Amphetamine Challenge Research Articles

Dopamine Release in Chronic Cannabis Users: A [11C]Raclopride Positron Emission Tomography Study

Low striatal dopamine 2/3 receptor (D(2/3)) availability and low ventrostriatal dopamine (DA) release have been observed in alcoholism and cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D(2/3) availability and DA release in abstinent cannabis users compared with control subjects and explored relationships to cannabis use history using [(11)C]raclopride positron emission tomography and an amphetamine challenge paradigm. Sixteen recently abstinent, psychiatrically healthy cannabis-using participants (27.3 ± 6.1 years, 1 woman, 15 men) and 16 matched control subjects (28.1 ± 6.7 years, 2 women, 14 men) completed two positron emission tomography scans, before and after injection of intravenous d-amphetamine (.3 mg/kg). Percent change in [(11)C]raclopride binding after amphetamine (change in nondisplaceable binding potential, ΔBP(ND)) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined. Cannabis users had an average consumption of 517 ± 465 estimated puffs per month, indicating mild to moderate cannabis dependence. Neither baseline BP(ND) nor ΔBP(ND) differed from control subjects in any region of interest, including ventral striatum. In cannabis-dependent subjects, earlier age of onset of use correlated with lower [ΔBP(ND)] in the associative striatum when controlling for current age. Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier or longer duration of use is related to lower DA release in the associative striatum. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.

Amphetamine challenge decreases yohimbine binding to α2 adrenoceptors in Landrace pig brain

The noradrenaline (NA) system is implicated in neurodegenerative and psychiatric disorders; however, our understanding is impaired by the lack of well-validated radioligands to assess NA function and release. Yohimbine, an α2 adrenoceptor antagonist, has recently been developed as a carbon-11 [11C]-labeled radioligand for positron emission tomography (PET) imaging studies. Here we explore the hypothesis that yohimbine can be used as an in vivo tracer of NA receptor binding and release during amphetamine challenges in Landrace pigs. Pigs underwent baseline PET scans with [11C]yohimbine and were then challenged with 10mg/kg d-amphetamine 20min prior to a second [11C]yohimbine scan. Using the Logan analysis model, volumes of distribution were calculated from fits of the kinetic data 25-90min post-yohimbine injection. Amphetamine decreased [11C]yohimbine volume of distribution in the brain regions under investigation, including the thalamus, caudate nucleus, and cortical regions. These data suggest that the binding of [11C]yohimbine to α2 adrenoceptors may be displaceable by increases in synaptic concentrations of the endogenous ligand, NA, and possibly dopamine, suggesting the possibility that [11C]yohimbine may be used as a surrogate marker of NA release in vivo.

Prenatal tetrahydrocannabinol (THC) alters cognitive function and amphetamine response from weaning to adulthood in the rat

Research suggests that not only is marijuana use prevalent among women of reproductive age, but a significant number of women continue to use marijuana and its derivatives throughout pregnancy. Many studies have shown, in both humans and animals, that marijuana exposure during adolescence and adulthood is detrimental to normal cognition and memory. In this study, we examined the effects of daily intravenous injections of 0.15mg/kg Δ9-tetrahydrocannabinol (THC), given to pregnant dams throughout gestation, on cognitive function in the offspring. Offspring were exposed to three tests: a passive avoidance test at postnatal day (PND) 22, an active place avoidance test at PND 45, and an attention task at PND 60, which assessed learning and long-term memory, spatial working memory and prediction, and attention, respectively. Other offspring were also given a 1mg/kg amphetamine challenge at PND 60. Passive avoidance testing showed that prenatal THC had no effect on acquisition but interfered with consolidation during retention testing. The active place avoidance task showed no treatment-related effects on acquisition but a significant treatment effect was observed in reversal performance in males. The attention task showed that a smaller percentage of THC-exposed rats completed the test, although the failure rate of both groups was quite high. Finally, THC exposed animals, both male and female, showed a dampened locomotor response to amphetamine, but females were more active than males overall. These results suggest that prenatal THC exposure has effects on certain aspects of cognitive function in rats from weaning to adulthood. These effects suggest that prenatal marijuana exposure could also alter cognitive function in humans and therefore have an impact on school performance and dampen responses to psychostimulants as well.

In Vivo Evidence for Low Striatal Vesicular Monoamine Transporter 2 (VMAT2) Availability in Cocaine Abusers

Positron emission tomography (PET) imaging studies in cocaine abusers have shown that low dopamine release in the striatum following an amphetamine challenge is associated with higher relapse rates. One possible mechanism that might lead to lower amphetamine-induced dopamine release is low availability of dopamine storage vesicles in the presynaptic terminals for release. Consistent with this hypothesis, postmortem studies have shown low levels of vesicular monoamine transporter, type 2 (VMAT2), the membrane protein that regulates the size of the vesicular dopamine pool, in cocaine abusers relative to healthy subjects. To confirm the postmortem findings, the authors used PET and the VMAT2 radioligand [¹¹C]-(+)-dihydrotetrabenazine (DTBZ) to assess the in vivo VMAT2 availability in a group of 12 recently abstinent cocaine-dependent subjects and matched healthy comparison subjects. [¹¹C]DTBZ nondisplaceable binding potential (BP(ND)) was measured by kinetic analysis using the arterial input function or, if arterial input was unavailable, by the simplified reference tissue method. [¹¹C]DTBZ BP(ND) was significantly lower in the cocaine abusers than in the comparison subjects in the limbic striatum (10.0% lower), associative striatum (-13.4%), and sensorimotor striatum (-11.5%). The results of this in vivo PET study confirm previous in vitro reports of low VMAT2 availability in the striatum of cocaine abusers. It also suggests a compensatory down-regulation of the dopamine storage vesicles in response to chronic cocaine abuse and/or a loss of dopaminergic terminals. Further research is necessary to understand the clinical relevance of this observation to relapse and outcome in abstinent cocaine abusers.

Unpredictable saccharin reinforcement enhances locomotor responding to amphetamine

Drug-naïve, non-deprived rats were trained to lever press for saccharin under fixed-ratio (FR) or variable-ratio (VR) schedules of reinforcement. Rats trained on the VR schedule in which saccharin reinforcement was not predicted by a fixed number of lever presses subsequently showed an enhanced locomotor response to a threshold amphetamine challenge injection (0.5 mg/kg IP) administered 2 weeks following the last saccharin session. This finding suggests that chronic exposure to gambling-like conditions of uncertain reinforcement can induce neuroadaptations in brain reward systems that are similar to those produced by repeated psychostimulant exposure and may lead to the development of addictive behaviors.

Within-Subject Comparison of [11C]-( + )-PHNO and [11C]raclopride Sensitivity to Acute Amphetamine Challenge in Healthy Humans

[(11)C]PHNO is a D(2)/D(3) agonist positron emission tomography radiotracer, with higher in vivo affinity for D(3) than for D(2) receptors. As [(11)C]-(+)-PHNO is an agonist, its in vivo binding is expected to be more affected by acute fluctuations in synaptic dopamine than that of antagonist radiotracers such as [(11)C]raclopride. In this study, the authors compared the effects of an oral dose of the dopamine releaser amphetamine (0.3 mg/kg) on in vivo binding of [(11)C]-(+)-PHNO and [(11)C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D(3) receptors is negligible and both tracers predominantly bind to D(2) receptors, the reduction of [(11)C]-(+)-PHNO binding potential (BP(ND)) was 1.5 times larger than that of [(11)C]raclopride. The gain in sensitivity associated with the agonist [(11)C]-(+)-PHNO implies that ∼65% of D(2) receptors are in the high-affinity state in vivo. In extrastriatal regions, where [(11)C]-(+)-PHNO predominantly binds to D(3) receptors, the amphetamine effect on [(11)C]-(+)-PHNO BP(ND) was even larger, consistent with the higher affinity of dopamine for D(3). This study indicates that [(11)C]-(+)-PHNO is superior to [(11)C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [(11)C]-(+)-PHNO also enables measurement of synaptic dopamine in D(3) regions.

Motor and locomotor responses to systemic amphetamine in three lines of selectively bred Long-Evans rats

The goal of the study was to measure spontaneous and amphetamine-induced motor and locomotor activity in three selectively bred lines of male Long-Evans rats. The number of 50kHz ultrasonic vocalizations (USVs) emitted in response to heterospecific play with human hand (“tickling”) had been measured daily in these lines of rats from 21 to 24days of age, as a criterion for dividing them into high vocalizing line, low vocalizing line, and random breeding and testing lines. This study sought to determine whether selection of rats based on their affective social-vocalizations also had effects on their locomotor performance and sensitivity to amphetamine. In this study adult animals from the 25th generation (with no further selection) were tested. The results showed that rats, which were selectively bred to emit high numbers of 50kHz vocalizations, also exhibited elevated levels of spontaneous locomotor activity. After systemic injection of d-amphetamine (1.5mg/kg), the level of motor and locomotor activity significantly increased further in all the lines as compared to saline controls. The horizontal and vertical activities and the distance covered by rats of the high line, both at the baseline and after amphetamine challenge, were significantly higher than those of the low line animals in absolute scores but not as proportion of relevant saline controls. Since appetitive 50kHz USVs and locomotor activity are both dependent on the activity of the dopamine system, it is concluded that selection of rats based on the expression of their positive emotional state is also selecting other features than vocalization, namely locomotor behavior. This may help explain why these animals are relatively resistant to depressogenic manipulations.

P.6.f.002 Attenuated behavioural responses to acute and chronic cocaine in adenosine 2A overexpressed transgenic rats

Striatal dopamine D2R homodimerization is increased in the dorsal striatum after acute amphetamine challenge and in the amphetamine-induced sensitized state, a well-known animal model of schizophrenia. Therefore, it was tested if the increase in D2R homoreceptor complexes found after acute amphetamine challenge in the saline or the amphetamine sensitized state leads to changes in the antagonistic adenosine A2AR-D2R interactions in the striatum. [3H]-raclopride binding was performed in membrane preparations from the ventral and dorsal striatum involving competition with the D2R like agonist quinpirole. In the ventral striatum CGS 21680 produced a significant increase of the KiH values (p < 0.05) in the amphetamine sensitized group when expressed in percent versus the corresponding values in saline sensitized rats after amphetamine challenge. However, in the dorsal striatum a significant change did not develop in the KiH values when expressed in percent of the corresponding values in saline sensitized rats after amphetamine challenge. In fact, the non-significant change was in the opposite direction towards a reduction of the KiH values. Taken together, a reduced affinity of the high affinity D2 agonist binding site (KiH value) developed in the ventral but not in the dorsal striatum as a result of increased antagonistic allosteric A2AR-D2R interactions in the amphetamine-induced sensitized state versus the saline sensitized state after an acute amphetamine challenge. The selective reappearance of antagonistic A2AR-D2R receptor-receptor interactions in the ventral striatum after amphetamine challenge in the amphetamine sensitized rat may give one possible mechanism for the atypical antipsychotic-like actions of A2AR receptor agonists.

Amphetamine sensitization in reproductively experienced female rats

Recent studies have supported the hypothesis that pregnancy and parturition are associated with altered sensitivity of brain dopamine systems. An increased behavioral sensitivity to a direct-acting D1/D2 receptor agonist (apomorphine) has also been observed several weeks after lactation, suggesting that these adaptations are long-lasting. To further characterize this phenomenon, the effects of reproductive experience on behavioral sensitization to an indirect-acting dopamine agonist (amphetamine) in female rats were studied. In two separate experiments, nulliparous and primiparous (12–16 weeks post-weaning) female rats were pretreated with amphetamine (1.0 or 5.0mg/kg) or vehicle (saline) once daily for 5 consecutive days. After 10 days of withdrawal, all animals were challenged with a low dose of amphetamine (25% of pretreatment dose). Locomotor activity was measured following each drug or vehicle administration. Locomotor sensitization to amphetamine challenge was observed in all animals pretreated with 1mg/kg, regardless of reproductive experience. In contrast, primiparous animals pretreated with 5mg/kg amphetamine displayed a significantly larger locomotor response to the challenge compared to nulliparous controls. The findings indicate enhanced behavioral sensitization to amphetamine in reproductively experienced rats, and confirm previous reports of lasting adaptations of dopamine systems following pregnancy and lactation.

Diazepam-induced neuronal plasticity attenuates locomotor responses to morphine and amphetamine challenges in mice

A single administration of benzodiazepine-site ligands of the inhibitory GABA(A) receptors has been shown to lead to persistently potentiated AMPA receptor-mediated responses in dopaminergic neurons of the ventral tegmental area (VTA). This plasticity has been suggested to be a common property of different kinds of addictive drugs. We now wanted to test if the plasticity induced by diazepam would also affect behaviors elicited by other drugs of abuse. Activity and plasticity of the VTA dopaminergic neurons are known to be essential for the initiation and/or sensitization of the psychomotor responses to morphine and amphetamine. The effect of diazepam pre-treatment (a single dose of 5 mg/kg) was studied 24-72 h later in behaving C57BL/6J mice on locomotor activity induced by acute and repeated administration of morphine (5 mg/kg) and amphetamine (2.5 mg/kg). The pre-treatment attenuated the locomotor-activating effect of morphine. On the other hand, it reduced the amphetamine-induced locomotor sensitization in male mice in N-methyl-d-aspartate (NMDA) receptor-dependent manner. The acute amphetamine effect was not affected. The results indicate that benzodiazepine-induced neural plasticity transiently reduces the sensitivity to psychomotor stimulation by opioids and stimulants.

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.

Amphetamine induced dopamine release increases anxiety in individuals recovered from anorexia nervosa.

Genetic, pharmacologic, and physiological data suggest that individuals with anorexia nervosa (AN) have altered striatal dopamine (DA) function. We used an amphetamine challenge and positron emission tomography [(11) C]raclopride paradigm to explore DA striatal transmission in 10 recovered (REC) AN compared with 9 control women (CW). REC AN and CW were similar for baseline, postamphetamine [(11) C]raclopride binding potential (BP(ND) ) and change (Δ) in BP(ND) for all regions. In CW, ventral striatum Δ BP(ND) was associated with euphoria (r = -0.76; p = 0.03), which was not found for REC AN. Instead, REC AN showed a significant relationship between anxiety and Δ BP(ND) in the precommissural dorsal caudate (r = -0.62, p = 0.05). REC AN have a positive association between endogenous DA release and anxiety in the dorsal caudate. This finding could explain why food-related DA release produces anxiety in AN, whereas feeding is pleasurable in healthy participants.

Glutamate transporter subtype 1 (GLT-1) activator ceftriaxone attenuates amphetamine-induced hyperactivity and behavioral sensitization in rats

BackgroundThe β-lactam antibiotic and glutamate transporter subtype 1 (GLT-1) activator ceftriaxone prevents relapse to cocaine-seeking and inhibits morphine-induced physical dependence and tolerance in rats, but its efficacy against amphetamine-induced behaviors is unknown. MethodsHere, we tested the hypothesis that ceftriaxone (200mg/kg, i.p.) inhibits hyperactivity produced by acute amphetamine administration (2mg/kg, i.p.) and sensitization of hyperactivity induced by repeated amphetamine exposure (2mg/kg, i.p.). For acute experiments, rats treated with ceftriaxone for 5 days were injected with amphetamine or saline on day 6. ResultsAmphetamine elicited less ambulatory and stereotypical activity in ceftriaxone-treated rats than in ceftriaxone-naïve rats. For chronic experiments, rats injected with ceftriaxone or saline for 8 days were also injected with amphetamine or saline on days 6–8 and then challenged with amphetamine 5 days later. Amphetamine produced greater ambulatory and stereotypical activity in amphetamine-pretreated rats than in rats previously naïve to amphetamine. Amphetamine challenge produced less ambulatory and stereotypical activity in rats pretreated with a combination of ceftriaxone (200mg/kg) and amphetamine than in rats pretreated with only amphetamine. ConclusionThe present demonstration that ceftriaxone attenuates amphetamine-induced hyperactivity and behavioral sensitization suggests its documented efficacy against adverse cocaine and morphine effects extends to amphetamine.

Increased in vivo [ 11C]raclopride binding to brain dopamine receptors in amphetamine-treated rats

The hypothesis that repeated daily doses of amphetamine increases the number of available dopamine D 2 receptors in vivo in rat striatum, and may enhance the response to subsequent amphetamine challenge doses, was examined. The in vivo binding potentials of [ 11C]raclopride, a D 2 receptor antagonist, were determined in male CD-1 rats under five conditions: (1) drug-naïve with saline challenge, (2) drug naïve with 5 mg/kg amphetamine challenge, (3) amphetamine-dosed (five daily repeated s.c. doses of 5 mg/kg amphetamine) and saline challenge, (4) amphetamine-dosed and amphetamine challenge, and (5) saline treated (five daily repeated s.c. doses) and saline challenged. Radiotracer studies in amphetamine-dosed animals were done after a 10-day drug free interval. In the amphetamine-dosed group the baseline [ 11C]raclopride binding was increased by 63% compared to saline-treated controls. The response to an amphetamine challenge, evidenced by a reduction of [ 11C]raclopride binding, was doubled in amphetamine-dosed animals (40%) compared to drug-naïve controls (20%). These results support increased baseline in vivo dopamine D 2 receptor antagonist radioligand binding after repeated amphetamine administration in rats.

Neuroendocrine and behavioral response to amphetamine challenge after exposure to an organophosphorus pesticide

Exposure to various stressors is known to result in sensitization to psychostimulants, a state related to the psychostimulant dependence and addiction. It has been shown in some studies that the rise in corticosterone (CORT) concentration is indispensable for both the induction and the expression of behavioral sensitization. Therefore, it might be suspected that behavioral hyposensitivity to amphetamine (AMPH) is somehow related to a reduced CORT response to the psychostimulant subsequent to the chlorphenvinphos (CVP) intoxication. The male adult Wistar rats received single i.p. injections of CVP at the doses 0.5, 1.0 or 3.0 mg/kg b.w., or pure corn oil. CORT concentration was determined in samples of blood drawn from the tail vein before and then 30, 60, 180 min and 24 h after injection. The other rats were divided into two groups and tested, three weeks after the CVP injection for the effect of AMPH (0.5 mg/kg b.w. i.p.) on the serum CORT concentration. In addition, behavioral sensitivity to AMPH was assessed by measuring locomotor activity of the animals in an open-field. 1) The stressor property of CVP was confirmed. The injection resulted in up to tenfold increase in the serum CORT concentration. The magnitude and duration of this response were dose-related. 2) Three weeks after the CVP exposure, the CORT response to AMPH was significantly increased. 3) The behavioral response to the psychostimulant, i.e. augmented locomotion, was significantly reduced compared to the control. The results confirm that CVP exposure causes behavioral hyposensitivity to AMPH. This effect, however, could not be ascribed to a diminished CORT response.

Effects of unilateral 6-OHDA lesions on [3H]-N-propylnorapomorphine binding in striatum ex vivo and vulnerability to amphetamine-evoked dopamine release in rat

It has been argued that agonist ligands for dopamine D2/3 receptors recognize a privileged subset of the receptors in living striatum, those which are functionally coupled to intracellular G-proteins. In support of this claim, the D2/3 agonist [3H]-N-propylnorapomorphine ([3H]NPA) proved to be more vulnerable to competition from endogenous dopamine than was the antagonist ligand [11C]raclopride, measured ex vivo in mouse striatum, and subsequently in multi-tracer PET studies of analogous design. Based on these results, we predicted that prolonged dopamine depletion would result in a preferential increase in agonist binding, and a lesser competition from residual dopamine to the agonist binding. To test this hypothesis we used autoradiography to measure [3H]NPA and [3H]raclopride binding sites in hemi-parkinsonian rats with unilateral 6-OHDA lesions, with and without amphetamine challenge. Unilateral lesions were associated with a more distinct increase in [3H]NPA binding ex vivo than was seen for [3H]raclopride binding in vitro. Furthermore, this preferential asymmetry in [3H]NPA binding was more pronounced in amphetamine treated rats. We consequently predict that agonist ligands should likewise be fitter than antagonists for detecting responses to denervation in positron emission tomography studies of idiopathic Parkinson's disease. Agonist binding increases in vivo are likely to reflect the composite of a sensitization-like phenomenon, and relatively less competition from endogenous dopamine, as seen in the lesioned side of 6-OHDA induced hemi-parkinsonism.

Naltrexone attenuates amphetamine-induced locomotor sensitization in the rat

Amphetamine, and other stimulants, readily induces behavioral sensitization, an effect hypothesized to reflect neurobiological changes that may underlie certain aspects of drug addiction. Apart from the effects on the dopamine system, previous studies have also shown that amphetamine interacts with other neurotransmitters, including the endogenous opioid system. The unselective opioid receptor antagonist naltrexone (NTX) modulates amphetamine-induced effects in both laboratory animals and humans. To further examine this interaction, the aim of the present study was to investigate the effect of NTX on the expression of locomotor sensitization and conditioned locomotor response in animals previously conditioned with amphetamine. Sensitization was induced by repeated administration of amphetamine (2 mg/kg) for 10 consecutive days. After a 10-day drug-free period, the rats were administered NTX (3 mg/kg) 30 minutes prior to the administration of a challenge dose of either amphetamine (0.5 mg/kg) (test for drug-induced sensitization) or saline (test for conditioned locomotor response). NTX had no effect on acute amphetamine-induced locomotor activity or on general locomotor activity in animals without a history of amphetamine conditioning. However, animals previously conditioned with amphetamine showed a sensitized locomotor response to the amphetamine challenge following the 10-day drug-free period. This sensitized response was significantly inhibited by NTX pre-treatment. In addition, NTX pre-treatment blocked the conditioned locomotor response when the amphetamine-conditioned animals were placed in the previously amphetamine-paired context. This study showed that NTX attenuates drug- and cue-induced locomotor behavior in amphetamine-conditioned animals, supporting recent clinical findings that indicated a potential role of NTX as a treatment for amphetamine dependence.

D1 and D2 dopamine receptors differentially mediate the activation of phosphoproteins in the striatum of amphetamine-sensitized rats.

Extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), and protein kinase B (PKB or Akt) in the striatum are differentially activated by acute and repeated amphetamine (AMPH) administration. However, the dopamine receptor subtypes that mediate transient vs. prolonged phosphorylation changes in these proteins induced by AMPH challenge in AMPH-sensitized rats are unknown. The role of the D1 and D2 class of dopamine receptors in the differential phosphorylation of striatal ERK, CREB, Thr308-Akt and Ser473-Akt and the expression of behavioral sensitization induced by AMPH challenge in AMPH-pretreated rats were determined. D1 or D2 dopamine receptor antagonists were injected before an AMPH challenge in AMPH-sensitized rats. After behavioral activity was recorded, rats were euthanized either 15min or 2h after AMPH challenge and striatal phosphoprotein status was analyzed by Western blotting. The D1 receptor antagonist (SCH23390) decreased stereotypical behavior whereas the D2 receptor antagonist (eticlopride) decreased all behavioral activity induced by an AMPH challenge in AMPH-sensitized rats. SCH23390, but not eticlopride, significantly decreased ERK, CREB, and Thr308-Akt phosphorylation in the striatum 15min, and ERK and CREB phosphorylation 2h, after AMPH challenge in AMPH-sensitized rats. In contrast, eticlopride, but not SCH23390, prevented a decrease in Akt phosphorylation 2h after AMPH challenge. These data indicate that the time course of phosphoprotein signaling is differentially regulated by D1 and D2 receptors in the striatum of AMPH-sensitized rats, suggesting that complex regulatory interactions are activated by repeated AMPH exposure.

Socially isolated rats exhibit changes in dopamine homeostasis pertinent to schizophrenia

Post-weaning social isolation of rats produces an array of behavioral and neurochemical changes indicative of altered dopamine function. It has therefore been suggested that post-weaning social isolation mimics some aspects of schizophrenia. Here we replicate and extent these findings to include an investigation of prefrontal cortical dopamine dynamics using in vivo microdialysis. Social isolation for 12 weeks after weaning caused increased locomotor activity in response to novelty and amphetamine challenge. In vivo microdialysis experiments revealed that while social isolation did not change basal dopamine levels in the nucleus accumbens, it did cause a significant reduction of basal dopamine release in the prefrontal cortex. In addition, social isolation lead to a significantly larger dopamine response to an amphetamine challenge, in both the nucleus accumbens and the prefrontal cortex compared to group housed controls. Taken together, these results indicate that post-weaning social isolation alters dopaminergic function with changes resembling subcortical hyperdopaminergia and prefrontal hypodopaminergia similar to what has been observed in schizophrenic patients.

Effects of single and group housing conditions and alterations in social and physical contexts on amphetamine-induced behavioral sensitization in rats

Repeated administration of amphetamine (AMPH) can produce behavioral sensitization. However, whether contextual elements and housing conditions influence AMPH-induced behavioral sensitization remains uncertain. This study was designed to examine the effects of housing conditions (single- vs. group-housed) and different contextual changes, including social (with two other co-drug partners) and physical (novel box) context changes, on AMPH-induced behavioral sensitization. During the training phase, all rats were exposed for 7 days to AMPH (1 mg/kg, intraperitoneally) in a Locometer chamber, with the exception of animals tested for the effects of physical context changes trained in a novel box. Following a 7-day withdrawal phase, all rats received an AMPH (0.5 mg/kg) challenge, and locomotor activity in a Locometer box was recorded before and after AMPH injection during the testing phase. Under group housing conditions, animals exposed to a different physical environment between the training and testing phases or accompanying co-drug partners during the training phase exhibited decreased AMPH-induced locomotor sensitization. In contrast, single housing conditions did not have an inhibitory effect on AMPH-induced behavioral sensitization after manipulations of the physical and social contexts. These results suggest that under group housing conditions, both physical and social context changes can attenuate AMPH-induced behavioral sensitization. The possible neural mechanisms underlying the involvement of different housing conditions in AMPH-induced behavioral sensitization are discussed.