Amphetamine-induced Locomotor Research Articles

Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse.

Mitochondrial dysfunction is strongly associated with autism spectrum disorder (ASD) and the Inner mitochondrial membrane protein 2-like (IMMP2L) gene is linked to autism inheritance. However, the biological basis of this linkage is unknown notwithstanding independent reports of oxidative stress in association with both IMMP2L and ASD. To better understand IMMP2L's association with behaviour, we developed the Immp2lKD knockout (KO) mouse model which is devoid of Immp2l peptidase activity. Immp2lKD -/- KO mice do not display any of the core behavioural symptoms of ASD, albeit homozygous Immp2lKD -/- KO mice do display increased auditory stimulus-driven instrumental behaviour and increased amphetamine-induced locomotion. Due to reports of increased ROS and oxidative stress phenotypes in an earlier truncated Immp2l mouse model resulting from an intragenic deletion within Immp2l, we tested whether high doses of the synthetic mitochondrial targeted antioxidant (MitoQ) could reverse or moderate the behavioural changes in Immp2lKD -/- KO mice. To our surprise, we observed that ROS levels were not increased but significantly lowered in our new Immp2lKD -/- KO mice and that these mice had no oxidative stress-associated phenotypes and were fully fertile with no age-related ataxia or neurodegeneration as ascertained using electron microscopy. Furthermore, the antioxidant MitoQ had no effect on the increased amphetamine-induced locomotion of these mice. Together, these findings indicate that the behavioural changes in Immp2lKD -/- KO mice are associated with an antioxidant-like phenotype with lowered and not increased levels of ROS and no oxidative stress-related phenotypes. This suggested that treatments with antioxidants are unlikely to be effective in treating behaviours directly resulting from the loss of Immp2l/IMMP2L activity, while any behavioural deficits that maybe associated with IMMP2L intragenic deletion-associated truncations have yet to be determined.

The contribution of medium spiny neuron subtypes in the nucleus accumbens core to compulsive-like ethanol drinking

Compulsive alcohol use, or drinking that persists despite negative or aversive consequences, is a defining characteristic of alcohol use disorder. Here, chemogenetic technology (i.e. Designer Receptors Exclusively Activated by Designer Drugs; DREADDs) was used to inhibit or excite the NAc core or selectively inhibit D1-or D2 receptor-expressing neurons in the NAc core to understand the role of the NAc core and how these subpopulations of neurons may influence compulsive-like ethanol (EtOH) drinking using C57BL/6J, Drd1-cre, and Drd2-cre male and female mice. Compulsive-like EtOH drinking was modeled with a two-bottle choice, drinking in the dark paradigm. The major finding of this study was that mice decreased compulsive-like EtOH intake when the NAc core was inhibited and there was no change of EtOH + quinine intake when the NAc core was excited. Interestingly, inhibition of D1-or D2 receptor-expressing neurons did not alter compulsive-like EtOH intake. Control experiments showed that NAc core excitation and selective inhibition of D1-or D2-receptor-expressing neurons had no effect on baseline EtOH drinking, intake of water, or intake of quinine-adulterated water. CNO reduced amphetamine-induced locomotion in the D1-CRE+ (but not the D2CRE+) group in a control experiment. Finally, pharmacological antagonism of D1 and D2 receptors together, but not separately, reduced quinine-resistant EtOH drinking. These results suggest that the NAc core is a critical region involved in compulsive-like EtOH consumption, and that both D1-and D2 receptor-expressing medium spiny neurons participate in controlling this behavior.

Virus-mediated overexpression of radixin in the nucleus accumbens inhibits the development of amphetamine-induced conditioned locomotor activity

Virus-mediated overexpression of radixin in the nucleus accumbens inhibits the development of amphetamine-induced conditioned locomotor activity

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats.

Synaptic pruning is a critical refinement step during neurodevelopment, and schizophrenia has been associated with overpruning of cortical dendritic spines. Both human studies and animal models implicate disrupted-in-schizophrenia 1 (DISC1) gene as a strong susceptibility factor for schizophrenia. Accumulating evidence supports the involvement of DISC1 protein in the modulation of synaptic elimination during critical periods of neurodevelopment and of dopamine D2-receptor-mediated signaling during adulthood. In many species, synaptic pruning occurs during juvenile and adolescent periods and is mediated by microglia, which can be over-activated by an immune challenge, giving rise to overpruning. Therefore, we sought to investigate possible interactions between a transgenic DISC1 model (tgDISC1) and juvenile immune activation (JIA) by the bacterial cell wall endotoxin lipopolysaccharide on the induction of schizophrenia-related behavioral and neurochemical disruptions in adult female and male rats. We examined possible behavioral aberrations along three major symptom dimensions of schizophrenia including psychosis, social and emotional disruptions, and cognitive impairments. We detected significant gene–environment interactions in the amphetamine-induced locomotion in female animals and in the amphetamine-induced anxiety in male animals. Surprisingly, gene–environment interactions improved social memory in both male and female animals. JIA alone disrupted spatial memory and recognition memory, but only in male animals. DISC1 overexpression alone induced an improvement in sensorimotor gating, but only in female animals. Our neurochemical analyses detected sex- and manipulation-dependent changes in the postmortem monoamine content of animals. Taken together, we here report sex-specific effects of environment and genotype as well as their interaction on behavioral phenotypes and neurochemical profiles relevant for schizophrenia.

Dose-dependent reduction in cocaine-induced locomotion by Clozapine-N-Oxide in rats with a history of cocaine self-administration

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are novel tools for the dissection of circuitry mediating behavior and neural function. Designer receptors based on the muscarinic M3 and M4 subtypes were designed to be activated by clozapine-N-oxide (CNO), a ligand previously shown to be an inert metabolite of clozapine. However, recent work in rats has shown that CNO is reverse metabolized to its parent compound. Furthermore, CNO administration (5 mg/kg IP) attenuates amphetamine-induced locomotion and the evoked dopamine response that accompanies it. As these systems are routinely used to probe the neurocircuitry underlying cocaine-seeking behavior, here we sought to determine whether CNO would have similar effects on cocaine-induced locomotion in rats with a history of cocaine self-administration. In order for muscarinic-based DREADDs to be utilized for the dissection of circuitry underlying behavioral responses to cocaine, the doses of CNO administered to induce DREADD signaling must themselves have no effect on cocaine-induced behavior. Male Sprague-Dawley rats self-administered cocaine (0.35 mg/infusion) for 12 days, followed by 14–21 days of instrumental extinction training. Rats then underwent locomotor testing. CNO (0, 3, or 5 mg/kg) was injected (utilizing a within-subjects design), followed 20 min later by cocaine (10 mg/kg IP). Locomotion was monitored for the following 120 min. We found that the 5, but not the 3 mg/kg, dose of CNO reduced cocaine-induced locomotion. Thus, studies utilizing DREAADs to probe cocaine-induced behavior should consider these findings when choosing a dose of CNO and include non-DREADD CNO controls.

Neurotensin in the nucleus accumbens reverses dopamine supersensitivity evoked by antipsychotic treatment

Long-term exposure to antipsychotics like haloperidol can increase sensitivity to dopamine agonist stimulation. This could contribute to treatment failure and increase relapse to psychosis. Chronic antipsychotic treatment elevates neurotensin levels in the nucleus accumbens (NAc), where the neuropeptide modulates dopamine function by signalling through NTS1 receptors. We hypothesized that increasing neurotensin activity in the NAc attenuates the expression of antipsychotic-induced dopamine supersensitivity, which is indicated by a potentiated psychomotor response to amphetamine. Rats received either continuous (CONT-HAL; achieved via subcutaneous osmotic minipump) or intermittent (INT-HAL; achieved via daily subcutaneous injection) haloperidol treatment for 16–17 days. Three to 5 days later, we injected neurotensin into the NAc and measured amphetamine-induced locomotion. Only CONT-HAL rats showed potentiated amphetamine-induced locomotion, indicating dopamine supersensitivity. Compared to intra-NAc saline, intra-NAc neurotensin suppressed amphetamine-induced locomotion in CONT-HAL rats, but not in INT-HAL or control rats. In a new cohort of CONT-HAL and INT-HAL rats, we measured striatal levels of proneurotensin mRNA and NTS1 receptors. The two treatments led to overlapping but also distinct neurochemical profiles. Neither treatment altered NTS1 receptor levels in the NAc, but both increased proneurotensin mRNA levels in the NAc core. In the caudate-putamen, only INT-HAL increased NTS1 receptor levels, while only CONT-HAL increased proneurotensin mRNA expression. Thus, antipsychotic-induced dopamine supersensitivity enhances the ability of neurotensin in the NAc to regulate dopamine-mediated behaviours, and this likely does not involve changes in local levels of NTS1 receptors or proneurotensin mRNA. We conclude that increasing neurotensin activity could be considered to attenuate antipsychotic-induced dopamine supersensitivity.

OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior

Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.

Modeling hypohedonia following repeated social defeat: Individual vulnerability and dopaminergic involvement

Social defeat in rodents putatively can model hypohedonia. The present studies examined models for assessing hypohedonia-like behavior and tested the hypotheses that 1) individual differences in baseline reward sensitivity predict vulnerability, and 2) defeat elicits changes in pharmacological measures of striatal dopaminergic function. Male Wistar rats (n=142) received repeated defeat (3 “triad” blocks of 3 defeats) or control handling. To determine whether defeat influenced consumption of SuperSac (glucose-saccharin) over an isocaloric, less preferred, glucose solution, a 2-choice paradigm was used. To determine repeated defeat effects on the reinforcing efficacy of SuperSac, a progressive-ratio schedule of reinforcement was used. Amphetamine-induced locomotor activity (0.08mg/kg, s.c.) was determined as a measure sensitive to striatal dopaminergic function. Defeat reduced SuperSac consumption during the first two triads—an effect seen in the third triad only in defeated rats with High vs. Low baseline SuperSac intake. The characteristic escalation in PR breakpoint for SuperSac normally seen in controls was absent in defeated rats, leading to a significant difference by the third triad. Defeat-induced blunting of the escalation in PR performance was greater in rats with High antecedent PR breakpoints and persisted 2.5weeks post-defeat. Repeated defeat also blunted amphetamine-induced locomotion 13days post-defeat. Thus, hypohedonic-like effects of social defeat were detected and accompanied by persistently attenuated striatal dopamine function. Early effects were seen for consumption of differentially-palatable solutions, and persistent effects were seen for the “breakpoint” motivational measure. The results implicate initial reward sensitivity as a risk factor for stress-induced hypohedonia.

Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens

While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats.

2-Bromoterguride-a potential atypical antipsychotic drug without metabolic effects in rats.

RationaleRecently, we showed that 2-bromoterguride acted as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A and α2C-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy.ObjectiveTo extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT2A receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs).ResultsAcute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity.ConclusionsOur data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain.

Repeated ventral midbrain neurotensin injections sensitize to amphetamine-induced locomotion and ERK activation: A role for NMDA receptors

Previous studies have shown that activation of ventral midbrain NMDA receptors is required to initiate sensitization by amphetamine. In view of the recent evidence that neurotensin modulates ventral midbrain glutamate neurotransmission, we tested the hypothesis that neurotensin is acting upstream to glutamate to initiate sensitization to the behavioral and neurochemical effects of amphetamine. During a first testing phase, adult male rats implanted with bilateral ventral midbrain cannulae were injected every second day for three days with D-[Tyr11]neurotensin (1.5 nmol/side), the preferred NMDA GluN2A/B antagonist, CPP (40 or 120 pmol/side), the selective GluN2B antagonist, Ro04-5595 (200 or 1200 pmol/side), CPP (40 or 120 pmol/side) + D-[Tyr11]neurotensin (1.5 nmol/side) or Ro04-5595 (200 or 1200 pmol/side) + D-[Tyr11]neurotensin (1.5 nmol/side) and locomotor activity was measured immediately after the injection. Five days after the last central injection, the locomotor response or the expression of phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) in neurons of different limbic nuclei was measured following a systemic injection of amphetamine sulfate (0.75 mg/kg, i.p.). Results show that amphetamine induced significantly stronger locomotor activity and pERK1/2 expression in the nucleus accumbens shell and infralimbic cortex in neurotensin pre-exposed animals than in controls (vehicle pre-exposed). These sensitization effects initiated by neurotensin were prevented by CPP, but not Ro04-5595. These results support the hypothesis that neurotensin is stimulating glutamate neurotransmission to initiate neural changes that sub-serve amphetamine sensitization and that glutamate is acting on NMDA receptors that are mostly likely composed of GluN2A, but not GluN2B, subunits.This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’.

Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain.

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT's role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H+ antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects.

Prenatal immune activation in mice blocks the effects of environmental enrichment on exploratory behavior and microglia density

Adverse environmental factors including prenatal maternal infection are capable of inducing long-lasting behavioral and neural alterations which can enhance the risk to develop schizophrenia. It is so far not clear whether supportive postnatal environments are able to modify such prenatally-induced alterations. In rodent models, environmental enrichment influences behavior and cognition, for instance by affecting endocrinologic, immunologic, and neuroplastic parameters. The current study was designed to elucidate the influence of postnatal environmental enrichment on schizophrenia-like behavioral alterations induced by prenatal polyI:C immune stimulation at gestational day 9 in mice. Adult offspring were tested for amphetamine-induced locomotion, social interaction, and problem-solving behavior as well as expression of dopamine D1 and D2 receptors and associated molecules, microglia density and adult neurogenesis. Prenatal polyI:C treatment resulted in increased dopamine sensitivity and dopamine D2 receptor expression in adult offspring which was not reversed by environmental enrichment. Prenatal immune activation prevented the effects of environmental enrichment which increased exploratory behavior and microglia density in NaCl treated mice. Problem-solving behavior as well as the number of immature neurons was affected by neither prenatal immune stimulation nor postnatal environmental enrichment. The behavioral and neural alterations that persist into adulthood could not generally be modified by environmental enrichment. This might be due to early neurodevelopmental disturbances which could not be rescued or compensated for at a later developmental stage.

5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity

Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025–0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate-putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.

Physiological and behavioral effects of amphetamine in BACE1(-/-) mice.

β-Site APP-cleaving Enzyme 1 (BACE1) is a protease that has been linked to schizophrenia, a severe mental illness that is potentially characterized by enhanced dopamine (DA) release in the striatum. Here, we used acute amphetamine administration to stimulate neuronal activity and investigated the neurophysiological and locomotor-activity response in BACE1-deficient (BACE1(-/-) ) mice. We measured locomotor activity at baseline and after treatment with amphetamine (3.2 and 10 mg/kg). While baseline locomotor activity did not vary between groups, BACE1(-/-) mice exhibited reduced sensitivity to the locomotor-enhancing effects of amphetamine. Using high-performance liquid chromatography (HPLC) to measure DA and DA metabolites in the striatum, we found no significant differences in BACE1(-/-) compared with wild-type mice. To determine if DA neuron excitability is altered in BACE1(-/-) mice, we performed patch-clamp electrophysiology in putative DA neurons from brain slices that contained the substantia nigra. Pacemaker firing rate was slightly increased in slices from BACE1(-/-) mice. We next measured G protein-coupled potassium currents produced by activation of D2 autoreceptors, which strongly inhibit firing of these neurons. The maximal amplitude and decay times of D2 autoreceptor currents were not altered in BACE1(-/-) mice, indicating no change in D2 autoreceptor-sensitivity and DA transporter-mediated reuptake. However, amphetamine (30 µm)-induced potassium currents produced by efflux of DA were enhanced in BACE1(-/-) mice, perhaps indicating increased vesicular DA content in the midbrain. This suggests a plausible mechanism to explain the decreased sensitivity to amphetamine-induced locomotion, and provides evidence that decreased availability of BACE1 can produce persistent adaptations in the dopaminergic system.

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

The neuromodulator dopamine signals through the dopamine D2 receptor (D2R) to modulate central nervous system functions through diverse signal transduction pathways. D2R is a prominent target for drug treatments in disorders where dopamine function is aberrant, such as schizophrenia. D2R signals through distinct G-protein and β-arrestin pathways, and drugs that are functionally selective for these pathways could have improved therapeutic potential. How D2R signals through the two pathways is still not well defined, and efforts to elucidate these pathways have been hampered by the lack of adequate tools for assessing the contribution of each pathway independently. To address this, Evolutionary Trace was used to produce D2R mutants with strongly biased signal transduction for either the G-protein or β-arrestin interactions. These mutants were used to resolve the role of G proteins and β-arrestins in D2R signaling assays. The results show that D2R interactions with the two downstream effectors are dissociable and that G-protein signaling accounts for D2R canonical MAP kinase signaling cascade activation, whereas β-arrestin only activates elements of this cascade under certain conditions. Nevertheless, when expressed in mice in GABAergic medium spiny neurons of the striatum, the β-arrestin-biased D2R caused a significant potentiation of amphetamine-induced locomotion, whereas the G protein-biased D2R had minimal effects. The mutant receptors generated here provide a molecular tool set that should enable a better definition of the individual roles of G-protein and β-arrestin signaling pathways in D2R pharmacology, neurobiology, and associated pathologies.

LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage.

Genetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage—an identified risk factor for schizophrenia—using a serum-exposure paradigm. This model exhibits behavioral, neurochemical and schizophrenia-related gene expression alterations in adult females. Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction—in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex—were induced upon prenatal serum exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was identified as a key molecular initiator of schizophrenia-like sequelae induced by serum. Prenatal exposure to LPA alone phenocopied many of the schizophrenia-like alterations seen in the serum model, whereas pretreatment with an antagonist against the LPA receptor subtype LPA1 prevented many of the behavioral and neurochemical alterations. In addition, both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that aberrant LPA receptor signaling associated with fetal brain hemorrhage may contribute to the development of some neuropsychiatric disorders.

Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity.

Pavlovian cues associated with junk-foods (caloric, highly sweet, and/or fatty foods), like the smell of brownies, can elicit craving to eat and increase the amount of food consumed. People who are more susceptible to these motivational effects of food cues may have a higher risk for becoming obese. Further, overconsumption of junk-foods leading to the development of obesity may itself heighten attraction to food cues. Here, we used a model of individual susceptibility to junk-foods diet-induced obesity to determine whether there are pre-existing and/or diet-induced increases in attraction to and motivation for sucrose-paired cues (ie, incentive salience or 'wanting'). We also assessed diet- vs obesity-associated alterations in mesolimbic function and receptor expression. We found that rats susceptible to diet-induced obesity displayed heightened conditioned approach prior to the development of obesity. In addition, after junk-food diet exposure, those rats that developed obesity also showed increased willingness to gain access to a sucrose cue. Heightened 'wanting' was not due to individual differences in the hedonic impact ('liking') of sucrose. Neurobiologically, Mu opioid receptor mRNA expression was lower in striatal 'hot-spots' that generate eating or hedonic impact only in those rats that became obese. In contrast, prolonged exposure to junk-food resulted in cross-sensitization to amphetamine-induced locomotion and downregulation of striatal D2R mRNA regardless of the development of obesity. Together these data shed light on individual differences in behavioral and neurobiological consequences of exposure to junk-food diets and the potential contribution of incentive sensitization in susceptible individuals to greater food cue-triggered motivation.

Testosterone attenuates and the selective estrogen receptor modulator, raloxifene, potentiates amphetamine-induced locomotion in male rats

Although sex steroids are known to modulate brain dopamine, it is still unclear how testosterone modifies locomotor behaviour controlled, at least in part, by striatal dopamine in adolescent males. Our previous work suggests that increasing testosterone during adolescence may bias midbrain neurons to synthesise more dopamine. We hypothesised that baseline and amphetamine-induced locomotion would differ in adult males depending on testosterone exposure during adolescence. We hypothesised that concomitant stimulation of estrogen receptor signaling, through a selective estrogen receptor modulator (SERM), raloxifene, can counter testosterone effects on locomotion.Male Sprague-Dawley rats at postnatal day 45 were gonadectomised (G) or sham-operated (S) prior to the typical adolescent testosterone increase. Gonadectomised rats were either given testosterone replacement (T) or blank implants (B) for six weeks and sham-operated (i.e. intact or endogenous testosterone group) were given blank implants. Subgroups of sham-operated, gonadectomised and gonadectomised/testosterone-replaced rats were treated with raloxifene (R, 5mg/kg) or vehicle (V), daily for the final four weeks. There were six groups (SBV, GBV, GTV, SBR, GBR, GTR). Saline and amphetamine-induced (1.25mg/kg) locomotion in the open field was measured at PND85.Gonadectomy increased amphetamine-induced locomotion compared to rats with endogenous or with exogenous testosterone. Raloxifene increased amphetamine-induced locomotion in rats with either endogenous or exogenous testosterone. Amphetamine-induced locomotion was negatively correlated with testosterone and this relationship was abolished by raloxifene.Lack of testosterone during adolescence potentiates and testosterone exposure during adolescence attenuates amphetamine-induced locomotion. Treatment with raloxifene appears to potentiate amphetamine-induced locomotion and to have an opposite effect to that of testosterone in male rats.

The dopamine D1–D2 receptor heteromer exerts a tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization

A role for the dopamine D1–D2 receptor heteromer in the regulation of reward and addiction-related processes has been previously implicated. In the present study, we examined the effects of D1–D2 heteromer stimulation by the agonist SKF 83959 and its disruption by a selective TAT-D1 peptide on amphetamine-induced locomotor sensitization, a behavioral model widely used to study the neuroadaptations associated with psychostimulant addiction. D1–D2 heteromer activation by SKF 83959 did not alter the acute locomotor effects of amphetamine but significantly inhibited amphetamine-induced locomotor responding across the 5day treatment regimen. In addition, a single injection of SKF 83959 was sufficient to abolish the expression of locomotor sensitization induced by a priming injection of amphetamine after a 72-hour withdrawal. Conversely, inhibition of D1–D2 heteromer activity by the TAT-D1 peptide enhanced subchronic amphetamine-induced locomotion and the expression of amphetamine locomotor sensitization. Treatment solely with the TAT-D1 disrupting peptide during the initial 5day treatment phase was sufficient to induce a sensitized locomotor phenotype in response to the priming injection of amphetamine. Together these findings demonstrate that the dopamine D1–D2 receptor heteromer exerts a tonic inhibitory control on neurobiological processes involved in sensitization to amphetamine, indicating that the dopamine D1–D2 receptor heteromer may be a novel molecular substrate in addiction processes involving psychostimulants.