Blockade of Astrocytic Glutamate Uptake in the Prefrontal Cortex Induces Anhedonia

Major depression is associated with both dysregulated glutamatergic neurotransmission and fewer astrocytes in limbic areas including the prefrontal cortex (PFC). These deficits may be functionally related. Notably, astrocytes regulate glutamate levels by removing glutamate from the synapse via the glutamate transporter (GLT-1). Previously, we demonstrated that central blockade of GLT-1 induces anhedonia and c-Fos expression in the PFC. Given the role of the PFC in regulating mood, we hypothesized that GLT-1 blockade in the PFC alone would be sufficient to induce anhedonia in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the PFC and examined the effects on mood using intracranial self-stimulation (ICSS). At lower doses, intra-PFC DHK produced modest increases in ICSS thresholds, reflecting a depressive-like effect. At higher doses, intra-PFC DHK resulted in cessation of responding. We conducted further tests to clarify whether this total cessation of responding was related to an anhedonic state (tested by sucrose intake), a nonspecific result of motor impairment (measured by the tape test), or seizure activity (measured with electroencephalogram (EEG)). The highest dose of DHK increased latency to begin drinking without altering total sucrose intake. Furthermore, neither motor impairment nor evidence of seizure activity was observed in the tape test or EEG recordings. A decrease in reward value followed by complete cessation of ICSS responding suggests an anhedonic-like effect of intra-PFC DHK; a conclusion that was substantiated by an increased latency to begin sucrose drinking. Overall, these results suggest that blockade of astrocytic glutamate uptake in the PFC is sufficient to produce anhedonia, a core symptom of depression.     

Blockade of the GLT-1 Transporter in the Central Nucleus of the Amygdala Induces both Anxiety and Depressive-Like Symptoms

Depression has been associated with abnormalities in glutamatergic neurotransmission and decreased astrocyte number in limbic areas. We previously demonstrated that global and prefrontal cortical blockade of the astrocytic glutamate transporter (GLT-1) induces anhedonia and c-Fos expression in areas that regulate anxiety, including the central amygdala (CEA). Given the role of the amygdala in anxiety and the high degree of comorbidity between anxiety and depression, we hypothesized that GLT-1 blockade in the CEA would induce symptoms of anhedonia and anxiety in rats. We microinjected the GLT-1 inhibitor, dihydrokainic acid (DHK), into the CEA and examined effects on intracranial self-stimulation (ICSS) as an index of hedonic state, and on behavior in two anxiety paradigms, elevated plus maze (EPM) and fear conditioning. At lower doses, intra-CEA DHK produced modest increases in ICSS responding (T0). Higher doses resulted in complete cessation of responding for 15 min, suggesting an anhedonic or depressive-like effect. Intra-CEA DHK also increased anxiety-like behavior such that percent time in the open arms and total entries were decreased in the EPM and acquisition of freezing behavior to the tone was increased in a fear-conditioning paradigm. These effects did not appear to be explained by non-specific changes in activity, because effects on fear conditioning were assessed in a drug-free state, and a separate activity test showed no significant effects of intra-CEA DHK on locomotion. Taken together, these studies suggest that blockade of GLT-1 in the CEA is sufficient to induce both anhedonia and anxiety and therefore that a lack of glutamate uptake resulting from glial deficits may contribute to the comorbidity of depression and anxiety.     

Social vs. environmental stress models of depression from a behavioural and neurochemical approach

Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). However, while CMS reproduces specifically core depressive symptoms such as anhedonia and helplessness, CSDS studies rely on the analysis of stress-induced social avoidance, addressing different neuropsychiatric disorders. Here, we study comparatively the two models from a behavioural and neurochemical approach and their possible relevance to human depression. Mice (C57BL/6) were exposed to CMS or CSDS for six weeks and ten days. Anhedonia was periodically evaluated. A battery of test applied during the fourth week after the stress procedure included motor activity, memory, anxiety, social interaction and helplessness. Subsequently, we examined glutamate, GABA, 5-HT and dopamine levels in the prefrontal cortex, hippocampus and brainstem. CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety and social avoidance, signs also common to anxiety and posttraumatic stress disorders. While both models disrupted the excitatory inhibitory balance in the prefrontal cortex, CMS altered importantly this balance in the brainstem. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical and brain stem areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes.     

Evaluation of reward processes in an animal model of depression

Rationale Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. Objective Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. Materials and methods The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. Results Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. Conclusions Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence.     

Postcocaine anhedonia. An animal model of cocaine withdrawal

Cocaine use frequently occurs in episodic, prolonged binges. Following such a cocaine binge, the user suffers from severe depressive symptoms mixed with irritability and anxiety ("crash"). The present study was an attempt to develop an animal model of postcocaine depression or anhedonia and to study the time course of this cocaine withdrawal symptom. Rats were allowed to self-administer cocaine intravenously for prolonged periods of time and their brain reward thresholds were then assessed using intracranial self-stimulation (ICSS) thresholds. ICSS thresholds were used operationally as a measure of the animals' "hedonic-anhedonic" state. It was found that during cocaine withdrawal ICSS thresholds were elevated compared to predrug baseline levels and to control animals' thresholds, reflecting an "anhedonic" state. The magnitude and duration of the "anhedonic" state was proportional to the amount of cocaine consumed during the binge. A measure of response latency provided evidence that this postcocaine elevation of thresholds is due to a desensitization of the reward pathways mediating ICSS reward and not to any nonspecific (e.g., performance) effects of the cocaine exposure.     

An analysis of dorsal and median raphe self-stimulation: effects of parachlorophenylalanine.

The role of serotonergic systems in intracranial self-stimulation (ICSS) of the dorsal and median raphe nuclei of rats was investigated. Intragastric administration of 400 mg/kg of parachlorophenylalanine (PCPA) depressed ICSS rates in the group with dorsal raphe electrode placements over a similar time course to the depletion of brain serotonin which results from treatment with PCPA. An intrasessional analysis of these behavioral changes on the fourth day after PCPA revealed that dorsal raphe ICSS was depressed over both halves of the 2 hr test session, whereas a significant depression in median raphe ICSS occurred only in the last hr of the session. The data from these studies suggest that brain serotonin systems contribute to the phenomenon of brain-stimulation reward in the dorsal and median raphe nuclei. The involvement of multiple neurochemical substrates of brain stimulation reward is discussed.     

Effects of κ-opioid receptor ligands on intracranial self-stimulation in rats

Rationale Elevations in cAMP response element binding protein (CREB) function within the mesolimbic system of rats reduce cocaine reward in place conditioning studies and increase immobility in the forced swim test. Each of these behavioral adaptations can be interpreted as a depressive-like effect (i.e., anhedonia, despair) that may reflect reduced activity of brain reward systems. Furthermore, each effect appears due to increases in CREB-mediated expression of dynorphin, since each is attenuated by intracranial injections of the -opioid receptor antagonist norBNI.Objectives Intracranial self-stimulation (ICSS) studies were conducted in rats to determine whether administration of a -agonist would have depressive-like effects on brain stimulation reward, and whether pretreatment with a -antagonist would attenuate any such effects. Conditions that have depressive effects in people (e.g., drug withdrawal) increase the threshold amounts of stimulation required to sustain ICSS in rats.Methods Sprague-Dawley rats with lateral hypothalamic stimulating electrodes were tested in a curve-shift variant of the ICSS procedure after systemic administration of the -agonist U-69593 alone, the novel -antagonist 5-acetamidinoethylnaltrindole (ANTI) alone, or co-administration of both drugs.Results U-69593 dose dependently increased ICSS thresholds, suggesting that activation of -receptors reduced the rewarding impact of the brain stimulation. ANTI had no effects on its own, but it attenuated increases in ICSS thresholds caused by the agonist.Conclusions These data provide further evidence that stimulation of brain -receptors may trigger certain depressive-like signs, and that antagonists may have efficacy as antidepressants without having reward-related actions of their own.     

Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats

Drug dependence is characterized by dysregulation of brain reward systems and increased sensitivity to stress. Chronic exposure to drugs of abuse is associated with increased expression of the neuropeptide dynorphin, the endogenous ligand for kappa opioid receptors (KORs). Activation of KORs causes depressive- and aversive-like responses in rodents, raising the possibility that drug-induced upregulation of dynorphin plays a role independence-associated negative states. Here we used "binge" exposure to cocaine (3 daily intraperitoneal injections of 15 mg/kg for 14 days) to examine the development of dependence-like behavior in the intracranial self-stimulation (ICSS) test and the forced swim test (FST). When rats were tested 1 h before their first scheduled injection of each day-a period of drug withdrawal corresponding to 20 h after their last injection on the previous day-there were exposure-dependent increases in ICSS thresholds (a putative indicator of anhedonia) and decreases in latencies to immobility in the FST (a putative indicator of behavioral despair). Administration of the long-lasting KOR antagonist norBNI (20 μg, intracerebroventricular) before the beginning of the binge regimen attenuated the development of cocaine withdrawal-induced anhedonia in the ICSS test. In contrast, administration of norBNI in the midst of the binge regimen had no effect on expression of cocaine withdrawal-induced anhedonia in the ICSS test, although it did attenuate despair-like behavior in the FST. These data suggest that blockade of KORs before exposure to a stressor (in this case, cocaine withdrawal or forced swimming) can attenuate the development of stress-induced behavioral adaptations. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

Glia mechanisms in mood regulation: a novel model of mood disorders

Introduction Recent evidence in clinical and preclinical studies has implicated glutamate neurotransmissions in pathophysiology of mood disorders. The regulation of amino acid neurotransmission, i.e., glutamate and gamma-aminobutyric acid (GABA) involves coordinated mechanisms of uptake and transport within a tripartite synaptic system that includes neurons and glia. Newly appreciated role of the glia, more specifically astrocytes on neuronal functions combined with reported postmortem abnormalities of glia in patients with mood disorders further supports the role of glia in mood disorders. Materials and methods This report presents some of our preliminary results utilizing glia-selective toxins and other pharmacological tools to suppress glial function within the limbic system to study the resulting behavioral abnormalities, and thus, elucidate glial involvement in the development of mood disorders. Results and discussion We demonstrate that chronic blockade of glutamate uptake by a glial/neuronal transporter antagonist l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) within the amygdala, a key area implicated in mood regulation, results in dose-dependent reduction in social exploratory behavior and disrupts circadian activity patterns consistent with symptoms of mood disorders. Similarly, the selective astrocytic glutamate transporter type 1 (GLT-1) blocker dihydrokainic acid (DHK) injected into the amygdala also results in reduced social interaction that is blocked by selective glutamate N-methyl-d-aspartate (NMDA) type receptor antagonist AP5. The results are discussed in the context of glial and glutamate mechanisms in mood disorders and potential therapeutic avenues to address these mechanisms.     

Long-term influence of d-amphetamine on mesolimbic brain-stimulation reward: comparison to chronic haloperidol and naloxone effects.

Rate-intensity functions for brain-stimulation reward from the dopamine (DA) A10 cell region of the ventral tegmental area (VTA) were assessed following chronic exposure to d-amphetamine (10.0 mg/kg), haloperidol (1.0 mg/kg), and naloxone (20.0 mg/kg). A reward depression developed when animals were tested daily 24 h following injection of amphetamine and haloperidol. In the case of amphetamine, this effect was transitory and a full recovery of intracranial self-stimulation (ICSS) was evident 5 days after drug abstinence. Low-dose (0.5 mg/kg) amphetamine challenge administered 50 days postdrug treatment decreased current thresholds indicating a long-lasting sensitization of mesolimbic reward processes. The reward depression induced by chronic haloperidol exposure showed no signs of recovery during the abstinence period and ICSS rates remained significantly reduced after amphetamine challenge 50 days later. These behavioral observations suggest that under conditions of continued demand the functional aspects of neuroleptic-induced depolarization inactivation of VTA neurons are enduring. Chronic exposure to naloxone did not modify reward thresholds indicating that opioid hypoactivity may not be a factor in the ICSS depression induced by long-term amphetamine and haloperidol treatment. These data were related to the possibility that stimulant-induced sensitization of motivational processes may evolve as a compensatory response to the transitory development of withdrawal depression.     

Chronic mild stress-induced anhedonia model of depression; sleep abnormalities and curative effects of electroshock treatment

A core symptom of human depressive disorder is anhedonia, the loss of interest or pleasure in daily activities. Anhedonia, measured as subsensitivity to reward, can be induced in rats by a regimen of repeated, mild, unpredictable stressors. Here, the hedonic state of rats was assessed using an intracranial self-stimulation (ICSS) procedure. The ICSS frequency threshold was determined before, during and after a period of exposure to the stress regimens. After 13 days of repeated mild stress, the ICSS threshold was significantly increased, suggesting a gradual decrease of sensitivity to reward. This anhedonic state lasted throughout the stress period. When stressed anhedonic animals were given electroshock treatment, the stress-induced increase in ICSS threshold was rapidly and completely reversed. Moreover, biological markers of human depression such as reduced latency to the first REM sleep episode or increased time spent in REM sleep were also found in electroencephalographic recordings of chronically stressed animals. These sleep abnormalities were observed beginning in the second week of a three-week stress regimen and progressively disappeared after termination of stress. In conclusion, these data provide further evidence supporting stress-induced anhedonia in rats as a unique animal model of human depression combining convergent elements of biological, etiological, symptomatological and therapeutic validity.     

Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats

Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder(MDD).Gap junctional communication is a main determinant of astrocytic function.However,it is unclear whether gap junction dysfunction is involved in MDD development.This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex(PFC) after chronic unpredictable stress(CUS),a rodent model of depression.Animals exposed to CUS and showing behavioral deficits in sucrose preference test(SPT) and novelty suppressed feeding test(NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43(Cx43),a major component of astrocyte gap junction,and abnormal gap junctional ultrastructure in the PFC.Furthermore,we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor(GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors.The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone,indicating the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the the cellular changes may be related to GR activation.We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors.The results demonstrate that carbenoxolone(CBX) infusions induced anhedonia in SPT,and anxiety in NSFT,and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia,a core symptom of depression.Together,this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.     

Clozapine attenuates disruptions in response inhibition and task efficiency induced by repeated phencyclidine administration in the intracranial self-stimulation procedure

Currently available antipsychotic medications lack satisfactory effectiveness against several symptom clusters of schizophrenia, including affective symptoms (e.g., anhedonia) and cognitive deficits (e.g., impulsivity). Translational animal models analogous to these symptoms are necessary to provide insights into the neurobiological events underlying these impairments and allow the development of improved schizophrenia treatments. We investigated the effects of repeated administration of the psychotomimetic phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor antagonist, on performance in the intracranial self-stimulation (ICSS) procedure, a test of reward function. We also explored how chronic treatment with clozapine, an atypical antipsychotic with limited effectiveness on affective and cognitive schizophrenia symptoms, would affect PCP-induced disruptions of ICSS performance. A single injection of 2 mg/kg PCP elevated ICSS thresholds, suggesting a reward deficit. Repeated PCP administration (2 mg/kg once daily for 2 consecutive days followed by a 10-day drug free period, and then 5 consecutive days of 2 mg/kg PCP daily, s.c., 30 min pretreatment) resulted in a small, but significant, lowering of ICSS reward thresholds, indicating increased reward function. Chronic clozapine did not alter the effects of repeated PCP on ICSS thresholds. Repeated PCP also increased the number of extra and timeout responses performed during the ICSS procedure, reflecting disinhibition of inappropriate responding and decreased task efficiency. Chronic clozapine attenuated the increase in extra responses induced by repeated PCP and tended to reduce the PCP-induced increase in timeout responses. These results suggest that repeated PCP administration does not produce an anhedonia-like state resembling that seen in schizophrenia. However, the increased impulsivity and reduced task efficiency seen with repeated PCP administration, and the sensitivity of these effects to attenuation with an atypical antipsychotic, suggest that repeated PCP administration may be a useful inducing condition for eliciting cognitive deficits with relevance to schizophrenia.     

Role of glutamate transporters in the modulation of stress-induced lactate metabolism in the rat brain

Rationale Lactate, like glucose, has recently been found to be an energy substrate for neural activity. It is indicated that lactate is produced by astrocytes under the regulation of glutamatergic tone. Objectives Using in vivo microdialysis technique, we measured extracellular lactate concentrations in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of rats. To investigate the role of the glutamate transporter in the modulation of footshock stress-induced energy demands in both brain regions, we attempted to determine whether the footshock stress-induced changes of extracellular lactate concentrations are attenuated by local perfusion of the glutamate uptake inhibitor dihydrokainate (DHK). Results Perfusion of 1.0 mM DHK produced an increase in basal extracellular lactate levels in the mPFC and BLA, whereas 0.1 mM DHK did not affect lactate concentrations in either region. DHK also attenuated stress-induced increment of extracellular lactate concentrations in the mPFC, and completely prevented it in the BLA. Conclusions These results suggest that glutamate transporters regulate lactate availability in astrocytes and indicate that the rapid energy demand induced by glutamate contributes to local lactate production.     

Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.     

Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors

Rationale

Chronic social defeat stress (CSDS) has been proposed as a model of depression. However, most CSDS studies rely only on the analysis of stress-induced social avoidance. Moreover, the predictive validity of the model has been poorly analyzed, let alone its interaction with biological risk factors.

Objectives

Here, we explore the validity of CSDS as a depression model. Further, the effect of decreased vesicular glutamate transporter 1 (VGLUT1), as a potential factor enhancing a depressive-like phenotype, was studied.

Methods

Mice were exposed to CSDS (10?days) followed by saline, venlafaxine, fluoxetine, or tianeptine treatment (30?days). The battery of behaviors included motor activity, memory, anxiety, social interaction, helplessness, and anhedonic-like behavior. Moreover, the behavioral effect of CSDS in VGLUT1 heterozygous (VGLUT1+/?) mice was studied, as well as the regulation of VGLUT1 mRNA.

Results

CSDS induced anhedonia, helplessness, hyperactivity, anxiety, social avoidance, and freezing, as well as downregulation of VGLUT1 mRNA in the amygdala. Repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. CSDS-induced social avoidance was reverted by tianeptine. Fluoxetine failed to revert most of the behavioral alterations. VGLUT1+/? mice showed an enhanced vulnerability to stress-induced social avoidance.

Conclusion

We suggest that CSDS is not a pure model of depression. Indeed, it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS-induced anhedonia and social avoidance are not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behavior, such as the amygdala, where the glutamatergic mechanism could play a key role.     

Effect of streptozotocin-induced diabetes on the function of the central nervous system in rodents]

The prevalence of cognitive disorder, depression, and anxiety is about 2-fold higher in diabetic patients than in the general population. This higher prevalence is also observed in Japanese patients with diabetes. It has been reported that streptozotocin (STZ)-induced diabetic rodents demonstrate cognitive impairment, depressive-like behavior, and anxiety-like behavior. In addition, plasma corticosterone levels are significantly increased in STZ-induced diabetic rodents. Therefore, STZ-induced diabetic rodents demonstrate similar features as in patients with depression. In this review, we summarized the effect of STZ-induced diabetes on the function of the central nervous system in rodents and the similarity to the clinical features of several psychiatric disorders such as depression.     

Simultaneous anhedonia and exaggerated locomotor activation in an animal model of depression

Rationale  Anhedonia, or hyposensitivity to normally pleasurable stimuli, is a cardinal symptom of depression. As such, reward circuitry may comprise a substrate with relevance to this symptom of depression. Objectives  Our aim was to characterize in the rat changes in the rewarding properties of a pharmacological and a natural stimulus following olfactory bulbectomy (OBX), a pre-clinical animal model of depression. Methods  We measured amphetamine enhancement of brain stimulation reward, changes in sucrose intake, as well as striatal cAMP response element binding protein (CREB) activity, a molecular index previously associated with depressant-like behavior. Moreover, since alteration of psychomotor activity is also a common symptom of depression, and psychostimulant reward and locomotion are thought to share common neurobiology, we used the same treatment schedule of amphetamine to probe for changes in locomotion. Results  Our findings show that OBX produces a behavioral phenotype characterized by both anhedonia and exaggerated locomotor activation. Thus, we observed a blunted response to the rewarding properties of amphetamine (1 mg/kg, 21 days post-lesion), a long-lasting reduction in sucrose intake and increased striatal CREB activity. In addition, the same dose of amphetamine, at a coincident time post-lesion, triggered an exaggerated response to its locomotor-stimulant actions. Conclusions  These paradoxical findings are not consistent with the notion that reward and locomotion are mediated by a common substrate; this dissociation may be useful in modeling psychiatric disorders such as mixed depressive states. In addition, our findings suggest that central reward circuitry may constitute a possible target for rationally designed therapeutics for depression.     

Acute and chronic desipramine treatment effects on rewarding electrical stimulation of the lateral hypothalamus

Two weeks of chronic desipramine HCl (DMI) (10 mg/kg, IP) treatment did not alter reward or motor/performance components of intracranial self-stimulation (ICSS) as assessed with the rate-frequency method. Acute DMI treatment produced an ICSS reward decrement relative to saline control treatment, which was similar in size on Day 1 and Day 15 of chronic testing. The failure to find a chronic DMI effect on ICSS reward suggests that ICSS in normal rats may not be a valid animal model of depression. A better paradigm may be to test the ability of antidepressants to reverse a chronic reduction in ICSS reward function that is first produced by some other method.