Charles H.K. West

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.

Testing the hypothesis that locus coeruleus hyperactivity produces depression-related changes via galanin

This paper reviews progress made in testing the idea that depression-related behavioral changes can arise from hyperactivity of locus coeruleus (LC) neurons which consequently inhibits activity of mesocorticolimbic dopamine neurons in the ventral tegmentum (VTA) via release of galanin from terminals on LC axons in VTA. Results from pre-clinical testing are described, including the most recent findings indicating that, in an animal model that shows long-lasting symptoms of depression, recovery to normal activity in the home cage is accelerated by infusion of a galanin receptor antagonist, galantide (M15), into VTA. Data are also described suggesting that all effective antidepressant treatments decrease activity of LC neurons.

Effects of antidepressant drugs on rats bred for low activity in the swim test.

To determine responsivity to antidepressant medication of Sprague-Dawley rats bred for low activity in the swim test [Swim Low-Active (SwLo) rats], these animals were given different antidepressant drugs via subcutaneously implanted minipumps for 1, 12, or 26 days, and then were tested for activity in the swim test and 2 days later in the open field. Antidepressant drugs given were amitriptyline, imipramine, desipramine (tricyclics), phenelzine (monoamine oxidase inhibitor (MAOI)], fluoxetine [selective serotonin reuptake inhibitor (SSRI)], venlafaxine, and bupropion (atypical). To assess specificity of response, the nonantidepressant drugs amphetamine, caffeine, and haloperidol were also tested. For comparison, several drugs were also tested in rats bred for high activity in the swim test [Swim High-Active (SwHi) rats]. When administered for 14 and/or 28 days (but not for 1 day), imipramine, desipramine, venlafaxine, phenelzine, and bupropion significantly increased struggling behavior of SwLo rats in swim test. No nonantidepressant drug significantly elevated struggling activity. Long-term administration of phenelzine and bupropion also significantly decreased floating behavior in the swim test, although amphetamine also had this effect at all times of administration. No significant effects of antidepressants were seen in SwHi rats. Amitriptyline and fluoxetine were ineffective in altering either struggling or floating in SwLo rats; however, a high dose of an SSRI (sertraline) did reduce floating, but this type of effect is probably not indicative of antidepressant action. Behavior in the open field was not consistently affected by any drug type. It is concluded that, based on pharmacological response profile in the swim test, SwLo rats represent depression that is responsive to potent norepinephrine reuptake-blocking antidepressants and also MAOIs; atypical depression may fit this profile.

Motor activation by amphetamine infusion into nucleus accumbens core and shell subregions of rats differentially sensitive to dopaminergic drugs

Selective breeding based on activity in a swim test has been used to produce lines of rats that show a high level of activity in the swim test (Swim High-active (SwHi) rats) and a low level of activity in the swim test (Swim Low-active (SwLo) rats). Previous studies have indicated that dopamine (DA) function is enhanced in SwHi rats and reduced in SwLo rats; a principal finding was that SwLo rats showed much smaller increases in ambulatory activity after systemic administration of amphetamine than did SwHi or non-selected rats. In light of the importance of the nucleus accumbens (NAC) in amphetamine-induced activity, the present study investigated whether DA function in NAC differs in SwHi and SwLo rats. Amphetamine was infused bilaterally into either the core or shell subregion of NAC, and ambulation or swim test activity was then measured. In SwLo rats, infusion of amphetamine (0.2-2.0 microg) into either NAC core or shell produced moderate increases in ambulation. In SwHi rats, infusion of amphetamine into NAC shell produced similar moderate increases in ambulation, but infusion into the core produced markedly larger dose-related increases in ambulation. In the swim test, infusion of amphetamine (1.0 microg) increased activity by affecting the dominant behavior of each line; i.e. struggling increased in SwHi rats and floating decreased in SwLo rats, with large effects seen in both lines with infusion into either NAC core or shell. These results support the idea that the distinct behavioral characteristics of SwHi and SwLo rats are mediated in part by differences in NAC-DA function.

A selective test for antidepressant treatments using rats bred for stress-induced reduction of motor activity in the swim test

Rationale and objectiveThis paper describes a new procedure for detecting effective antidepressant treatments. The procedure uses the swim-test susceptible (Susceptible) rat which has been selectively bred to show decreased struggling behavior in a swim test after exposure to a mild stressor. The ability of treatments to block this decrease in swim-test activity was assessed as a method for detecting effective antidepressants.ResultsIn both male and female Susceptible rats, chronic (14-day) treatment with different antidepressant drugs delivered via osmotic minipump [i.e., three tricyclics (desmethylimipramine, imipramine, amitriptyline), two selective serotonin reuptake inhibitors (fluoxetine and sertraline), a monoamine oxidase inhibitor (phenelzine), and two atypical antidepressants (venlafaxine and bupropion)] all prevented the stress-induced decrease in swim-test struggling normally shown by these rats. Electroconvulsive shock had a similar effect. Unlike antidepressant drugs, 14-day treatment with various nonantidepressant drugs [i.e., a stimulant (amphetamine), an anxiolytic (chlordiazepoxide), an antihistamine (chlorpheniramine), and an anticholinergic (scopolamine)] did not have this effect. Antidepressant drug treatment for 1 day (i.e., acute treatment) was also ineffective in this test. The procedure described above requires use of the Susceptible rat—swim test resistant rats (i.e., rats selectively bred to be resistant to decreased swim-test activity after exposure to stressful conditions) showed no significant differences in swim-test behavior between stress and nonstress conditions after 14-day drug treatment, and randomly bred Sprague–Dawley rats did not show a decrease in swim-test activity following exposure to the mild stressor that is the basis for the test.ConclusionThese results suggest that the procedure described here, which uses a rat subject that has been bred for vulnerability to stressful conditions, may be a selective screening technique for effective antidepressant treatments.

Increasing the work requirements lowers the threshold of naloxone for reducing self-stimulation in the midbrain of rats

Rats were trained to lever-press for intracranial self-stimulation (ICSS) with electrodes in the midbrain central gray area. The effects of naloxone (0.1-30.0 mg/kg, SC) on a continuous reinforcement (CRF) schedule were determined. Rats were then re-trained on higher fixed-ratio (FR) schedules, and naloxone was re-tested at FR: 5, 10, 15 and 20. Only moderate reductions in lever-pressing rates were obtained at the highest dose of naloxone under CRF and FR: 5 schedules. In contrast, pronounced, dose-dependent reductions in ICSS rates occurred at FR: 10, 15 and 20. The time-course for this reduction at FR: 20 was consistent with an opiate-antagonistic action of naloxone. The modest decrease in locomotor activity produced by naloxone in a matched group of control rats was not sufficient to account for the effects on ICSS. The threshold of naloxone for reducing the rate of ICSS lever-pressing was lowered by increasing the effort and/or time requirement for each reinforcement.

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.

Enhanced responses of nucleus accumbens neurons in male rats to novel odors associated with sexually receptive females.

One group of male rats was trained to associate novel odors with three different environmental conditions: the presence of (i) a sexually receptive female (RF), (ii) an unreceptive female (UF) and (iii) no other rat (NO). A second group of males received no training. Single units in nucleus accumbens (NAC) were then recorded in anesthetized animals and their responsiveness to various odors was tested. Odors that had been associated with receptive females during training evoked significantly more unit responses in NAC than did the same odors in untrained males. There were no differences between trained and untrained males in the numbers of units responsive to odors associated with unreceptive females and with the empty training chamber. In trained animals, both the percentage of responding units and the magnitude of olfactory-evoked responses were significantly larger with RF-associated odors than with either UF or NO odors. Both of these effects were more pronounced in rats that had ejaculated with females during training than in rats that had not. Findings demonstrated that pairing odors with the presentation of sexually receptive females enhanced the responsiveness of NAC neurons to those odors and indicated a role for NAC in associating environmental stimuli with natural reward processes.

Responses of units in the mesolimbic system to olfactory and somatosensory stimuli : modulation of sensory input by ventral tegmental stimulation

It is well known that neurons of the nigrostriatal dopamine (DA) system respond to sensory stimuli, and our primary objective here was to ascertain if neurons in the terminal regions of the mesolimbic DA system respond to sensory input also. In addition, the effects of electrical stimulation of the ventral tegmentum, which contains the DA cells of origin of the mesolimbic system, on sensory-evoked responses in mesolimbic neurons was studied. In rats anesthetized with chloral hydrate, responses of single units to olfactory and somatosensory stimuli were recorded in 6 forebrain regions including nucleus accumbens and olfactory tubercle. Both increases and decreases in spontaneous firing rates were evoked in 225 of 336 units by one or more of the 8 types of sensory stimuli employed (5 olfactory, 3 somatosensory). Excitatory responses occurred twice as frequently as inhibitory responses, but a few units responded with excitatory responses to some stimuli and inhibitory responses to others. The proportions of units responsive to olfactory and/or somatosensory stimuli were different in different regions. After electrical stimulation of the ventral tegmentum, sensory-evoked responses were changed in 30 of the 49 units tested (61%). There were increases, decreases or combinations of a decrease followed by an increase in sensory-evoked responses, which persisted for 1-10 min after the application of a single electrical stimulus train. Haloperidol (0.3 mg/kg, i.p.) either blocked the effect of tegmental stimulation or decreased all responses. The present results demonstrated that units in the terminal regions of the mesolimbic DA system are responsive to sensory input and that these responses can be affected by prior electrical stimulation of the ventral tegmentum.

Influence of chronic administration of antidepressant drugs on mRNA for galanin, galanin receptors, and tyrosine hydroxylase in catecholaminergic and serotonergic cell-body regions in rat brain

Activity of locus coeruleus (LC) neurons and release of the peptide galanin (GAL), which is colocalized with norepinephrine (NE) in LC neurons, has been implicated in depression and, conversely, in antidepressant action. The present study examined the influence of chronic administration (for 14days, via subcutaneously-implanted minipump) of antidepressant (AD) drugs representing three different classes (tricyclic [desipramine], selective serotonin reuptake inhibitor [SSRI] [paroxetine], and monoamine oxidase inhibitor [MAOI] [phenelzine]) on mRNA for GAL, GAL receptors (GalR1, GalR2, and GalR3), and tyrosine hydroxylase (TH), the rate-limiting enzyme for NE synthesis, in four brain regions--LC, A1/C1, dorsal raphe (DRN), and ventral tegmentum (VTA) of rats. Consistent with previous findings that chronic administration of AD drugs decreases activity of LC neurons, administration of AD drugs reduced mRNA for both GAL and TH in LC neurons. GAL and TH mRNA in LC neurons was highly correlated. AD drugs also reduced GAL and TH mRNA in A1/C1 and VTA but effects were smaller than in LC. The largest change in mRNA for GAL receptors produced by AD administration was to decrease mRNA for GalR2 receptors in the VTA region. Also, mRNA for GalR2 and GalR3 receptors was significantly (positively) correlated in all three predominantly catecholaminergic brain regions (LC, A1/C1, and VTA). Relative to these three brain regions, unique effects were seen in the DRN region, with the SSRI elevating GAL mRNA and with mRNA for GalR1 and GalR3 being highly correlated in this brain region. The findings show that chronic administration of AD drugs, which produces effective antidepressant action, results in changes in mRNA for GAL, GAL receptors, and TH in brain regions that likely participate in depression and antidepressant effects.