Irwin Lucki

Comorbid diabetes and depression are a major clinical challenge as the outcomes of each condition are worsened by the other. This article is based on the presentations and discussions during an international meeting on diabetes and depression convened by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in collaboration with the National Institute of Mental Health and the Dialogue on Diabetes and Depression. While the psychological burden of diabetes may contribute to depression in some cases, this explanation does not sufficiently explain the relationship between these two conditions. Shared biological and behavioral mechanisms, such as hypothalamic-pituitary-adrenal axis activation, inflammation, autonomic dysfunction, sleep disturbance, inactive lifestyle, poor dietary habits, and environmental and cultural risk factors, are important to consider in understanding the link between depression and diabetes. Both individual psychological and pharmacological depression treatments are effective in people with diabetes, but the current range of treatment options is limited and has shown mixed effects on glycemic outcomes. More research is needed to understand what factors contribute to individual differences in vulnerability, treatment response, and resilience to depression and metabolic disorders across the life course and how best to provide care for people with comorbid diabetes and depression in different health care settings. Training programs are needed to create a cross-disciplinary workforce that can work in different models of care for comorbid conditions.

The receptors responsible for mediating the antidepressant effects of selective serotonin reuptake inhibitors are largely unknown. The role of the 5-HT4 receptor in mediating the antidepressant-like effects of fluoxetine in a modified rat forced swim test was examined. Fluoxetine (20 mg/kg) decreased immobility and increased swimming, a pattern shown to represent its actions on the serotonergic system. The selective 5-HT4

The regulation of extracellular levels of serotonin (5-HT) and dopamine in response to cocaine by 5-HT1A receptors was examined using in vivo microdialysis and the 5-HT1A receptor antagonist 4-(2′-methoxy-)-phenyl-1-[2′-(N-2″-pyridinyl)-p-fluorobenzamido-]ethyl-piperazine (p-MPPF). Pretreatment with p-MPPF significantly augmented the increase in extracellular levels of both 5-HT and dopamine in the nucleus accumbens produced by systemic administration of cocaine. Levels of 5-HT or dopamine

Rationale  Variations in the effects of antidepressant drugs between different mouse strains are important for drug discovery and could lead to the identification of genes that predict differences in drug efficacy.Objectives  This study compared behavioral baselines and dose-dependent responses to the selective serotonin reuptake inhibitor (SSRI) citalopram in eight inbred mouse strains (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ, A/J, 129/SvEmsJ, 129/SvImJ, and BTBR) using

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREB(alpha delta) mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREB(alpha delta) mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREB(alpha delta) mutant mice. Serotonin depletion decreased neurogenesis in CREB(alpha delta) mutant mice to WT levels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB(alpha delta) mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB(alpha delta) mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREB(alpha delta) mutant mice responded to chronic AD treatment in the NIH paradigm, only CREB(alpha delta) mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment.

An iodinated cocaine derivative, N-(3'-iodopropen-2'-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl) tropane (IPT), was evaluated as a probe for in vitro and in vivo labeling of dopamine (DA) and serotonin (5-HT) transporters in Sprague-Dawley rat brain. Saturation analysis of [125I]IPT in rat striatal homogenates, in two different buffer solutions, Tris-HCl and phosphate, demonstrated a one-site binding with affinities (Kd) of 0.25 +/- 0.02 and 0.16 +/- 0.02 nM and densities (Bmax) of 939 +/- 161 and 1,982 +/- 137 fmol/mg protein, respectively. Competition by known DA transporter ligands showed a rank order of RTI-55 > IPT > GBR12909 > mazindol > (-)cocaine. Binding to 5-HT transporter sites was evaluated in rat cortical homogenates. Saturation experiment results showed a single site with a Kd value of 1.2 +/- 0.2 nM and a Bmax value of 100 +/- 20 fmol/mg protein. The rank order of potency of several monoamine uptake inhibitors (paroxetine > fluoxetine > mazindol > R-nisoxetine > GBR12909) suggests that [125I] IPT labels 5-HT transporters in rat cortical homogenates. Both ex vivo and in vitro autoradiographic studies revealed high densities of [125I]IPT binding sites in the caudate nucleus, putamen, olfactory tubercle and nucleus accumbens, areas known to be rich in dopaminergic innervation. Moderate accumulation of activity was also observed in the substantia nigra. The dorsal raphe, a region with a high density of 5-HT innervation, was labeled using in vitro autoradiography with [125I]IPT, but the labeling using ex vivo autoradiography was less prominent at 30 min postinjection and not noticeable at 60 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)

Although the rewarding effects of cocaine are generally attributed to its ability to increase dopamine (DA) transmission, cocaine demonstrates approximately equal affinity for dopamine and serotonin (5-HT) transporters in vitro. However, there have been few direct systematic comparisons of the effects of cocaine on DA and 5-HT transmission in vivo. The present experiments compared the effects of systemic cocaine administration, local cocaine infusion and the systemic administration of cocaine during infusion on extracellular levels of DA and 5-HT in the nucleus accumbens (NAc). In vivo microdialysis in awake unrestrained rats was used to measure the effects of systemic administration and local infusion of cocaine on extracellular DA and 5-HT levels simultaneously in the NAc. Systemic cocaine (10-25 mg/kg, IP) dose-dependently increased DA and 5-HT levels, but the increase in DA was larger than for 5-HT at 18 mg/kg. Infusion of cocaine (0.1-10.0 mM) into the NAc increased both DA and 5-HT levels, but the effect on DA was larger than 5-HT at 0.1 and 3 mM cocaine. The influence of cocaine on DA and 5-HT somatodendritic autoreceptors was examined when cocaine (25 mg/kg) was administered systemically during cocaine infusion. The increase in DA and 5-HT levels during cocaine infusion was attenuated by the systemic injection of cocaine during cocaine infusion, but the decrease of 5-HT was greater than that for DA. Cocaine produced a larger impact on DA than 5-HT neurotransmission under specific conditions. A series of physiological mechanisms, i.e. terminal density, neurotransmitter interactions and somatodendritic regulation, are discussed as factors responsible for facilitating cocaine's effects on DA relative to 5-HT.

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their antidepressant-like effects by increasing synaptic concentrations of serotonin (5-HT). The rat forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Procedural modifications recently introduced by our laboratory have enabled SSRI-induced behavioral responses to be measured in the modified FST. The use of this model to understand the pharmacological and physiological mechanisms underlying the role of 5-HT in the behavioral effects of antidepressant drugs is reviewed. Although all antidepressants reduced behavioral immobility, those antidepressants that increase serotonergic neurotransmission predominantly increase swimming behavior whereas those that increase catacholaminergic neurotransmission increase climbing behavior. The 5-HT(1A), 5-HT(1B/1D) and 5-HT(2C) receptors are the 5-HT receptors most important to the therapeutic effects of SSRIs, based on extensive evaluation of agonists and antagonists of individual 5-HT receptor subtypes. Studies involving chronic administration have shown that the effects of antidepressants are augmented following chronic treatment. Other studies have demonstrated strain differences in the response to serotonergic compounds. Finally, a physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF).

Few studies have examined the relationship between genetics, stress, and sex-linked differences in neurotransmitter systems. Examining serotonin (5-HT) receptor knockout mice on stress-induced behavioral depression, female 5-HT1B receptor knockout mice demonstrated significantly reduced immobility than either male 5-HT1B receptor knockout mice or male and female wild-type mice on the tail suspension test (TST) and forced swimming test. The behavioral phenotype was identified as likely due to a disinhibition of 5-HT release, because depletion of 5-HT with parachlorophenylalanine selectively reduced immobility of female 5-HT1B receptor knockout mice in the TST. In contrast, male and female 5-HT1A receptor knockout mice demonstrated reduced immobility compared with control mice, but the depletion of 5-HT with PCPA did not reverse the antidepressant-like phenotype. Microdialysis studies confirmed significantly higher baseline levels of hippocampal 5-HT in female, but not male, 5-HT1B receptor knockout mice. Both male and female 5-HT1B receptor knockout mice demonstrated augmented dialysate responses to fluoxetine. Also, both male and female 5-HT1B receptor knockout mice demonstrated reductions of immobility in the TST after treatment with fluoxetine. Therefore, female 5-HT1B receptor knockout mice demonstrate a sex-linked disinhibition of 5-HT release that sustained higher baseline levels of hippocampal 5-HT and behavioral vulnerability to 5-HT depletion.

This report describes the use of microdialysis in conjunction with deep brain stimulation (DBS) surgery to assess extracellular levels of neurotransmitters within the human basal ganglia (BG). Electrical stimulation of the subthalamic nucleus (STN) is an efficacious treatment for advanced Parkinson's disease, yet the mechanisms of STN DBS remain poorly understood. Measurement of neurotransmitter levels within the BG may provide insight into mechanisms of DBS, but such an approach presents technical challenges. After microelectrode recordings confirmed location of STN, a custom microdialysis guide cannula was inserted. A CMA (Stockholm, Sweden) microdialysis probe was then positioned to the same depth as the microrecording electrode in STN or 2mm inferiorly to record in the substantia nigra. The catheter was perfused at a rate of 2.0 microL/min with a sterile mock CSF solution and samples of extracellular fluid were collected at regular intervals. Dialysate samples were analyzed using high-pressure liquid chromatography (HPLC) detection procedures for quantitation of glutamate, gamma-aminobutyric acid (GABA), and dopamine. Levels of neurotransmitters were reliably identified in dialysate samples using HPLC. By monitoring concentrations of glutamate, GABA and dopamine, we were able to demonstrate what seemed to be a steady state baseline within approximately 30 min. Microdialysis during DBS surgery is a feasible method for assessing levels of glutamate, GABA and dopamine within the human BG. Obtaining a steady state baseline of neurotransmitter levels appears feasible, thus making future studies of intraoperative microdialysis during DBS meaningful.

Unipolar depression is characterized by mood dysregulation that is manifested in recurrent affective episodes over the lifetime of an individual. This chapter covers the epidemiology, pathology, genetics, and brain circuitry associated with unipolar depression. In addition, animal models of depression that have been useful in characterizing neurobiological causes for depression and development of new treatments are reviewed. Effective treatments exist

The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects.

The novel antidepressant reboxetine is a selective norepinephrine reuptake inhibitor. In this study, the antidepressant-like effects of reboxetine were characterized in a modified rat forced swim test. Further, in order to investigate the role of the locus coeruleus and lateral tegmental noradrenergic systems in the mediation of reboxetine's effects, the impact of different chemical lesions of these two pathways was examined on the behavioral responses induced by reboxetine in the forced swim test. Reboxetine (5-20 mg/kg, s.c.) dose-dependently decreased immobility and swimming behavior in the forced swim test while it simultaneously increased climbing behavior. These effects were similar to those previously demonstrated with tricyclic antidepressants and are indicative of reboxetine's effects on the noradrenergic system. Discrete local injections of the neurotoxin 6-hydroxydopamine were employed to lesion the ventral noradrenergic bundle arising from cells located in the lateral tegmentum. This resulting lesion completely prevented reboxetine (10 mg/kg, s.c.)-induced decreases in immobility and increases in climbing behavior, demonstrating that an intact ventral noradrenergic bundle is required for the manifestation of reboxetine-induced antidepressant-like behavior in the test. In contrast, lesions of the dorsal noradrenergic bundle which consists of neurons arising from the nucleus locus coereleus, were achieved by systemic pretreatment with the selective noradrenergic neurotoxin N-(2-chloroethyl)-N-2-bromobenzylamine (DSP-4; 50 mg/kg, i.p.). The ability of reboxetine (10 mg/kg, s.c.) to increase climbing and decrease immobility was augmented by DSP-4 pretreatment. Furthermore, neither lesions of the dorsal noradrenergic bundle nor the ventral noradrenergic bundle altered baseline immobility scores in the forced swim test. Taken together, these data suggest that forebrain regions innervated by these two distinct noradrenergic pathways exert opposing influences on the behavioral response to reboxetine in the rat forced swim test.

Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of 99mTc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel 99mTc-labeled tropane derivative, [99mTc]TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i. v. injection into rats, [99mTc]TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, beta-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [99mTc]TRODAT-1 was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 microg per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [99mTc]TRODAT-1 showed primarily the original compound (>95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [99mTc]TRODAT-1 were obtained for male and female rats. Ex vivo autoradiography results of rat brain sections further confirmed the high uptake and retention of [99mTc]TRODAT-1 in the striatal region. In vitro binding studies measuring the affinity to dopamine transporters for the free ligand, TRODAT-1, and a nonradioactive rhenium derivative, Re-TRODAT-1, showed Ki values of 9.7 nM and 14.1 nM, respectively. Behavioral studies in rats using the free ligand, TRODAT-1 and Re-TRODAT-1 indicated that, unlike other tropane derivatives, they displayed no effect on locomotor activity, suggesting low toxicity. These results strongly support the conclusions that this novel 99mTc radioligand binds selectively to dopamine transporters in the brain and that is is potentially useful for in vivo assessment of the loss of dopamine neurons in Parkinson's and other neurodegenerative diseases.

Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two ...