Evaluation of luteolysis, follicle size, and time to ovulation in Holstein heifers treated with two different analogs and doses of prostaglandin-F2α.

Objectives were to evaluate the effect of 2 analogs of PGF2α (cloprostenol vs. dinoprost) and 2 doses (1 injection vs. 2 injections) on luteolysis, follicle diameter, hormonal concentrations, and time to ovulation in dairy heifers. Holstein heifers were fitted with automated estrus detection devices and had their estrous cycle synchronized using PGF2α and an intravaginal insert containing progesterone. Heifers detected in estrus were blocked by weight and randomly assigned to 1 of 4 treatments in a 2 × 2 factorial arrangement: cloprostenol on d 7 after estrus (CLOx1; n = 45), cloprostenol on d 7 and 8 after estrus (CLOx2; n = 41), dinoprost on d 7 after estrus (DINx1; n = 43), or dinoprost on d 7 and 8 after estrus (DINx2; n = 44). Treatment with the first injection of PGF2α was defined as experiment d 0. Area and blood flow of corpus luteum (CL) and diameter of follicles >5 mm were recorded every 12 h from d 0 to estrus and every 6 h thereafter until ovulation. Blood was sampled every 6 h from d 0 until ovulation. Heifers treated with cloprostenol had shorter interval to luteolysis (± SEM; CLOx1 = 23.5 ± 2.2, CLOx2 = 22.9 ± 2.2, DINx1 = 32.6 ± 2.7, DINx2 = 26.4 ± 2.1 h); however, time to ovulation was not affected by treatment. A smaller proportion of heifers treated with a single injection of PGF2α underwent luteolysis compared with heifers treated with 2 injections (CLOx1 = 84.6 ± 6.2, CLOx2 = 100.0 ± 0.0, DINx1 = 59.7 ± 9.8, DINx2 = 96.3 ± 2.7%). Proportion of heifers that ovulated was smaller for DINx1 compared with other treatments (CLOx1 = 88.8 ± 5.1, CLOx2 = 100.0 ± 0.0, DINx1 = 55.2 ± 9.7, DINx2 = 94.4 ± 3.4%). Ovulatory follicle diameter was larger for DINx1 (18.2 ± 2.7 mm) compared with DINx2 (17.4 ± 2.7 mm), whereas dose did not affect the diameter of the ovulatory follicle in heifers treated with cloprostenol (CLOx1 = 17.6 ± 2.7 vs. CLOx2 = 17.8 ± 2.8 mm). Among heifers that underwent luteolysis, progesterone concentrations from 18 to 36 h after treatment were lesser in heifers treated with cloprostenol compared with those treated with dinoprost. Type of PGF2α did not affect progesterone concentrations past 36 h from treatment; however, heifers treated with 2 PGF2α injections had lesser progesterone concentrations and CL blood flow from 36 to 72 h after treatment compared with heifers that received a single PGF2α injection.

Resilience in Pre-Columbian Caribbean House-Building: Dialogue Between Archaeology and Humanitarian Shelter.

This paper responds to questions posed by archaeologists and engineers in the humanitarian sector about relationships between shelter, disasters and resilience. Enabled by an increase in horizontal excavations combined with high-resolution settlement data from excavations in the Dominican Republic, the paper presents a synthesis of Caribbean house data spanning a millennium (1400 BP- 450 BP). An analysis of architectural traits identify the house as an institution that constitutes and catalyses change in an emergent and resilient pathway. The "Caribbean architectural mode" emerged in a period of demographic expansion and cultural transition, was geographically widespread, different from earlier and mainland traditions and endured the hazards of island and coastal ecologies. We use archaeological analysis at the house level to consider the historical, ecological and regional dimensions of resilience in humanitarian action.

Dopamine receptor inactivation in the caudate-putamen differentially affects the behavior of preweanling and adult rats.

The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used to study the ontogeny of dopamine (DA) receptor functioning in young and adult rats. Most notably, systemic administration of EEDQ blocks the DA agonist-induced behaviors of adult rats, while leaving the behavior of preweanling rats unaffected. The purpose of the present study was to: (a) determine whether the age-dependent actions of EEDQ involve receptors located in the dorsal caudate-putamen (CPu) and (b) confirm that EEDQ's behavioral effects result from the inactivation of DA receptors rather than some other receptor type. In Experiment 1, EEDQ or DMSO was bilaterally infused into the CPu on PD 17 or PD 84. After 24h, rats were given bilateral microinjections of the full DA agonist R(-)-propylnorapomorphine (NPA) or vehicle into the dorsal CPu and behavior was assessed for 40 min. In Experiment 2, preweanling rats were treated as just described, except that DA receptors were protected from EEDQ-induced alkylation by administering systemic injections of D1 (SCH23390) and D2 (sulpiride) receptor antagonists. As predicted, microinjecting EEDQ into the dorsal CPu attenuated the NPA-induced locomotor activity and stereotypy of adult rats. In contrast, rats given bilateral EEDQ infusions on PD 17 exhibited a potentiated locomotor response when treated with NPA. Experiment 2 showed that DA receptor inactivation was responsible for NPA's actions. A likely explanation for these results is that EEDQ inactivates a sizable percentage of DA receptors on PD 17, but leaves the remaining receptors in a supersensitive state. This receptor supersensitivity, which probably involves alterations in G protein coupling, could account for NPA-induced locomotor potentiation. It is likely that adult rats to not show a similar EEDQ-induced change in receptor dynamics or DA receptor inactivation was more complete in older animals and effectively eliminated the expression of DA agonist-induced behaviors.

Age-dependent effects of kappa-opioid receptor stimulation on cocaine-induced stereotyped behaviors and dopamine overflow in the caudate-putamen: an in vivo microdialysis study.

kappa-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate-putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because kappa-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether kappa-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaine-induced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 microg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying kappa-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why kappa-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.

Postnatal manganese exposure alters dopamine transporter function in adult rats: Potential impact on nonassociative and associative processes.

In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 microg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [3H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaine-induced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [3H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mn-induced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior.

Effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial prefrontal cortex of preweanling rats.

The purpose of this study was to determine whether aripiprazole, a D2-like partial agonist increasingly prescribed to children, alters DA synthesis via actions at autoreceptors in the dorsal striatum and medial prefrontal cortex (mPFC) of preweanling rats. The ability of dopaminergic agents to alter DOPA accumulation in the striatum and mPFC was measured after NSD-1015 on postnatal day (PD) 20. Dopaminergic tone was manipulated by administering reserpine, gamma-butyrolactone (GBL), or through amphetamine withdrawal. Results showed that the partial agonists aripiprazole and terguride increased striatal DOPA accumulation under normosensitive conditions, but decreased DOPA accumulation in states of low dopaminergic tone. A different pattern of results was observed in the mPFC, because terguride and haloperidol, but not aripiprazole, increased DOPA accumulation under normosensitive conditions. In conclusion, the present data show that aripiprazole affects striatal synthesis modulating autoreceptors in an adult-typical manner during the late preweanling period. Unlike in adult rats, however, the mPFC of preweanling rats appears to contain transitory synthesis modulating autoreceptors that are sensitive to drug manipulation.

Effects of acute and repeated methamphetamine treatment on the ultrasonic vocalizations of postnatal rats.

Repeated exposure to cocaine (COC) has been reported to both increase ultrasonic vocalizations (USVs) of postnatal rats and enhance the crying of human infants. The purpose of the present study was to determine whether acute or repeated treatment with another commonly abused psychostimulant, methamphetamine (MAP), would affect the USV production of postnatal rats. In the first experiment, USVs were measured 30 min after rats were given an acute injection of saline or MAP (1, 2, 4, or 8 mg/kg ip) on postnatal day (PD) 10. In the second experiment, rats were exposed to MAP (0, 1, or 4 mg/kg/day ip) on PD 2-8 or PD 2-9. On PD 10, rats were given an acute injection of saline or MAP (1 or 4 mg/kg ip) 30 min prior to behavioral assessment. Results showed that acute treatment with MAP (4 or 8 mg/kg) decreased the USVs of rats on PD 10, while repeated exposure to MAP did not affect the USV emissions of rats subsequently treated with saline or MAP. The reason why acute MAP treatment decreased USV production is uncertain, but it is possible that MAP alleviates isolation distress by stimulating reward processes. Alternatively, MAP increases heart rate and blood pressure, so acute treatment with this drug may decrease USV emissions through peripheral physiological mechanisms (i.e., by reducing abdominal compression reactions).

Chronic amphetamine exposure during the preweanling period does not affect avoidance learning or novelty-seeking of adult rats.

The purpose of the present study was to determine whether exposure to amphetamine during the preweanling period would impact the learning or reward processes of rats tested in adulthood. In three experiments we examined whether amphetamine treatment (0-10 mg/kg per day) on postnatal days 11-17 altered the subsequent performance of adult Sprague-Dawley rats on a step-down passive avoidance, active avoidance, or novelty-seeking task. There was no evidence that postnatal amphetamine exposure affected performance on any of these tasks. These results suggest that the long-term impact of pre- and postnatal psychostimulant exposure differs, because in utero stimulant treatment is known to produce learning deficits and decrease reinforcement efficacy of rats tested in adulthood.

Tetanic stimulation and metabotropic glutamate receptor agonists modify synaptic responses and protein kinase activity in rat auditory cortex.

We investigated whether tetanic-stimulation and activation of metabotropic glutamate receptors (mGluRs) can modify field-synaptic-potentials and protein kinase activity in rat auditory cortex, specifically protein kinase A (PKA) and protein kinase C (PKC). Tetanic stimulation (50 Hz, 1 s) increases PKA and PKC activity only if the CNQX-sensitive field-EPSP (f-EPSP) is also potentiated. If the f-EPSP is unchanged, then PKA and PKC activity remains unchanged. Tetanic stimulation decreases a bicuculline-sensitive field-IPSP (f-IPSP), and this occurs whether the f-EPSP is potentiated or not. Potentiation of the f-EPSP is blocked by antagonists of mGluRs (MCPG) and PKC (calphostin-C, tamoxifen), suggesting that the potentiation of the f-EPSP is dependent on mGluRs and PKC. PKC antagonists block the rise in PKC and PKA activity, which suggests that these may be coupled. In contrast, ACPD (agonist at mGluRs) decreases both the f-EPSP and the f-IPSP, but increases PKC and PKA activity. Quisqualate (group I mGluR agonist), decreases the f-IPSP, and increases PKA activity, suggesting that the increase in PKA activity is a result of activation of group I mGluRs. Additionally, the increase in PKC and PKA activity appears to be independent of the decrease of the f-EPSP and f-IPSP, because PKC antagonists block the increase in PKC and PKA activity levels but do not block ACPD's effect on the f-EPSP or f-IPSP. These data suggest that group I mGluRs are involved in potentiating the f-EPSP by a PKC and possibly PKA dependent mechanism which is separate from the mechanism that decreases the f-EPSP and f-IPSP.

Long-term effects of postnatal amphetamine treatment on striatal protein kinase A activity, dopamine D(1)-like and D(2)-like binding sites, and dopamine content.

The purpose of the present study was to determine whether exposure to amphetamine during the preweanling period would alter dopaminergic functioning in the dorsal striatum of adult rats. In three experiments, we assessed the effects of repeated amphetamine treatment on striatal protein kinase A (PKA) activity, dopamine (DA) D(1)-like and D(2)-like binding sites, and DA content. Rats were pretreated with saline or amphetamine (2.5 mg/kg, ip) for 7 consecutive days starting on postnatal day (PD) 11. At PD 90, rats were killed and their dorsal striata (i.e., caudate-putamen) were removed and frozen until time of assay. Amphetamine pretreatment produced long-term reductions in both striatal PKA activity and DA content. Early amphetamine exposure also resulted in an upregulation of D(2)-like binding sites, while leaving D(1)-like binding sites unaffected. It is likely that the upregulation of D(2)-like binding sites was stimulated by the persistent decline in striatal DA levels. Although speculative, it is possible that excess striatal D(2)-like receptors were responsible for inhibiting PKA activity through actions on the cAMP signal transduction pathway. The behavioral relevance of these amphetamine-induced neurochemical changes has not yet be determined.

Amphetamine treatment during the preweanling period produces enduring changes in striatal protein kinase A activity.

The purpose of this study was to determine whether chronic exposure to amphetamine during the preweanling period causes enduring changes in behavioral and neuronal functioning. In two experiments rats were injected with saline or amphetamine (2.5 or 5.0 mg/kg) on postnatal days (PD) 11-15. Rats then received a challenge injection of saline or 2.5 mg/kg amphetamine on PD 23 or PD 90 and locomotor activity was measured. After behavioral assessment, rats were killed, and their dorsal striata and nucleus accumbens were dissected and later assayed for protein kinase A (PKA) activity. Interestingly, amphetamine treatment during the preweanling period produced an enduring decline in dorsal striatal and accumbal PKA activity that was still apparent in adulthood. These reductions in PKA activity were not related to the occurrence of locomotor sensitization, because rats did not exhibit a sensitized locomotor response when challenged with amphetamine at PD 23 or PD 90.

Cocaine-induced behavioral sensitization in the young rat.

RATIONALE: Repeated psychostimulant treatment has been shown to sensitize the locomotor activity of young rats, but there is conflicting evidence suggesting that this sensitized response will persist across only a few drug abstinence days. OBJECTIVE: The purpose of the present study was to determine whether: (a) young rats are capable of expressing a sensitized locomotor response after an extended drug abstinence period, and (b) the longevity of the sensitized response is critically affected by either the number of drug pretreatment days or environmental conditioning factors. METHODS: Young rats were pretreated with saline or cocaine (15 mg/kg or 30 mg/kg, i.p.) for either five or ten consecutive days [i.e., on postnatal days (PD) 16-20 or PD 11-20]. After each daily injection, rats were placed in activity chambers, and locomotion was measured for 30 min. To assess environmental conditioning factors, some rats were injected with saline prior to being placed in the activity chambers and then injected with cocaine prior to being returned to the home cage. After one or seven abstinence days (i.e., on PD 22 or PD 28), rats received a challenge injection of saline or cocaine (15 mg/kg) in the activity chamber and locomotion was assessed. RESULTS: Young rats exhibit cocaine-induced locomotor sensitization after either a short (1-day) or long (7-day) drug abstinence period. When a long abstinence period was used, locomotor sensitization was only apparent when cocaine pretreatment lasted for 10 days. Conditioning factors were also important for determining whether locomotor sensitization was expressed, because young rats pretreated with cocaine in the home cage did not show a sensitized locomotor response after seven abstinence days. CONCLUSIONS: Young rats are capable of showing cocaine-induced locomotor sensitization after an extended abstinence period. Both the number of drug pretreatment days and the environmental context in which cocaine was given (i.e., the activity chamber or home cage) influenced the longevity of cocaine-induced locomotor sensitization.

Role of dopamine D(1) receptors for kappa-opioid-mediated locomotor activity and antinociception during the preweanling period: a study using D(1) receptor knockout mice.

kappa-Opioid receptor agonists both increase the locomotor activity of preweanling rats and induce antinociception. To determine whether dopamine (DA) D(1) receptors are necessary for either of these kappa-opioid-mediated effects we used D(1) (D(1A)) receptor knockout mice (i.e., D(1)-deficient mice). Heterozygous, wild-type, and D(1)-deficient mice (13 days old at testing) were injected with the kappa-opioid receptor agonist U-50,488 methanesulfonate (0.0, 0.2, 1. 0, 2.5, or 5.0 mg/kg, s.c.) and locomotor activity was measured for 60 min. In a separate experiment, tail-flick latencies of heterozygous, wild-type, and D(1)-deficient 13-day-old mice were assessed both before and after treatment with U-50,488 (0.0, 1.0, 2. 5, 5.0, or 10.0 mg/kg, s.c.). Results showed that lower doses of U-50,488 (0.2 and 1.0 mg/kg) increased the locomotor activity of 13-day-old mice regardless of genotype. Besides affecting locomotion, kappa-opioid receptor stimulation induced antinociception in preweanling mice, as U-50,488 caused a dose-dependent increase in the tail-flick latencies of heterozygous, wild-type, and D(1)-deficient mice. U-50,488's locomotor activating and analgesic effects did not differ according to genotype, thus suggesting that D(1) receptors are not necessary for kappa-opioid-mediated locomotor activity and antinociception during the preweanling period.

Electrophysiological and morphological analyses of cortical neurons obtained from children with catastrophic epilepsy: dopamine receptor modulation of glutamatergic responses.

The present study examined the electrophysiological effects produced by activation of specific dopamine (DA) receptors and the distribution of DA receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1) and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16 years) undergoing epilepsy surgery. DA receptor activation produced differential effects depending on the receptor subtype that was activated. D1 receptor family agonists generally enhanced cortical excitability and favored the emergence of epileptogenic activity. In contrast, D2 receptor family agonists had more variable effects on cortical excitability and the expression of epileptiform discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA-mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis showed that the DA receptor subtypes and glutamate receptor subunits examined were present in all cortical layers and areas throughout development. Whole-cell voltage clamp recordings of pyramidal neurons visualized with differential interference contrast optics and infrared videomicroscopy indicated that these neurons displayed a persistent Na(+) current, followed by an outward current. DA reduced the outward current but had little effect on the persistent Na(+) current. These results suggest a dual role for DA's actions in the human cerebral cortex. Activation of D2 receptors or antagonism of D1 receptors may help control seizures in children.

Effects of repeated methylphenidate treatment in the young rat: sensitization of both locomotor activity and stereotyped sniffing.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in young rats. In 4 experiments, rats (starting at Postnatal Day 10 or 16) were pretreated on 5 consecutive days with saline or MPH (2.5-20.0 mg/kg i.p.). Sensitization was assessed after 1 or 7 abstinence days, with rats receiving a test day challenge injection of either a low dose of MPH (2.5 mg/kg) or the same dose of MPH as given during pretreatment. Results show that a test day injection of 2.5 mg/kg MPH produced a sensitized locomotor response in rats pretreated with 2.5-20.0 mg/kg MPH. This MPH-induced locomotor sensitization was evident only after 1 abstinence day. Various pretreatment doses of MPH (5, 10, 15, or 20 mg/kg) were capable of sensitizing the stereotyped sniffing of young rats, but only rats pretreated and tested with the highest dose (20 mg/kg) of MPH showed an augmented stereotyped sniffing response that was still robust after 7 abstinence days. Results indicate that young rats are capable of exhibiting sensitization after an extended abstinence period, which contrasts with previous research suggesting that psychostimulant treatment does not produce long-term sensitization in young rats.

Kappa opioid-mediated behavioral sensitization in the preweanling rat: relationship to Fos immunoreactivity.

When given acutely, drugs that stimulate kappa opioid receptors (e.g., U-50,488) enhance the locomotor activity of preweanling rats and induce regional increases in Fos immunoreactivity (IR). In contrast, the effects of chronic treatment with kappa opioid agonists are unknown. The purpose of the present study was two-fold: first, to determine whether repeated treatment with a kappa opioid agonist would sensitize the locomotor activity of preweanling rats and, second, to determine whether changes in Fos IR correspond with the occurrence of locomotor sensitization. To test these hypotheses, rats were injected with U-50,488 (5 mg/kg, s.c.) or saline on either postnatal days (PD) 5-9 or PD 11-15. For rats pretreated on PD 5-9, a test day injection of U-50,488 or saline was given after either 1 or 7 abstinence days (i.e., at PD 11 or PD 17). For rats pretreated on PD 11-15, a test day injection of U-50,488 or saline was given after 1 abstinence day (i.e., at PD 17). In two additional experiments, the acute and chronic effects of U-50,488 treatment were assessed in adult rats. As expected, repeated treatment with U-50,488 produced locomotor sensitization at both PD 11 and PD 17, but only when the test day occurred 1, and not 7, days after cessation of drug pretreatment. Thus, the persistence of the sensitized response was very brief. Test day treatment with U-50,488 stimulated Fos IR in various brain regions of the preweanling rat, including the medial striatum, nucleus accumbens, lateral habenula, and septal area. Chronic treatment with U-50,488 depressed Fos expression in a number of brain regions (relative to acutely treated rats); however, these changes in Fos IR did not necessarily coincide with the occurrence of behavioral sensitization. Repeated treatment with U-50,488 did not produce locomotor sensitization in adult rats, so Fos IR was not assessed in this age group. Therefore, while acute treatment with U-50,488 both increased locomotor activity and stimulated Fos IR in preweanling rats, chronic U-50,488 treatment produced behavioral changes that did not correspond with Fos expression.

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.

Effects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A-deficient mouse.

The role of dopamine D1A receptors in mediating amphetamine-induced sensitization was investigated using the D1A-deficient mouse. During the drug pre-exposure phase, D1A-deficient and control mice were injected for five consecutive days with saline or amphetamine (2 mg/kg, i.p.). Locomotor activity was measured on the first and fifth pre-exposure day. After three abstinence days, mice were given either amphetamine or saline and locomotor activity was again assessed. Mice were then sacrificed and protein kinase A (PKA) activity was measured. In contrast to control mice, D1A-deficient mice did not show a progressive increase in locomotor activity across days. Importantly, both control and mutant mice did exhibit behavioral sensitization, because mice pre-exposed and tested with amphetamine were more active than mice acutely tested with the drug. Even so, the amphetamine-induced locomotor activity of the mutant mice was significantly reduced when compared with similarly treated control mice, indicating that the sensitized response was less pronounced in the D1A-deficient mouse. PKA activity also varied depending on genotype, since amphetamine decreased PKA activity in control but not D1A-deficient mice.

Dopaminergic function in the neostriatum and nucleus accumbens of young and aged Fischer 344 rats.

Age-dependent alterations in behavioral and neuronal functioning were assessed in young (2-3 month), middle-aged (12 month), and aged (24 month) Fischer 344 rats treated with the indirect dopamine agonist amphetamine (2.25 or 5 mg/kg), the D1 agonist SKF 38393 (7.5, 15, 30 mg/kg), or the D2 agonist quinpirole (0.3, 1.0, 3.0 mg/kg). Drug-induced changes in activity and stereotypy were measured during a 90-min testing session, with Fos immunohistochemistry being used to assess the neuronal response to dopamine agonist treatment. As expected, aged rats given amphetamine (5 mg/kg) had fewer activity counts and higher stereotypy scores than young rats. Middle-aged rats also had fewer activity counts but were similar in stereotypy scores to young rats. Amphetamine also induced different patterns of Fos immunoreactivity in the neostriatum and nucleus accumbens of young and aged rats, as Fos expression in aged rats exhibited a distinctive dorsal to ventral pattern of decline. In general, SKF 38393 had few age-related actions, although aged rats did show a slight relative increase in stereotypy. In contrast, the D2 agonist quinpirole substantially enhanced the motor activity and Fos expression of young rats, while only modestly affecting aged rats. Hence, these results suggest that the D2 receptor is more vulnerable to the effects of aging than the D1 receptor.