Synergistic interaction between caloric restriction and amphetamine in food-unrelated approach behavior of rats

Rationale

Approach behavior is regulated by the brain integrating information about environment and body state. Psychoactive drugs interact with this process.

Objectives

We examined the extent to which caloric (i.e., food) restriction, amphetamine (AMPH) and lithium interact in potentiating locomotor activity and responding reinforced by visual stimulus (VS), a reward unrelated to energy homeostasis.

Methods

Rats either had ad libitum access to food or received daily rations that maintained 85–90 % of their original body weights. Leverpressing turned on a cue light for 1 s and turned off house light for 5 s. AMPH and lithium were administered through intraperitoneal injections and diet, respectively.

Results

Food restriction or AMPH (1 mg/kg) alone had little effect on VS-reinforced responding; however, the combination of the two conditions markedly potentiated VS-reinforced responding (fourfold). Food restriction lasting 7 days or longer was needed to augment AMPH's effect on VS-reinforced responding. AMPH (0.3–3 mg/kg) potentiated locomotor activity similarly between food-restricted and ad libitum groups. Repeated injections of AMPH-sensitized locomotor activity, but not VS-reinforced responding. In addition, while chronic lithium treatments (0.2 % lithium carbonate chow) reduced VS-reinforced responding, chronic lithium further augmented AMPH-potentiated VS-reinforced responding.

Conclusions

Food restriction interacts with psychoactive drugs to potentiate goal-directed responding unrelated to food seeking in a much more powerful manner than previously thought. The novel finding that lithium can augment a psychostimulant effect of AMPH suggests caution when combining lithium and psychostimulant drugs in clinical settings.     

Responding for conditioned reinforcement in C57BL/6 and CD-1 mice,and Sprague-Dawley rats: Effects of methylphenidate and amphetamine

Rationale

Characterization of responding for conditioned reinforcement in mice is important to implement genetic tools in examining the neurobiological mechanisms underlying reward-related learning and incentive motivation.

Methods

Inbred C57BL/6 mice, outbred CD-1 mice, and outbred Sprague–Dawley rats underwent Pavlovian conditioning in which a conditioned stimulus (CS) was paired with saccharin. Subsequently, subjects were allowed to respond for that CS in tests of responding for conditioned reinforcement. Experiments measured the effects of methylphenidate (MPH) and amphetamine (AMPH) on lever pressing for conditioned reinforcement in mice and rats. We further examined the stability of responding for conditioned reinforcement in mice after repeated testing and the extinction of this behaviour following omission of the reinforcer. We also determined whether the CS exhibited reinforcing properties if it was not paired with saccharin.

Results

C57BL/6 and CD-1 mice learned to respond for a conditioned reinforcer similarly to rats, and the behaviour was stable over time. MPH increased responding in CD-1 mice and rats, but not in C57BL/6 mice. AMPH only increased responding in rats. Responding was reduced following omission of the conditioned reinforcer, and responding was only established when the CS was paired with saccharin.

Conclusions

These experiments characterize a conditioned reinforcement test which produces stable responding in two different mouse backgrounds. These findings also show that dopaminergic psychomotor stimulants can differently affect rats and mice in tests of responding for conditioned reinforcement.     

Differential susceptibility to ethanol and amphetamine sensitization in dopamine D3 receptor-deficient mice

Rationale

Dopamine D3 receptors (D3Rs) have been implicated in behavioral sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. We used D3R knockout (D3 KO) mice to examine whether the D3R plays a permissive role in EtOH and amphetamine (AMPH) sensitization. We also investigated whether EtOH sensitization is accompanied by alterations in D3R mRNA expression or binding.

Materials and methods

After comparing EtOH sensitization in C57Bl/6 mice and DBA/2 mice, D3 KO, wild type (WT), and for comparison, D1 and D2 KOs received five biweekly injections of EtOH (2.2 g/kg, i.p.) or saline. Another group of D3 KOs and WT controls received six times AMPH (1.5 mg/kg, i.p.). D3R mRNA and binding were measured in EtOH-sensitized DBA/2 mice with in situ hybridization and [¹²⁵I]-7-OH-PIPAT autoradiography, respectively.

Results

C57Bl/6 mice expressed EtOH sensitization albeit to a lesser extent than DBA/2 mice. Compared to WT mice, D3 KOs were resistant to EtOH sensitization. The behavioral profile of D3 KOs was more similar to D1 KOs than D2 KOs, which also failed to develop EtOH sensitization. However, D3 KOs developed AMPH sensitization normally. EtOH sensitization was not accompanied by changes in either D3R mRNA or D3R binding in the islands of Calleja, nucleus accumbens, dorsal striatum, or cerebellum.

Conclusions

These results suggest a necessary role for the D3R in EtOH but not AMPH sensitization, possibly through postreceptor intracellular mechanisms. Results also suggest that different neurochemical mechanisms underlie sensitization to different drugs of abuse.     

Wirkungen von Psychopharmaka auf das Explorationsverhalten von MÄusen

1. Locomotion (number of crossed squares) in an open field-situation and exploration (number of explored holes) in a planche à trous situation have been determined in mice naive to the experimental situation.
2. The sedative properties of chlorpromazine, haloperidol, and reserpine were represented by a simultaneous decrease of exploration and locomotion.
3. Chlordiazepoxide, oxazepam, and diazepam in low doses caused an increase of locomotion, in higher doses a decrease of exploration, and finally an inhibition of both types of behavior.
4. After phenobarbital the locomotion and exploration of the animals was considerably increased.
5. Amphetamine caused a significant inhibition of exploration in low doses which did not increase locomotion. When locomotion was enhanced the exploration still remained depressed.
6. Imipramine in large doses caused a decrease of both locomotion and exploration. No equivalents could be found for the antidepressant properties of the drug.
7. Mescaline caused an increase of locomotion and a decrease of exploration, but only in a dose range which has to be considered neurotoxic.

     

Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

Rationale

Enhancement of N-methyl-d-aspartate receptor (NMDAR) activity through its glycine modulatory site (GMS) is a novel therapeutic approach in schizophrenia. Brain concentrations of endogenous GMS agonist d-serine and antagonist N-acetyl-aspartylglutamate are regulated by serine racemase (SR) and glutamic acid decarboxylase 2 (GCP2), respectively. Using mice genetically, under-expressing these enzymes may clarify the role of NMDAR-mediated neurotransmission in schizophrenia.

Objectives

We investigated the behavioral effects of two psychotomimetic drugs, the noncompetitive NMDAR antagonist, phencyclidine (PCP; 0, 1.0, 3.0, or 6.0?mg/kg), and the indirect dopamine receptor agonist, amphetamine (AMPH; 0, 1.0, 2.0, or 4.0?mg/kg), in SR ?/? and GCP2 ?/+ mice. Outcome measures were locomotor activity and prepulse inhibition (PPI) of the acoustic startle reflex. Acute effects of an exogenous GMS antagonist, gavestinel (0, 3.0, or 10.0?mg/kg), on PCP-induced behaviors were examined in wild-type mice for comparison to the mutants with reduced GMS activity.

Results

PCP-induced hyperactivity was increased in GCP2 ?/+ mice, and PCP-enhanced startle reactivity was increased in SR ?/? mice. PCP disruption of PPI was unaffected in either mutant. In contrast, gavestinel attenuated PCP-induced PPI disruption without effect on baseline PPI or locomotor activity. AMPH effects were similar to controls in both mutant strains.

Conclusions

The results of the PCP experiments demonstrate that convergence of pharmacological and genetic manipulations at NMDARs may confound the predictive validity of these preclinical assays for the effects of GMS activation in schizophrenia. The AMPH data provide additional evidence that hyperdopaminergia in schizophrenia may be distinct from NMDAR hypofunction.     

Effects of the fatty acid amide hydrolase inhibitor URB597 on coping behavior under challenging conditions in mice

Rationale

Recent evidence suggests that in addition to controlling emotional behavior in general, endocannabinoid signaling is engaged in shaping behavioral responses to challenges. This important function of endocannabinoids is still poorly understood.

Objectives

Here we investigated the impact of blockade of fatty acid amide hydrolase (FAAH), the degrading enzyme of anandamide on behavioral responses induced by challenges of different intensity.

Methods

Mice treated with FAAH inhibitor URB597 were either manually restrained on their backs (back test) or received foot-shocks.

Results

The behavior of mice showed bimodal distribution in the back test: they either predominantly showed escape attempts or equally distributed time between passivity and escape. URB597 increased escapes in animals with low escape scores. No effects were noticed in mice showing high escape scores, which is likely due to a ceiling effect. We hypothesized that stronger stressors would wash out individual differences in coping; therefore, we exposed mice to foot-shocks that decreased locomotion and increased freezing in all mice. URB597 ameliorated both responses. The re-exposure of mice to the shock cage 14 days later without delivering shocks or treatment was followed by reduced and fragmented sleep as shown by electrophysiological recordings. Surprisingly, sleep was more disturbed after the reminder than after shocks in rats receiving vehicle before foot-shocks. These reminder-induced disturbances were abolished by URB597 administered before shocks.

Conclusions

These findings suggest that FAAH blockade has an important role in the selection of behavioral responses under challenging conditions and—judging from its long-term effects—that it influences the cognitive appraisal of the challenge.     

Analysis of vigilant scanning behavior in mice using two-point digital video tracking

Rationale

Vigilant scanning of the environment is a major risk assessment activity in many species. However, due to difficulties in its manual scoring, scanning has rarely been quantified in laboratory rodent studies.

Objectives and methods

We developed a novel method for automated measurement of vigilant scanning in mice, based on simultaneous tracking of an animal’s nose- and center-points. The studied scanning parameters included the frequency and duration of scans and scanning (nose-point) speed. The sensitivity of these parameters to anxiolytic diazepam (1–2?mg/kg) and anxiogenic FG-7142 (5?mg/kg) was evaluated upon exposure to the context (conditioning chamber) before and 24?h after footshock.

Results

Scanning behavior was observed in all C57BL/6, 129xC57BL/6, and DBA/2 mice, as recurrent stationary episodes accompanied by observatory head movements. These episodes respectively comprised 28?±?1%, 29?±?1%, and 24?±?2% of preexposure time. Diazepam dose-dependently decreased the scanning frequency and duration, without affecting the scanning speed. Fear conditioning increased freezing and inhibited other behaviors upon reexposure, with scanning being only marginally affected and still comprising 17?±?2%, 16?±?2%, and 19?±?1% of reexposure time, respectively. Consequently, scanning accounted for most (DBA/2) or virtually all (C57BL/6 and 129xC57BL/6) gross motor activities upon reexposure. FG-7142 mirrored the effects of conditioning, inducing behavioral inhibition with scanning being least affected.

Conclusions

Two-point tracking is effective for studying vigilant scanning in mice. Using this approach, we show that scanning is a key risk assessment activity in both unconditioned and conditioned mice; scanning is resistant to threat-induced behavioral inhibition and is highly sensitive to anxiolytic treatment.     

Altered locomotor and stereotyped responses to acute methamphetamine in adolescent, maternally separated rats

Rationale

Neonatal maternal separation (MS) has been used to model the effects of early life stress in rodents. MS alters behavioral responses to a variety of abused drugs, but few studies have examined its effects on methamphetamine sensitivity.

Objectives

We sought to determine the effects of MS on locomotor and stereotyped responses to low-to-moderate doses of methamphetamine in male and female adolescent rats.

Methods

Male and female rat pups were subjected to 3 h per day of MS on postnatal days (PN) 2–14 or a brief handling control procedure during the same period. During adolescence (approximately PN 40), all rats were tested for locomotor activity and stereotyped behavior in response to acute methamphetamine administration (0, 1.0, or 3.0 mg/kg, s.c.).

Results

MS rats of both sexes exhibited increased locomotor activity in a novel environment, relative to handled controls. MS increased the locomotor response to methamphetamine (METH), and this effect occurred at different doses for male (3.0 mg/kg) and female (1.0 mg/kg) rats. MS also increased stereotyped behavior in response to METH (1.0 mg/kg) in both sexes.

Conclusions

MS enhances the locomotor response to METH in a dose- and sex-dependent manner. These results suggest that individuals with a history of early life stress may be particularly vulnerable to the psychostimulant effects of METH, even at relatively low doses.     

Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms

Rationale

Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated.

Objective

In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats.

Results

The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine.

Conclusions

Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.     

Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator

Rationale

Methamphetamine (METH) is a highly potent and addictive psychostimulant with severe detrimental effects to the health of users. Currently, METH addiction is treated with a combination of cognitive and behavioral therapies, but these traditional approaches suffer from high relapse rates. Furthermore, there are currently no pharmacological treatment interventions approved by the FDA specifically for the treatment of METH addiction.

Objectives

Metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) have shown promise in significantly attenuating drug self-administration and drug-seeking in reinstatement paradigms. However, studies assessing the potential efficacy of mGluR5 NAMs that have been tested in human subjects are lacking. The current study sought to assess the effect of the mGluR5 NAM fenobam on METH-seeking behavior.

Methods

Rats were trained to self-administer METH (0.05 mg/kg i.v.), and following extinction, tested for effects of fenobam (5, 10, or 15 mg/kg intraperitoneal) on cue- and drug-induced reinstatement of METH-seeking. To determine if fenobam also alters reinstatement of seeking of natural reinforcers, separate groups of rats were trained to self-administer sucrose or food pellets and were tested for the effects of fenobam on cue-induced reinstatement of sucrose- and food-seeking.

Results

Fenobam attenuated drug- and cue-induced reinstatement of METH-seeking behavior at doses of 10 and 15 mg/kg. Fenobam also attenuated cue-induced reinstatement of sucrose- and food-seeking at all doses tested.

Conclusions

The mGluR5 NAM fenobam attenuates the reinstatement of METH-seeking behavior, but these effects may be due to nonspecific suppression of general appetitive behaviors.     

Effects of chronic social defeat stress on behavior and choline acetyltransferase, 78-kDa glucose-regulated protein, and CCAAT/enhancer-binding protein (C/EBP) homologous protein in adult mice

Rationale

Social defeat stress induces physiological and behavioral symptoms, including anxiety, anhedonia, immune deficits, and altered expression of key brain genes.

Objectives

The present study investigated the effects of social defeat stress on the behaviors and expressions of Chat, Grp78, and chop in the brains of adult mice.

Methods

Adult mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. In experiment 1, behavioral tests were conducted, and brains were processed for Western blotting at day 27 after stress. In experiment 2, social avoidance tests were conducted, and brains were processed for Western blotting at day 12 after stress.

Results

The results indicate decreased and increased locomotion and anxiety behavior in all defeated mice. Decrease in social interaction, increased immobility, and impaired memory performance were only observed in susceptible mice. A decrease in the Chat level at days 12 and 27 was noted in the prefrontal cortex (PFC), amygdala (Amyg), and dorsal hippocampus (HIP) in defeated mice. The expression levels of Grp78 and chop measured on days 12 and 27 were significantly greater in the Amyg of susceptible mice. In the PFC and HIP, defeated mice displayed different patterns in the levels of Grp78 and chop expressions measured on days 12 and 27.

Conclusions

The present study demonstrated that chronic social defeat stress in mice produces stress-related behaviors. Different response patterns were noted for Grp78 and chop expression among the groups in terms of brain regions and time-course effects.     

Interaction between the mGlu receptors 5 antagonist, MPEP, and amphetamine on memory and motor functions in mice

Rationale

Metabotropic glutamate mGlu receptors 5 (mGluR5) receptors are abundant in corticolimbic circuitry where they modulate glutamate and dopamine signal transduction.

Objectives

In this study, we explored the hypothesis that mGluR5 antagonist, (2-methyl-6-(phenylethynyl)pyridine hydrochloride) (MPEP), facilitates dopamine-dependent effects on memory and motor functions.

Methods

To this aim, we examined the effects of different doses (from 0 to 24 mg/kg) of the mGluR5 antagonist, MPEP, on the modulation of amphetamine-dependent behaviors, namely passive avoidance, locomotor activity, and rotation behavior in intact and dopamine-depleted CD1 male mice.

Results

We demonstrated that a low dose (3 mg/kg) of MPEP, which is void of behavioral effects on its own, facilitates amphetamine-induced effects independently on the behavior measured both in naïve and in dopamine-lesioned mice; this synergistic effect is lost when higher doses of MPEP are used.

Conclusion

The results are discussed in terms of possible balance between dopamine and glutamate activity in regulating the proper fine tuning of information processing.     

Serotonergic lesions of the dorsal hippocampus differentially modulate locomotor hyperactivity induced by drugs of abuse in rats: implications for schizophrenia

Rationale

Psychotomimetic drug-induced locomotor hyperactivity is a widely used animal model of psychotic states, such as in schizophrenia. We previously found that serotonergic lesions of the dorsal, but not ventral, hippocampus in rats result in enhanced phencyclidine-induced locomotor hyperactivity.

Objectives

The objective of this study was to investigate the effect of serotonin depletion in the dorsal and ventral hippocampus on hyperlocomotion induced by ketamine, cocaine, 3,4-methylenedioxymethampethamine (MDMA), methamphetamine, and d-amphetamine.

Materials and methods

Male Sprague–Dawley rats were bilaterally microinjected with vehicle or the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the dorsal or ventral hippocampus using a stereotaxic approach. Separate cohorts of rats were used for each drug of abuse; each rat received saline and a low, medium, and high dose of the drug in a random-sequence, repeated-measures protocol. Locomotor hyperactivity following treatment was measured using automated photocell cages.

Results

Similar to phencyclidine, 5,7-DHT-induced lesions of the dorsal hippocampus enhanced ketamine-induced hyperlocomotion at all doses. They also reduced methamphetamine-induced hyperlocomotion at the high dose only and caused a minor, biphasic modulation of responses to cocaine. Locomotor responses to d-amphetamine and MDMA were unchanged by lesions of the dorsal hippocampus. Serotonergic lesions of the ventral hippocampus did not significantly alter locomotor hyperactivity induced by any of the drugs investigated.

Conclusions

These findings further implicate a role for serotonin in the dorsal hippocampus in modulating the behavioral effects of dissociative anesthetics, such as ketamine, with more subtle effects on psychostimulant drugs of abuse. The dorsal hippocampus may be a site of serotonergic dysfunction in aspects of schizophrenia.     

Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice

Rationale

Psychostimulants such as amphetamine and methylphenidate, which target the dopamine transporter (DAT), are the most frequently used drugs for the treatment of hyperactivity and cognitive deficits in humans with attention deficit hyperactivity disorder (ADHD). While psychostimulants can increase activity in healthy subjects, they exert a “paradoxical” calming effect in humans with ADHD as well as in hyperactive mice lacking the dopamine transporter (DAT-KO mice). However, the mechanism of action of these drugs and their impact on cognition in the absence of DAT remain poorly understood.

Objectives

This study was conducted to investigate the effects of psychostimulants and noradrenergic and serotonergic drugs on cognition in DAT-KO mice and normal (WT) littermates.

Methods

We used a recently developed behavioral apparatus, the automated H-maze. The H-maze involves the consecutive learning of three different rules: delayed alternation, nonalternation, and reversal tasks.

Results

Treatment of WT animals with the psychostimulants replicated the behavior observed in untreated DAT-KO mice while “paradoxically” restoring cognitive performances in DAT-KO mice. Further investigation of the potential involvement of other monoamine systems in the regulation of cognitive functions showed that the norepinephrine transporter blocker atomoxetine restored cognitive performances in DAT-KO mice without affecting hyperactivity. In contrast, the nonselective serotonin receptor agonist 5CT, which antagonizes hyperactivity in DAT-KO mice, had no effect on cognitive functions.

Conclusions

Taken together, these data allow dissociation of the locomotor and cognitive effects of ADHD drugs and suggest that the combination of DAT-KO mice with the automated H-maze can constitute a powerful experimental paradigm for the preclinical development of therapeutic approaches for ADHD.     

Prenatal corticosterone and adolescent URB597 administration modulate emotionality and CB1 receptor expression in mice

Rationale

The central endocannabinoid system (eCB system) sustains the activity of the hypothalamus–pituitary–adrenal (HPA) axis in mediating individual emotional responses. Deviation in maturational trajectories of these two physiological systems, may persistently adjust individual behavioral phenotype.

Objective

We investigated, in outbred CD1 male mice, whether exposure to prenatal stress may influence short- and long-term emotional and neurochemical responses to a pharmacological stimulation of the eCB system during adolescence.

Methods

To mimic prenatal stress, pregnant mice were supplemented with corticosterone in the drinking water (33.3 mg/l); their adolescent male offspring received daily injections of the fatty acid amide hydrolase inhibitor, URB597 (0.4 mg/kg), in order to enhance eCB signaling. Mice were then tested for: locomotor activity during adolescence and locomotor activity, anxiogenic, and anhedonic profiles in adulthood. We analyzed the expression of CB1 receptors (CB1Rs) in prefrontal cortex, hippocampus, striatum, and cerebellum in adulthood.

Results

Corticosterone administration (PC group) resulted, in adolescence, in a reduction in body weight and locomotion, while in adulthood, in increased anxiety-related behavior and reduced CB1Rs expression in cerebellum. URB597 exposure reduced locomotor activity and increased anhedonia in adulthood. CB1Rs were up-regulated in striatum and hippocampus and down-regulated in the cerebellum. PC-URB597 mice failed to show reductions in locomotion; exhibited increased risk assessment behavior; and showed reduced CB1Rs expression within the prefrontal cortex.

Conclusions

Present results provide support to the hypothesis that precocious manipulations mapping onto the HPA axis and eCB system may persistently adjust individual emotional responses and eCB system plasticity.     

Repeated exposure to MDMA and amphetamine: sensitization, cross-sensitization, and response to dopamine D1- and D2-like agonists

Rationale

Acute exposure to (±) 3, 4-methylenedioxymethamphetamine (MDMA) produces hyperlocomotion that is preferentially expressed in the periphery of closed chambers. Following repeated administration, however, a sensitized hyperlocomotor response is preferentially expressed in the center of an activity box, so that the response resembles the more generalized activity that is produced by d-amphetamine (AMPH).

Objectives

The present study was designed to determine whether common neuroadaptations underlie the acute and sensitized responses to MDMA and AMPH.

Methods

Rats were pretreated with five daily injections of MDMA (10.0?mg/kg), AMPH (2.0?mg/kg), or saline. Following a 2-day drug-free period, dose–response curves for hyperactivity produced by MDMA (2.5–10.0?mg/kg), AMPH (0.5–2.0?mg/kg), SKF-81297 (1.0–2.0?mg/kg), or quinpirole (0.25–1.0?mg/kg) were obtained.

Results

Effects of MDMA and AMPH were increased by pretreatment with both drugs. The sensitized response following MDMA exposure was preferentially expressed in the center compartment, but, following AMPH pretreatment, the sensitized response was observed in both compartments. Cross-sensitization was unidirectional; AMPH pretreatment failed to sensitize to the effects of MDMA, but MDMA pretreatment sensitized to the effects of AMPH. MDMA and AMPH pretreatment produced marginal increases in the effects of SKF-81297. The response to quinpirole was, however, greater following MDMA, but not AMPH, pretreatment.

Conclusions

These data suggest that repeated MDMA exposure produces sensitization via a unique neurochemical effect.     

Activity density in the open field: a measure for differentiating the effect of psychostimulants

Traditional open-field activity measures do not provide a sharp behavioral differentiation across psychomotor stimulants such as d-amphetamine (AMPH) and cocaine (COC) in the mouse. We used Software for the Exploration of Exploration (SEE) to investigate and develop a novel behavioral endpoint to characterize the "structure" of AMPH- and COC-induced locomotor behavior in two inbred strains of mouse, C57BL/6 (B6) and DBA/2 (D2). We suggest a measure we term "activity density" as a means to differentiate the behavioral effects of COC and AMPH. Activity density is defined as the activity divided by the range over which it took place. It characterizes the restriction of behavioral repertoire that does not result merely from inactivity. In both the B6 and D2 mice, AMPH increased activity density in a dose-dependent fashion by restricting the range of activity compared with COC doses producing the same level of activity. While AMPH restricted the range in both genotypes, characterizing the geographical region in which the restriction took place further differentiated the genotypes. The newly developed activity density measure thus provides a more general measure than stereotypy of the path, and can differentiate the effects of AMPH and COC both within and across genotypes.     

An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

Rationale

The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M₄ acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M₄ receptors could be a novel target for modulating psychostimulant effects of cocaine.

Objectives

For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M₄ receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice.

Methods

To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition, the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated.

Results

We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M₄ receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M₄ receptor knockout mice. Furthermore, selective deletion of the M₄ receptor gene in dopamine D₁ receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M₄ receptors co-localized with D₁ receptors.

Conclusions

These results show that positive allosteric modulators of the M₄ receptor deserve attention as agents in the future treatment of cocaine abuse.     

Antidepressant response to chronic citalopram treatment in eight inbred mouse strains

Rationale

The antidepressant response exhibits a characteristic delay. BALB/cJ mice respond to chronic, but not subchronic, treatment with selective serotonin reuptake inhibitors (SSRIs), providing a model of antidepressant onset. Identification of other mouse strains exhibiting this phenotype will provide additional tools for studying mechanisms of the antidepressant response.

Objectives

We aimed to identify inbred mouse strains that respond to chronic, but not subchronic, SSRI treatment in the forced swim test (FST). We also assessed whether response correlated with genotype at the functional C1473G polymorphism in tryptophan hydroxylase-2 (Tph2).

Methods

BALB/cJ, three closely related strains (BALB/cByJ, SEA/GnJ, A/J), and four distantly related strains (C57BL/6J, C57BL/10J, CAST/EiJ, SM/J) received the SSRI citalopram (0?C30?mg/kg/day in drinking water) for ~4?weeks and were assessed for locomotion and FST behavior. Citalopram-responsive strains were assessed identically following ~1?week of treatment. C1473G genotypes were determined.

Results

BALB/cJ and related strains carried the 1473G allele and responded to chronic citalopram treatment in the FST. BALB/cJ, BALB/cByJ, and SEA/GnJ mice showed either no response or an attenuated response to subchronic treatment. Distantly related strains carried the 1473C allele and showed no response to citalopram. No relationship was found between the antidepressant response and baseline immobility or locomotion.

Conclusions

BALB/cJ and related strains exhibit an antidepressant response to chronic SSRI treatment that emerges over time and is likely a heritable trait. This antidepressant response is associated with carrying the 1473G allele in Tph2. In conclusion, BALB/cJ and related strains provide valuable models for studying the therapeutic mechanisms of SSRIs.