Injection Of Amphetamine Research Articles

Rescue of dopamine transporter function in hypoinsulinemic rats by a D2 receptor-ERK-dependent mechanism.

The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D(2) receptors indirectly by increasing extracellular DA. Supporting a role for D(2) receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D(2) receptor antagonist raclopride before systemic AMPH. D(2) receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D(2) receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.

Effects of muscimol, amphetamine, and DAMGO injected into the nucleus accumbens shell on food-reinforced lever pressing by undeprived rats

Previous studies have shown that large increases in food intake in nondeprived animals can be induced by injections of both the GABAA agonist muscimol and the μ-opioid agonist DAMGO into the nucleus accumbens shell (AcbSh), while injections of the catecholamine agonist amphetamine have little effect. In the current study we examined whether injections of these drugs are able to increase food-reinforced lever pressing in nondeprived rats. Twelve subjects were trained to lever press on a continuous reinforcement schedule while food deprived and were then tested after being placed back on ad libitum feeding. Under these conditions, responding was markedly increased by injections of either muscimol or DAMGO, although the onset of the effects of the latter drug was delayed by 30–40min. In contrast, amphetamine injections failed to increase reinforced lever pressing, although they did enhance responding on a non-reinforced lever, presumably reflecting alterations in behavioral activation. These results demonstrate that stimulation of GABAA and μ-opioid receptors within the AcbSh is able to promote not only food intake, but also food-directed operant behavior. In contrast, stimulation of AcbSh dopamine receptors may enhance behavioral arousal, but does not appear to specifically potentiate behaviors directed toward food procurement.

Amphetamine modifies ethanol intake of psychosocially stressed male rats

Studies of socially housed rodents have provided significant information regarding the consequences of exposure to stressors. Psychosocial stressors are known to alter the ingestion of ethanol and the activity of the dopaminergic neuronal system. Since both stressors and ethanol are known to affect the function of dopaminergic neurons, we employed amphetamine to assess the role of this neural system on the ingestion of ethanol by psychosocially stressed male rats. Male rats housed two per cage were designated as dominant or subdominant rats based on evaluations of agonistic behavior and body weight changes. The dyad-housed rats and a group of single-housed rats were sequentially assessed for ethanol intake after injections of saline or amphetamine (0.3, 0.9 or 2.7mg/kg i.p.) both prior to dyad housing and subsequently again during dyad-housing. Prior to dyad housing ethanol intake of future subdominant rats was higher than that of future dominant rats. Dyad-housing significantly increased ethanol intake of dominant rats. Pre-dyad the highest dose of amphetamine potently depressed ethanol ingestion. Sensitivity to amphetamine's depressant effect on ethanol intake was higher at the dyad test in all subjects, most prominently in single-housed rats. In contrast to the single-housed rats, the dyad-housed rats displayed saccharin anhedonia. It can be concluded that dopaminergic system modulates, at least partially, the psychosocial stress-induced changes in ethanol intake. Furthermore, the level of ethanol ingestion at the pre-dyad test was predictive of future hierarchical status.

The Roles of Dopamine Receptor and Adrenoreceptor on the Inhibition of Gastric Emptying and Intestinal Transit by Amphetamine in Male Rats

Amphetamine, a central nervous stimulant, acts on the central nervous system (CNS) by increasing levels of norepinephrine, serotonin and dopamine (DA) in the brain. It stimulates the colonic motility and gastrointestinal (GI) function via the brain-gut connections as well as diminishes appetite to control bodyweight, but the mechanism between amphetamine and GI motility was unclear. We investigated the role of DA receptor and adrenoreceptor in the inhibitory effects of amphetamine on GI motility in male rats. After fasting overnight, the male rats received an intraperitoneal (i.p.) injection of amphetamine (3 mg/ml/kg) 15 min after i.p. injection of different antagonists for dopamine receptors and adrenoreceptors. Gastric emptying and intestinal transit were assessed 15 min after intragastric instillation of a test meal containing radioactive Na₂⁵¹CrO₄ and 10% charcoal. Haloperidol, a DA receptor antagonist, acting exactly as the selective D₂ receptor antagonist, eticlopride, completely prevented amphetamineinduced inhibition of gastric emptying and intestinal transit in male rats. The selective D₁ receptor antagonist, SCH 23390, significantly attenuated the amphetamine-induced inhibition of gastric emptying and intestinal transit in male rats. Both selective and nonselective α adrenoreceptor antagonist, phentolamine, prazosin and yohimbine, did not reverse the inhibitory effects of amphetamine on gastric emptying and intestinal transit. Propanolol, a β adrenoreceptor antagonist, partially attenuated the amphetamine-induced inhibition of gastric emptying but did not significantly attenuate intestinal transit. These results suggest that amphetamine-induced inhibition of gastric emptying and intestinal transit is mediated by an action on dopaminergic mechanism and adrenoreceptor with little involvement. These findings may clarify the influence of central nervous stimulant on GI tract and may provide the appropriate medication in CNS.

GABAA and dopamine receptors in the nucleus accumbens shell differentially influence performance of a water-reinforced progressive ratio task

Several authors have shown that injections of the GABAA agonist muscimol into the medial shell region of the nucleus accumbens (AcbSh) result in large increases in food, but not water, intake. In previous studies we demonstrated that intra-AcbSh injections of either muscimol or of the indirect dopamine agonist amphetamine increase response output on a food-reinforced progressive ratio schedule. In the current experiment we extended these observations by examining the effects of muscimol and amphetamine injections on the performance of a water-reinforced progressive ratio task in mildly deprived animals. We found that muscimol did not affect the number of responses made in the water-reinforced task, even though a marked increase in responding was observed after amphetamine. Muscimol did, however, significantly increase food intake in the same animals. The results suggest that the enhancing effects of intra-AcbSh muscimol differ from those of amphetamine in that they are selective for food-reinforced behaviors.

Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants, including amphetamine, methamphetamine and MDMA. Previous studies have shown that in transgenic mice lacking the TAAR1 gene (TAAR1 knockout; KO) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type (WT) mice. Further, the psychostimulant effects of cocaine can be diminished by selective activation of TAAR1. These findings suggest that TAAR1 might be implicated in the rewarding properties of psychostimulants. To investigate the role of TAAR1 in the rewarding effects of drugs of abuse, the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and TAAR1 KO mice. In locomotor activity studies, both single and repeated exposure to d-amphetamine or methamphetamine generated significantly higher levels of total distance traveled in TAAR1 KO mice compared to WT mice. In conditioned place preference (CPP) studies, TAAR1 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training. In morphine-induced CPP, both WT and KO genotypes displayed similar levels of CPP. Results from locomotor activity studies suggest that TAAR1 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants. That methamphetamine-but not morphine-induced CPP was augmented in TAAR1 KO mice suggests a selective role of TAAR1 in the conditioned reinforcing effects of methamphetamine. Collectively, these findings provide support for a regulatory role of TAAR1 in methamphetamine signaling.

Amphetamine-Induced Locomotion and Brain Stimulation Reward Research and Applications

Amphetamine, a dopamine agonist, has an effect on increasing dopamine level in certain brain regions, like the nucleus accumben and the ventral tegmental area (Yoshida et al., 1992). Hence, it increases reward-related functions. In the current study, we examined the changes in the frequency of locomotion in previously habituated mice after 3mg/kg amphetamine injections. In the same way, we also monitored the changes in bar pressing rates of previously trained rates after 2mg/kg amphetamine injections. Though not showing a significant statistical result, both graphs and discussions supported that amphetamine injection increased horizontal quadrants crossings compared with saline injection. While the amphetamine administration increased bar press rate in previously trained rats at low frequencies, it led the rats to fewer bar presses at higher frequencies compared with both the baseline and the saline condition. The results of both experiments consistent with past studies which claim that amphetamine acts as a dopaminergic agonist and increases reinforcing capacity through enhancement of dopaminergic transmission (Gallistel & Karras, 1984).

Behavioral phenotyping of glutathione-deficient mice: Relevance to schizophrenia and bipolar disorder

Redox-dysregulation represents a common pathogenic mechanism in schizophrenia (SZ) and bipolar disorder (BP). It may in part arise from a genetically compromised synthesis of glutathione (GSH), the major cellular antioxidant and redox-regulator. Allelic variants of the genes coding for the rate-limiting GSH synthesizing enzyme glutamate–cysteine–ligase modifier (GCLM) and/or catalytic (GCLC) subunit have been associated with SZ and BP. Using mice knockout (KO) for GCLM we have previously shown that impaired GSH synthesis is associated with morphological, functional and neurochemical anomalies similar to those in patients. Here we asked whether GSH deficit is also associated with SZ- and BP-relevant behavioral and cognitive anomalies. Accordingly, we subjected young adult GCLM-wildtype (WT), heterozygous and KO males to a battery of standard tests. Compared to WT, GCLM-KO mice displayed hyperlocomotion in the open field and forced swim test but normal activity in the home cage, suggesting that hyperlocomotion was selective to environmental novelty and mildly stressful situations. While spatial working memory and latent inhibition remained unaffected, KO mice showed a potentiated hyperlocomotor response to an acute amphetamine injection, impaired sensorymotor gating in the form of prepulse inhibition and altered social behavior compared to WT. These anomalies resemble important aspects of both SZ and the manic component of BP. As such our data support the notion that redox-dysregulation due to GSH deficit is implicated in both disorders. Moreover, our data propose the GCLM-KO mouse as a valuable model to study the behavioral and cognitive consequences of redox dysregulation in the context of psychiatric disease.

Adolescent rat circadian activity is modulated by psychostimulants

Circadian pattern of activity regulates many aspects of mammalian physiology and behavior to particular times of the day by entraining the circadian clocks to external environmental signals. Since circadian rhythms are sensitive to many pharmacological agents, it is important to understand if the repetitive use of psychostimulants such as amphetamine will alter the circadian rhythm behavioral activity pattern. The present study uses male Sprague–Dawley rats to study the long-term effects of amphetamine on the locomotor circadian rhythm activity pattern. Rats were randomly assigned to a testing cage that recorded their locomotor activity nonstop for eleven days using the open field assay, as follows: one day of baseline activity was recorded and then the experimental group was injected with amphetamine (0.6 mg/kg) for 6 days, no treatment for 3 days (i.e., washout days) and then re-challenged with amphetamine for one more day while the control group was treated similarly with saline. The Cosine Curve Statistical Analysis (CCSA) test was used to fit a 24-hour curve to activity pattern. Results indicate that repetitive daily amphetamine injections cause behavioral sensitization and a significant change of circadian rhythm of locomotor activity pattern, and elicit behavioral expectation to receive the drug or expression of withdrawal during the washout days. The results suggest that either changes in circadian rhythm caused sensitization and withdrawal or sensitization and withdrawal caused the change in circadian rhythm activity.

Synergistic interaction between baclofen administration into the median raphe nucleus and inconsequential visual stimuli on investigatory behavior of rats.

Noncontingent administration of amphetamine into the ventral striatum or systemic nicotine increases responses rewarded by inconsequential visual stimuli. When these drugs are contingently administered, rats learn to self-administer them. We recently found that rats self-administer the GABA(B) receptor agonist baclofen into the median (MR) or dorsal (DR) raphe nuclei. We examined whether noncontingent administration of baclofen into the MR or DR increases rats' investigatory behavior rewarded by a flash of light. Contingent presentations of a flash of light slightly increased lever presses. Whereas noncontingent administration of baclofen into the MR or DR did not reliably increase lever presses in the absence of visual stimulus reward, the same manipulation markedly increased lever presses rewarded by the visual stimulus. Heightened locomotor activity induced by intraperitoneal injections of amphetamine (3 mg/kg) failed to concur with increased lever pressing for the visual stimulus. These results indicate that the observed enhancement of visual stimulus seeking is distinct from an enhancement of general locomotor activity. Visual stimulus seeking decreased when baclofen was co-administered with the GABA(B) receptor antagonist, SCH 50911, confirming the involvement of local GABA(B) receptors. Seeking for visual stimulus also abated when baclofen administration was preceded by intraperitoneal injections of the dopamine antagonist, SCH 23390 (0.025 mg/kg), suggesting enhanced visual stimulus seeking depends on intact dopamine signals. Baclofen administration into the MR or DR increased investigatory behavior induced by visual stimuli. Stimulation of GABA(B) receptors in the MR and DR appears to disinhibit the motivational process involving stimulus-approach responses.

Repeated amphetamine exposure disrupts dopaminergic modulation of amygdala-prefrontal circuitry and cognitive/emotional functioning.

Repeated exposure to psychostimulants such as amphetamine (AMPH) disrupts cognitive and behavioral processes mediated by the medial prefrontal cortical (mPFC) and basolateral amygdala (BLA). The present study investigated the effects of repeated AMPH exposure on the neuromodulatory actions of dopamine (DA) on BLA-mPFC circuitry and cognitive/emotional processing mediated by these circuits. Rats received five AMPH (2 mg/kg) or saline injections (controls) over 10 d, followed by 2-4 week drug washout. In vivo neurophysiological extracellular recordings in urethane-anesthetized rats were used to obtain data from mPFC neurons that were either inhibited or excited by BLA stimulation. In controls, acute AMPH attenuated BLA-evoked inhibitory or excitatory responses; these effects were mimicked by selective D(2) or D(1) agonists, respectively. However, in AMPH-treated rats, the ability of these dopaminergic manipulations to modulate BLA-driven decreases/increases in mPFC activity was abolished. Repeated AMPH also blunted the excitatory effects of ventral tegmental area stimulation on mPFC neural firing. Behavioral studies assessed the effect of repeated AMPH on decision making with conditioned punishment, a process mediated by BLA-mPFC circuitry and mesocortical DA. These treatments impaired the ability of rats to use conditioned aversive stimuli (footshock-associated cue) to guide the direction of instrumental responding. Collectively, these data suggest that repeated AMPH exposure can lead to persistent disruption of dopaminergic modulation of BLA-mPFC circuitry, which may underlie impairments in cognitive/emotional processing observed in stimulant abusers. Furthermore, they suggest that impairments in decision making guided by aversive stimuli observed in stimulant abusers may be the result of repeated drug exposure.

Circadian modulation of amphetamine sensitization in rats does not require the suprachiasmatic nucleus

Repeated exposure to amphetamine results in a long-lasting increase in the ability of the drug to elicit locomotor behavior (Robinson and Becker 1986). This sensitized behavioral response to amphetamine (AMPH) in rats depends on a temporal match between the times that sensitizing injections of AMPH are given and the time of testing. A temporal match between training and testing is also required for expression of conditioned place preference (CPP) in rodents. Whereas the sensitization rhythm is abolished if rats are housed in constant light (which produces circadian arrhythmicity), the CPP rhythm persists in arrhythmic hamsters with complete lesions of the suprachiasmatic nucleus (SCN). We now report that the AMPH sensitization rhythm also persists in hamsters following complete SCN ablation. The loss of a sensitivity rhythm in constant light suggests that a disorganized signal being produced by SCN might influence an AMPH sensitive oscillator, affecting the establishment or maintenance of the extra-SCN rhythm.

Amphetamine-induced incentive sensitization of sign-tracking behavior in adolescent and adult female rats.

Age-specific behavioral and neural characteristics may predispose adolescents to initiate and escalate use of alcohol and drugs. Adolescents may avidly seek novel experiences, including drugs of abuse, because of enhanced incentive motivation for drugs and natural rewards, perhaps especially when that incentive motivation is sensitized by prior drug exposure. Using a Pavlovian conditioned approach (PCA) procedure, sign-tracking (ST) and goal-tracking (GT) behavior was examined in amphetamine-sensitized and control adolescent and adult female Sprague-Dawley rats, with expression of elevated ST behavior used to index enhanced incentive motivation for reward-associated cues. Rats were first exposed to a sensitizing regimen of amphetamine injections (3.0 mg/kg/ml d-amphetamine per day) or given saline (0.9% wt/vol) once daily for 4 days. Expression of ST and GT was then examined over 8 days of PCA training consisting of 25 pairings of an 8-s presentation of an illuminated lever immediately followed by response-independent delivery of a banana-flavored food pellet. Results showed that adults clearly displayed more ST behavior than adolescents, reflected via both more contacts with, and shorter latencies to approach, the lever. Prior amphetamine sensitization increased ST (but not GT) behaviors regardless of age. Thus, when indexed via ST, incentive motivation was found to be greater in adults than adolescents, with a prior history of amphetamine exposure generally sensitizing incentive motivation for cues predicting a food reward regardless of age.

Differential sensitivity to amphetamine’s effect on open field behavior of psychosocially stressed male rats

Studies of socially housed rodents have provided significant information regarding the mechanisms of stress and of stress-related disorders. Since psychosocial stress is known to alter the functional activity of dopaminergic system, we employed amphetamine (AMP) to evaluate the involvement dopamine in mediating the behavioral consequences of psychosocial stress. Male rats housed two per cage were designated as dominant (DOM) or subdominant (Sdom) based on initial evaluations of agonistic behaviors and body weight changes. Diad-housed rats and a group of single-housed (SiH) rats were tested in an open field after injections of saline or amphetamine (0.9 or 2.7 mg/kg IP) prior to and again while diad-housing. Compared to future DOM rats, saline-injected future Sdom rats entered the open field center less frequently, spent less time in rearing behavior and groomed less. At the pre-diad test AMP treatment elevated locomotor activity of all rats, while stimulation of center entries was more marked in future DOM rats. At the diad test, AMP's locomotor stimulant effect was evident in all experimental groups with DOM rats showing higher effects compared to Sdom and SiH rats. Amphetamine's stimulation of center entries in DOM rats was similar to the pre-diad test, but it was diminished in Sdom rats, while stimulation of rearing behavior was most evident in diad-housed rats. The dopaminergic system modulates the psychosocial stress-induced differences in explorative and emotional behaviors. Furthermore, behavioral traits like frequency of grooming behavior and of center entries were predictive of future hierarchical status.

Role of nitric oxide in amphetamine-induced sensitization of schedule-induced polydipsic rats

Repeated injections of amphetamine (AMPH) can progressively augment behavioral responses, a phenomenon known as behavioral sensitization. AMPH-induced behavioral sensitization can be demonstrated in a rat model of schedule-induced polydipsia (SIP). The aim of this study was to investigate the effects of a nonspecific nitric oxide (NO) synthase inhibitor, N(G)-nitro arginine methyl ester (L: -NAME), on the AMPH sensitization effects in SIP. Rats were trained to establish SIP. The induction of AMPH sensitization in SIP was tested in either the home cage or a test cage. L: -NAME (50 mg/kg, i.p.) was co-administered with AMPH for five consecutive days, and its effect on induction was examined 3 and 14 days after withdrawal. The effect of L: -NAME on expression was examined on the final testing day by co-administration with AMPH in previously sensitized SIP rats. AMPH-induced behavioral sensitization in SIP rats only occurred when AMPH was injected in the home cage. Pretreatment with L: -NAME successfully blocked the induction of this sensitization following both short and long-term withdrawal. Once sensitization had been established, L: -NAME had no further influence. These results suggest that SIP behavior observed after repeated AMPH treatment is mediated by an NO-associated mechanism.

Heightened locomotor-activating effects of amphetamine administered into the nucleus accumbens in adolescent rats

There is a shift in sensitivity to systemically administered psychostimulants in adolescence, as evidenced by less amphetamine-induced locomotor activity in adolescent compared to adult rodents. Locomotor activating effects of amphetamine are dependent on drug actions in the core of the nucleus accumbens (NAc), but the contribution of this region to age differences in amphetamine sensitivity has not been studied directly. In the present study, we investigated the development of the NAc using targeted injections of amphetamine (0, 3, or 6 μg/side) directly into the NAc core in early (postnatal day 30; P30) or late (P45) adolescence, or in adulthood (P75). Locomotor activity was recorded during two 1 h sessions, 48 h apart. Amphetamine increased locomotor activity at all ages. P45 rats were more active than adults only at the 3 μg/side dose, but this difference was not significant when baseline activity was taken into account. In contrast, P30 rats were more active than adults at the 6 μg/side dose, indicating that the magnitude of the locomotor response is highest in early adolescence. Results of the present study are the first to directly show a developmental difference in the sensitivity of the NAc to amphetamine under conditions in which the influence of pharmacokinetic factors and regulatory brain regions is minimized.

Sensitized activation of Fos and brain-derived neurotrophic factor in the medial prefrontal cortex and ventral tegmental area accompanies behavioral sensitization to amphetamine

Behavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. Male Sprague–Dawley rats underwent unilateral intra-VTA infusion of the retrograde tracer Fluorogold (FG), followed by 5 daily injections of either amphetamine (2.5 mg/kg, i.p.) or saline vehicle. Four weeks later, rats were challenged with amphetamine (1.0 mg/kg, i.p.) or saline (1.0 mL/kg, i.p.). Repeated amphetamine treatment produced locomotor sensitization upon drug challenge. Two hours later, rats were euthanized, and mPFC sections were double-immunolabeled for either Fos-FG or Fos-BDNF. Tissue from the VTA was also double-immunolabeled for Fos-BDNF. Amphetamine challenge increased Fos and BDNF expression in the mPFC regardless of prior drug experience, and further augmented mPFC BDNF expression in sensitized rats. Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.

Enhanced Incentive Motivation for Sucrose-Paired Cues in Adolescent Rats: Possible Roles for Dopamine and Opioid Systems

Vulnerability to the effects of drugs of abuse during adolescence may be related to altered incentive motivation, a process believed to be important in addiction. Incentive motivation can be seen when a neutral stimulus acquires motivational properties through repeated association with a primary reinforcer. We compared adolescent (postnatal day (PND) 24-50) and adult (>PND 70) rats on a measure of incentive motivation: responding for a conditioned reinforcer (CR). Rats learned to associate the delivery of 0.1 ml of 10% sucrose with a conditioned stimulus (CS; light and tone); 30 pairings per day were given over 14 days. Then, we measured responding on a lever delivering the CS (now a CR) after injections of amphetamine (0, 0.25 or 0.5 mg/kg). We also examined responding for CR when the CS and sucrose were paired or unpaired during conditioning, and responding for the primary reinforcer (10% sucrose) in control experiments. Finally, we examined the effects of D(1) and D(2) dopamine receptor antagonists (SCH 39166 and eticlopride, respectively) and an opioid receptor antagonist (naltrexone) on responding for a CR in adolescent rats. Adolescents but not adults acquired responding for a CR, but adolescents responded less than adults for the primary reinforcer. Responding for a CR depended upon the pairing of the CS and sucrose during conditioning. Both dopamine and opioid receptor antagonists reduced responding for the CR. Therefore, incentive motivation may be enhanced in adolescents compared with adults, and incentive motivation may be mediated in part by both dopamine and opioid systems.

Effects of risperidone and paliperidone pre-treatment on locomotor response following prenatal immune activation

Aim Limited data are available regarding pharmacological characteristics of effective interventions for psychosis prevention. Enrollment challenges in psychosis prevention trials impede screening diverse interventions for efficacy. Relevant animal models could help circumvent this barrier. We previously described prevention with risperidone of abnormal behavior following neonatal hippocampal lesion. We aimed to extend those findings evaluating risperidone and paliperidone following prenatal immune activation, a developmental model of a schizophrenia risk factor. We evaluated a later developmental time point to determine persistent effects of drug treatment. Methods Pregnant Sprague–Dawley rats were injected with poly I:C or saline on gestational day 14. Offspring of poly I:C and saline-treated dams received risperidone (0.45 mg/kg/d), paliperidone (0.05 mg/kg/d), or vehicle from postnatal days 35–70. Locomotor responses to novelty, saline injection, and amphetamine (1 and 5 mg/kg) were determined at three months, i.e., 21 days following antipsychotic discontinuation. Results Risperidone and paliperidone had persistent effects on behavioral response to amphetamine (1 mg/kg) at 3 months, ameliorating the impact of prenatal immune activation on offspring of poly I:C-treated dams. Risperidone, but not paliperidone, also exerted persistent effects in offspring of saline-treated dams on locomotor response to saline and amphetamine (5 mg/kg) injection. Conclusions Risperidone and paliperidone pre-treatment of poly I:C offspring during peri-pubertal development stabilized response to amphetamine exposure persisting into early adulthood. Prenatal immune activation provides a model for evaluating effects of an environmental risk factor for schizophrenia, and has potential utility for identifying pharmacological approaches to early intervention.

Do excitatory and inhibitory conditioning processes underlie psychomotor sensitization to amphetamine? An analysis using simple and multiple regressions

Excitatory or inhibitory conditioning processes have been proposed to account for the context-dependent establishment of amphetamine psychomotor sensitization in rodents. The purpose of this study was to test the predictions of these theories in mice. We first assessed the consequence of the extinction of post-sensitization conditioned activity (CR) on the ulterior expression of sensitization. We also assessed the relations between several measures of sensitization and conditioned hyperactivity revealed on a saline challenge using simple and multiple regression analyses. Context-dependent sensitization was induced via 7 amphetamine injections in the test context given alternately with 7 saline injections in another context in paired mice, unpaired mice receiving the converse pretreatment. Context-dependent sensitization (drug challenge) and the CR (saline challenge) were revealed subsequently. After CR extinction (over 7 every-other-day repetition of the saline challenge), mice were tested again for context-dependent sensitization. Against the excitatory conditioning model, CR extinction spared context-dependent sensitization in paired mice, and regression analyses revealed no significant correlations between the size of the CR and several measures of sensitization. In apparent agreement with the inhibitory conditioning model, unpaired mice expressed higher levels of sensitization in the test context after extinction than before. However, regression analyses did not indicate that activity on the saline challenge was related to measures of sensitization in unpaired mice. Therefore, the present results support neither the excitatory nor the inhibitory conditioning models of context-dependent sensitization, but remain compatible with theories proposing that other inhibitory mechanisms modulate sensitization.