylation. Behavioral results showed that neither D1 nor D2 receptor stimulation was necessary for the induction of cocaine sensitization in preweanling rats. EEDQ disrupted the sensitization process, suggesting that another receptor type sensitive to EEDQ alkylation was necessary for the induction process. Expression of the sensitized response was prevented by an acute injection of a D1 receptor antagonist. The pattern of DA antagonist-induced effects described for preweanling rats is, with few exceptions, similar to what is observed when the same drugs are administered to adult rats. Thus, it appears that maturational changes in D1 and D2 receptor systems are not responsible for ontogenetic differences in the behavioral manifestation of cocaine sensitization. [ABSTRACT FROM AUTHOR]

Serotonin 5-HT 1A receptor agonists increase locomotor activity of both preweanling and adult rodents. The part played by the 5-HT 1B receptor in locomotion is less certain, with preliminary evidence suggesting that the actions of 5-HT 1B receptor agonists are not uniform across ontogeny. To more fully examine the role of 5-HT 1B receptors, locomotor activity and axillary temperatures of preweanling and adult male and female rats was assessed. In the first experiment, adult (PD 70) and preweanling (PD 10 and PD 15) male and female rats were injected with the 5-HT 1B agonist CP 94253 (2.5–10 mg/kg) immediately before locomotor activity testing and 60 min before axillary temperatures were recorded. In the second experiment, specificity of drug action was determined in PD 10 rats by administering saline, WAY 100635 (a 5-HT 1A antagonist), or GR 127935 (a 5-HT 1B antagonist) 30 min before CP 94253 (10 mg/kg) treatment. CP 94253 significantly increased the locomotor activity of preweanling rats on PD 10, an effect that was fully attenuated by GR 127935. Conversely, CP 94253 significantly decreased the locomotor activity of male and female adult rats, while CP 94253 did not affect the locomotor activity of PD 15 rats. Regardless of age, CP 94253 (2.5–10 mg/kg) significantly reduced the axillary temperatures of preweanling and adult rats. When considered together, these results show that 5-HT 1B receptor stimulation activates motor circuits in PD 10 rats; whereas, 5-HT 1B receptor agonism reduces the overall locomotor activity of adult rats, perhaps by blunting exploratory tendencies. [ABSTRACT FROM AUTHOR]

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: Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2 S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. [Copyright &y& Elsevier]

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]

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: 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]

Neuronal adaptations involving dopaminergic, glutamatergic, and serotonergic neurotransmitter systems are responsible for behavioral sensitization. Because of common underlying mechanisms, cross-sensitization between compounds of different drug classes can be observed. The purpose of the present study was to determine whether a one- or four-day pretreatment regimen of RU 24969 (a 5-HT 1A/1B receptor agonist) would reciprocally cross-sensitize with cocaine or methamphetamine in male and female preweanling rats. Rats were pretreated with RU 24969 (0 or 5 mg/kg) for 4 days (PD 17–20) and then challenged with cocaine (10 or 20 mg/kg) or methamphetamine (1 or 2 mg/kg) on PD 22. Reciprocal cross-sensitization was also assessed (i.e., rats were pretreated with psychostimulants and tested with RU 24969). In a follow-up experiment, the ability of RU 24969 and cocaine to reciprocally cross-sensitize was assessed using a one-day pretreatment regimen. Reciprocal cross-sensitization between cocaine and RU 24969 was evident in preweanling rats, whereas methamphetamine and RU 24969 did not cross-sensitize. When a one-trial pretreatment regimen was used, cross-sensitization was only detected when rats were pretreated with RU 24969 and tested with cocaine, but not the reverse. In sum, the present results show that the nonselective 5-HT 1A/1B receptor agonist RU 24969 cross-sensitizes with cocaine, but not methamphetamine, in preweanling rats. This dichotomy may be a function of cocaine having a greater affinity for the serotonin transporter than methamphetamine. • RU 24969 reciprocally cross-sensitized with cocaine in preweanling rats. • RU 24969 and methamphetamine did not cross-sensitize. • The differential ability to cross-sensitize may be due to affinity for the 5-HTT. [ABSTRACT FROM AUTHOR]

• RU 24969 increases locomotion, while reducing body temperature and motoric capacity. • Repeated RU 24969 treatment caused a pronounced tolerance response to develop. • A subsensitivity of 5-HT 1 receptors may be responsible for the tolerance response. Serotonin (5-HT) 1A and 1B receptors have been implicated in behavioral sensitization, but adult rats appear to develop tolerance to RU 24969 (a 5-HT 1A/1B receptor agonist) rather than a sensitized response. The purpose of the present study was to determine whether a one- or four-day pretreatment regimen of RU 24969 would cause sensitization or tolerance in male and female preweanling rats. Depending on experiment, rats were pretreated with RU 24969 (0, 2.5, or 5 mg/kg) for 1 or 4 days (PD 17–20), while testing with lower or higher doses of RU 24969 occurred on PD 22. Locomotor activity, motoric capacity, and axillary temperatures were recorded. The role of Pavlovian contextual conditioning was assessed by administering RU 24969 to rats in either the home cage or a novel environment. On the first pretreatment day, RU 24969 caused both an increase in forward locomotion and motoric impairment, along with a substantial decrease in axillary temperatures. Repeated treatment with the same dose of RU 24969 caused all three dependent measures to show a tolerance response. When given a higher dose of RU 24969 on the test day, the responses lost due to repeated drug treatment were fully (locomotor activity) or partially (motoric capacity and axillary temperatures) reinstated. There was no evidence of behavioral tolerance. Results are consistent with the hypothesis that a subsensitivity of 5-HT 1A/1B receptors is at least partially responsible for the tolerance caused by RU 24969, but dispositional tolerance cannot be excluded as a contributing factor. [ABSTRACT FROM AUTHOR]

Abstract: Methylphenidate is commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) in school-aged children, and there is an increasing trend to prescribe methylphenidate to younger preschool-aged children. While the efficacy of methylphenidate is not in question, there is evidence that early methylphenidate treatment may have long-term effects on later drug responsiveness. The goal of this study was to determine whether early exposure to methylphenidate would alter morphine-induced conditioned place preference (CPP) and sucrose-reinforced lever-pressing in young adult rats. We also assessed whether early methylphenidate exposure would impact dopamine D2 binding sites. Sprague–Dawley rats were treated with methylphenidate (0, 2, or 5 mg/kg) once a day from PD 11–PD 20. On PD 60, morphine-induced CPP or sucrose-reinforced lever-pressing was assessed. A 10-day CPP procedure was used, which included 1 preconditioning day, 8 conditioning days, and 1 test day. After CPP testing, D2 receptor binding was determined in striatal and accumbal tissue samples. In the sucrose experiment, rats were trained to lever-press on a progressive ratio schedule for one sucrose pellet. Results showed that early exposure to methylphenidate (5 mg/kg) increased the magnitude of morphine-induced CPP. Exposure to methylphenidate did not alter the number of D2 binding sites, however, there were positive correlations between the number of D2 binding sites and the strength of the CPP. In the sucrose-reinforced lever-press experiment, rats exposed to methylphenidate (2 and 5 mg/kg) had higher break points than saline controls. These results suggest that early exposure to methylphenidate alters reward system functioning, thereby making these systems more sensitive to appetitive stimuli. [Copyright &y& Elsevier]

Abstract: Partial D2 receptor agonists (e.g., terguride, preclamol, and aripiprazole) have antagonist-like effects at normosensitive D2 postsynaptic receptors and synthesis modulating autoreceptors. In reserpine-pretreated adult and young rats, however, partial D2 agonists function like high efficacy agonists at D2 postsynaptic receptors and autoreceptors (i.e., terguride increases locomotor activity and decreases dopamine synthesis). The purpose of the present study was to examine the time-course of these pharmacological effects. In all experiments, preweanling rats were given daily injections of reserpine (1 mg/kg, i.p.) or vehicle on postnatal day (PD) 16–PD 20. In the dopamine synthesis experiments, the ability of terguride (0.8 mg/kg) to reduce striatal DOPA accumulation (in NSD-1015 treated rats) was assessed either 5 h or 1, 2, 4, or 8 days (Experiment 1) or 4, 8, 12, 16, 20, or 24 days (Experiment 2) after reserpine pretreatment. In the behavioral experiments, locomotor activity of vehicle or terguride (0.8 mg/kg, i.p.) treated rats was assessed 5 h or 1, 2, 4, or 8 days after the 5-day reserpine regimen. Results from the dopamine synthesis experiments showed that terguride caused agonist-like effects (i.e., decreased DOPA accumulation) at only the 5 h and 1 day time points, although terguride did not induce its normal antagonist-like effects even 20 days after reserpine pretreatment. In the behavioral experiments, terguride stimulated locomotor activity for only the initial 2 days after reserpine pretreatment. The results of the present study show that the agonistic effects of terguride at pre- and postsynaptic receptors are short-lived, but terguride may not exhibit normal antagonistic effects, at least at synthesis modulating autoreceptors, until long after conclusion of reserpine pretreatment. [Copyright &y& Elsevier]

Abstract: Recreational use of methylenedioxymethamphetamine (MDMA) has dramatically increased among juveniles and young adults of child-bearing age, and the potential for fetal exposure has increased. For this reason, it is surprising that comparatively few studies have assessed the long-term impact of early MDMA exposure on serotonin (5-HT) and dopamine (DA) neurotransmitter systems. The purpose of this study was to determine whether repeated exposure to MDMA during the preweanling period would cause long-term changes in 5-HT and DA functioning. Rats were treated with saline or 20 mg/kg MDMA (two injections per day) from postnatal day (PD) 11–20. At PD 90, rats were killed, and their dorsal striatum, prefrontal cortex, and hippocampus were removed. 5-HT and DA content, as well as their metabolites, were measured using HPLC. In addition, cAMP-dependent protein kinase A (PKA) activity and agonist-stimulated [35S]GTPγS binding was assayed using tissue homogenates from each brain region. Results indicated that early MDMA exposure caused a decrease in PKA activity and 5-HT content in the prefrontal cortex and hippocampus while increasing the efficacy of 5-HT1A receptors as measured by agonist-stimulated [35S]GTPγS binding. Additionally, DA content was reduced in the dorsal striatum and prefrontal cortex. These data indicate that early MDMA exposure has long-term effects on the 5-HT and DA neurotransmitter systems that may be mediated, at least partially, by changes in 5-HT1A receptor sensitivity. [Copyright &y& Elsevier]

Abstract: There is evidence that partial D2-like dopamine agonists (e.g., terguride) may not affect D2-like postsynaptic receptors in an adult-typical manner during the preweanling period. To determine whether synthesis modulating dopamine autoreceptors are also affected in an adult atypical manner by partial D2-like agonists, preweanling rats were treated either acutely or repeatedly with reserpine (low dopaminergic tone) or vehicle (high dopaminergic tone). The ability of terguride, quinpirole (a full D2-like agonist), or haloperidol (a D2-like antagonist) to alter striatal DOPA accumulation was assessed after NSD-1015 treatment on postnatal day (PD) 21. In a separate set of experiments, terguride''s ability to modulate dopamine synthesis was assessed in rats treated with the nerve impulse flow inhibitor γ-butyrolactone (GBL). Results showed that both terguride and quinpirole reduced striatal DOPA accumulation during a state of low dopaminergic tone (i.e., after reserpine pretreatment). During a state of high dopaminergic tone (i.e., after vehicle pretreatment), terguride had similar effects as haloperidol and increased DOPA accumulation. Terguride, like quinpirole, partially inhibited the GBL-induced increase in striatal DOPA accumulation. When considered together, these results indicate that synthesis modulating D2-like autoreceptors are functional during the late preweanling period, and they respond in an adult-typical manner to a partial D2-like agonist. [Copyright &y& Elsevier]

Partial D2-like receptor agonists act as functional antagonists when given during periods of high dopaminergic tone (e.g., when self-administering cocaine or amphetamine). For this reason, we determined whether pretreatment with the partial D2-like agonist terguride would block the induction and/or expression of cocaine-induced behavioral sensitization in preweanling rats. More specifically, we examined (a) whether repeated administration of terguride alone (0.4–1.6 mg/kg) would support behavioral sensitization (Experiment 1); (b) whether injecting preweanling rats with terguride (0.1–1.6 mg/kg) during the pretreatment phase would block the induction and ultimate expression of cocaine-induced behavioral sensitization (Experiment 2); and (c) whether injecting rats with terguride (0.2–0.8 mg/kg) on the test day would block the expression of cocaine sensitization (Experiment 3). Results showed that repeated terguride administration did not induce behavioral sensitization by itself, nor did it block the induction of cocaine sensitization in preweanling rats. Interestingly, terguride reduced, but did not fully attenuate, the locomotor activity of cocaine-treated rats during the pretreatment phase. When given on the test day, terguride also depressed cocaine-induced locomotor activity, but rather than blocking the expression of behavioral sensitization, terguride seemed to cause a general reduction in locomotion. Because partial D2-like agonists attenuate cocaine- and amphetamine-induced reward, it has been proposed that this class of drug might serve as an effective pharmacotherapy for psychostimulant abuse. Although partial D2-like agonists may prove useful in this regard, results from the present study suggest that terguride would not block sensitization components of the addiction process. [Copyright &y& Elsevier]

• Ketamine increased the locomotion of female rats across ontogeny, but only minimally enhanced the locomotion of male adolescent and adult rats. • Ketamine's locomotor stimulating effects are mediated through a monoaminergic mechanism. • It appears that ketamine enhances locomotor activity through indirect actions rather than having direct effects at the presynaptic terminal. Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d- amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d- amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87–96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons. [ABSTRACT FROM AUTHOR]