Milburn Spencer Emery

Galanin: A Significant Role in Depression?

Abstract: This paper describes a hypothesis that attempts to account for how changes in noradrenergic systems in the brain can affect depression‐related behaviors and symptoms. It is hypothesized that increased activity of the locus coeruleus (LC) neurons, the principal norepinephrine (NE)‐containing cells in the brain, causes release of galanin (GAL) in the ventral tegmentum (VTA) from LC axon terminals in which GAL is colocalized with NE. It is proposed that GAL release in VTA inhibits the activity of dopaminergic cell bodies in this region whose axons project to forebrain, thereby resulting in two of the principal symptoms seen in depression, decreased motor activation and decreased appreciation of pleasurable stimuli (anhedonia). The genesis of this hypothesis, which derives from studies using an animal model of depression, is described as well as recent data consistent with the hypothesis. The formulation proposed suggests that GAL antagonists may be of therapeutic benefit in the treatment of depression.

Effects of dopamine β-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice

RationaleDopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE), thus playing a critical role in catecholamine metabolism.Objectives/MethodsWe examined the effects of Dbh gene dosage and the DBH inhibitor disulfiram in mice with zero, one, or two null Dbh alleles (+/+, +/−, and −/− mice).ResultsDBH protein levels in adrenal and prefrontal cortex (PFC) and adrenal DBH activity were proportional to number of wild-type alleles. Adrenal DA was slightly increased in +/− mice and markedly increased (80-fold) in −/− mice compared to wild-type animals. While adrenal NE and epinephrine (EPI) were undetectable in −/− mice, adrenal concentrations of NE and EPI were similar in +/+ and +/− mice, suggesting that the increase in DA maintains the normal rate of β-hydroxylation in Dbh +/− mice. Disulfiram had little effect on adrenal catecholamine levels, regardless of genotype or dose. NE was absent in the PFC of −/− mice, but only slightly reduced in +/− animals compared to wild-type animals. PFC DA was increased twofold in +/− mice and fivefold in −/− mice, and the NE to DA ratio was reduced (∼35%) in +/− mice, compared to wild-type mice. Disulfiram significantly decreased PFC NE and increased DA in +/+ and +/− animals, with the disulfiram and genotype effects on the PFC NE to DA ratio apparently additive.ConclusionsThe data reveal potentially important and apparently additive effects of Dbh genotype and disulfiram administration on PFC catecholamine metabolism. These effects may have implications for genetic control of DBH activity in humans and for understanding therapeutic effects of disulfiram.

Detection of lnterleukin-1 Bioactivity in Various Brain Regions of Normal Healthy Rats

Although interleukin-1 (IL-1) has been implicated in an array of brain functions, past studies usually have failed to detect IL-1 bioactivity in the brain of normal healthy animals. However, in view of the potency of IL-1 in brain, small amounts of this cytokine may normally act in brain, and such quantities can escape detection by assay methods usually employed. Although bioassays are highly sensitive for detecting IL-1, these can be compromised by molecules in brain tissue other than IL-1, and attempts to purify IL-1 from brain tissue can result in significant loss of IL-1 from samples. In this study, we have refined our method of assessing brain IL-1 bioactivity by first semi-isolating IL-1 with a Sephadex minicolumn and then measuring IL-1 activity with a sensitive D10 cell assay. To confirm that our assay was specific for IL-1, a monoclonal antibody against IL-1 receptor was used to block any observed IL-1 activity. We report here that IL-1 bioactivity can be reliably detected in both the cell-free supernatant and cell lysate of brainstem, cortex, diencephalon, and hippocampus of normal rat brain. These results lend support to some recent studies that found IL-1 may play important roles in the functions of normal brain.

Rats selectively bred for high and low swim-test activity show differential responses to dopaminergic drugs

Abstract  Rationale: Selective breeding of Sprague-Dawley rats has been used to generate a line of animals with very low swim-test activity (SwLo) in an attempt to model certain characteristics of depression. For comparison with the SwLo animals, a line bred for high swim-test activity (SwHi) and a non-selectively bred line (SwNS) have been generated. Previous studies using these lines suggested an inverse relationship between dopamine (DA) function in the brain and inactivity in the swim test. Objectives: The current experiments investigated the possibility that SwLo and SwHi rats show differences in central DA processes, as suggested by responsiveness to DA agonists. Results: The increase in ambulation produced by d-amphetamine (0.25– 1.0 mg/kg) was largest in SwHi rats and smallest in SwLo rats, with SwNS rats showing an intermediate response. Amphetamine levels in plasma and brain tissue were similar in SwHi and SwLo rats, indicating that pharmacokinetic differences were not responsible for the behavioral differences. Repeated amphetamine administration produced enhancement in the ambulation-increasing effects of this drug (i.e., sensitization), with significant enhancement seen in all three lines. Apomorphine in doses that stimulate postsynaptic receptors (0.25– 4.0 mg/kg) produced mainly increased sniffing behaviors in SwHi and SwNS rats and oral behaviors in SwLo rats, suggesting that the lines differ in proportions of D1, D2, and D3 postsynaptic receptors. Conclusions: The findings suggest that DA function differs in lines of rats selectively bred for differences in swim behavior, a feature that may make these lines useful for studying certain depressive symptoms that might be related to DA function.

In vivo Induction of lnterleukin-1 Bioactivity in Brain Tissue after Intracerebral Infusion of Native gp120 and gp160

We have previously reported that intracerebral infusion of recombinant human immunodeficiency virus envelope protein gp120 induced interleukin-1 (IL-1) bioactivity in rat brain. In this study, we test

Platelet thromboxane A2 secretion in patients with major depression responsive to electroconvulsive therapy.

Objective: To determine a) whether clinical response to electroconvulsive therapy (ECT) is associated with decreased platelet activation in patients with major depressive disorder (MDD) and b) if any medical/demographic characteristics predict response to ECT or changes in platelet activation. Increased platelet activation may underlie the increased risk of coronary artery disease (CAD) in patients with MDD. Methods: Before their first and sixth ECT treatments, study patients (n = 44) completed the Beck Depression Inventory (BDI) to assess the severity of depressive symptoms. Activity of the platelet thromboxane (TBX) A2 pathway was assessed by measuring the morning spot urinary concentrations of 11-dehydroxy-thromboxane B2 (11-D-TBX B2), a major metabolite of platelet-derived TBX A2. Results: Multivariate logistic regression analyses revealed that improvement on the BDI was significantly more likely in patients without a history of hypertension (p = .02) and in patients who were prescribed a greater number of “platelet-altering” medications (p = .03). During a course of ECT, a decrease in urinary 11-D-TBX B2 was significantly more likely to occur in ECT nonresponders (p = .01) and younger patients (p = .02). Conclusions: Clinical response to ECT coadministered may not be associated with decreases in platelet-derived TBX. Future studies will confirm which somatic “antidepression” treatments offer optimal thrombovascular benefits for depressed patients with multiple risk factors for, or clinically evident, cerebral disease or CAD. 5HT = serotonin; 11-D-TBX B2 = 11-dehydroxy-thromboxane B2; ASA = aspirin; BDI = Beck Depression Inventory; CAD = coronary artery disease; ECG = electrocardiogram; ECT = electroconvulsive therapy; ECT-1 = first ECT; ECT-6 = sixth ECT; ELISA = enzyme-linked immunosorbent assay; GPIIb/IIIa = glycoprotein IIb/IIIa; TBX = thromboxane; MDD = major depressive disorder; MI = myocardial infarction; SSRIs = selective serotonin reuptake inhibitors.