Yousef Tizabi

Antidepressant effects of nicotine in an animal model of depression

Abstract Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg SC) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the α4β2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the α7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders.

Region-selective stress-induced increase of glutamate uptake and release in rat forebrain

The study describes stress-induced changes in high-affinity uptake and release of glutamate by synaptosomal preparations from several regions of rat brain. The results demonstrate that restraint stress can lead to increased glutamate uptake and release in limbic forebrain regions (frontal cortex, hippocampus and septum) but not in the striatum. The increase in glutamate uptake was evident after 30 min of stress. A plateau (140-150% of unhandled controls) was reached after 1 h and was maintained after 4 h of continuous stress. The stress-induced increase in glutamate uptake was observed with glutamate concentrations of up to 10 microM, but not with 500 microM. the results indicate that forebrain glutamatergic terminals are activated by stressful stimuli in a regionally selective manner, and suggest that enhanced high-affinity uptake is important in clearing increased levels of released glutamate.

Hyperactivity in the offspring of nicotine-treated rats: role of the mesolimbic and nigrostriatal dopaminergic pathways.

To evaluate the involvement of the mesolimbic and nigrostriatal dopaminergic systems in hyperactivity in offspring of nicotine-treated dams, timed-pregnant Sprague-Dawley rats were implanted SC on gestational day 4 with osmotic minipumps to receive saline or nicotine (3 or 6 mg/kg/day) for 16 days. Hyperactive and nonhyperactive male offspring of nicotine-treated dams as well as nonhyperactive offspring of saline-treated dams were selected and sacrificed at day 22 postnatally. Discrete brain areas (the nucleus accumbens [NAcc], striatum [STR], frontal cortex [FC], ventral tegmental area [VTA], and substantia nigra [SN]) were microdissected for the evaluation of dopamine (DA) concentration and/or the D2 receptor subtype. Dopamine concentration was decreased in the VTA and STR but was increased in the SN of the hyperactive offspring. The reduction in striatal DA level was associated with a reduction in the number of D2 receptors in that area. The data suggest a role for the VTA and striatal dopaminergic system in offspring hyperactivity.

Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar–Kyoto rats

Preclinical as well as limited clinical studies indicate that ketamine, a non-competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5-5.0 mg/kg i.p.) and chronically (0.5-2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an effective dose of ketamine also resulted in an increase in AMPA/NMDA receptor density ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in the hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression.

Neuroinflammation, Neurodegeneration, and Depression

Neurodegeneration and depression are two common co-morbid conditions, particularly within the aging population. Research has linked neuroinflammation as a major contributing factor to both of these diseases. The key to neuroinflammation effects on neurodegeneration and depression appears to lie within the dysregulation of the control and release of pro- and anti-inflammatory cytokines. This can come from an internal or external insult to the system, or from changes in the individual due to aging that culminate in immune dysregulation. The need to reduce neuroinflammation has led to extensive research into neuroprotectants. We discuss the efficacy found with nicotine, alcohol, resveratrol, curcumin, and ketamine. Our main focus will be on what research tells us about the connections between neuroinflammation, neurodegeneration, and depression, and the hope that neuroprotectants research gives people suffering from neurodegeneration and depression stemming from neuroinflammation. We will conclude by making suggestions for future research in this area.

Hyperactivity induced by prenatal nicotine exposure is associated with an increase in cortical nicotinic receptors

Prenatal exposure to nicotine may lead to hyperactivity. To evaluate possible involvement of central nicotinic receptors in this condition, pregnant Sprague-Dawley rats were implanted with osmotic minipumps to receive nicotine (6 mg/kg/day) or saline throughout gestation. A total of 222 pups (118 males and 104 females) from 24 dams were measured for locomotor activity. Male and female hyperactive and nonhyperactive offspring from each treatment group were selected and analyzed for nicotinic receptor concentrations in various brain regions. Hyperactive male offspring that were prenatally exposed to nicotine exhibited a significant increase in the cortical receptor densities without a change in binding affinity. Hyperactive offspring of saline-treated dams did not show an increase in cortical nicotinic receptors. These results suggest that hyperactive male offspring of nicotine-exposed dams are also susceptible to neurochemical effects of intrauterine nicotine exposure.

The effect of isolation on catecholamine concentration and turnover in discrete areas of the rat brain

Summary In normal grouped rats there are large variations in the rate of decline of catecholamines (CA) in 23 brain regions following inhibition of tyrosine hydroxylase. This suggests that regardless of the neuronal origin there are variations in turnover activity of CA terminals in different brain areas. Following tyrosine hydroxylase inhibition, the largest reductions of norepinephrine (NE) and dopamine (DA) were observed in the cell body areas. Furthermore, there is no distinction in turnover between regions innervated by the dorsal or ventral noradrenergic pathways. After 13 weeks of isolation, a significant decrease in the steady-state NE concentration was observed in the hippocampus, nucleus amygdaloideus centralis, while an increase was seen in the entorhinal cortex. A decrease in steady-state DA concentration was found in the amygdaloid centralis, while an increase was noted in the olfactory tubercle. Therefore, both a rise and fall in steady-state levels of amines occur in a few discrete regions of the brain. A decrease in turnover of NE was observed in 6 of 23 areas (hippocampus, amygdaloid centralis, cingulate cortex, caudate, nucleus interstitialis stria terminalis, paraventricular nucleus) following alpha methyl- p -tyrosine treatment. A decrease in turnover of DA was seen in the amygdaloid centralis. In prolonged isolation, it appears that the reduction of external stimuli results in a decrease in catecholaminergic activity in some limbic areas which may correlate with increased levels of emotionality and aggression.

Desensitization of the Hypothalamic-Pituitary-Adrenal Axis following Prolonged Administration of Corticotropin-Releasing Hormone or Vasopressin

The responses of the hypothalamic-pituitary-adrenal axis during chronic stress are characterized by normal or slightly elevated plasma ACTH, increased hypothalamic corticotropin-releasing hormone (CRH) and vasopressin secretion, decreased pituitary CRH receptors and hypersensitivity of the ACTH and glucocorticoid responses to a novel stress. To determine the role of CRH and vasopressin in the pituitary hyperresponsiveness to a superimposed stress, pituitary CRH receptors and plasma ACTH responses were measured in rats receiving minipump infusions of CRH or a combination of CRH and vasopressin (VP), 50 ng/min of each for 50 h. Rats were killed by decapitation with or without exposure to ether vapor for 5 min or immobilization for 15 or 30 min, and blood was collected for ACTH and corticosterone determinations. The pituitary CRH receptor concentration measured by binding 125I-Tyr-oCRH, was reduced by 45 and 80% in CRH- and CRH-plus-VP-infused rats, respectively, with no changes in receptor affinity. Acute stress by ether exposure or immobilization had no effect on pituitary CRH receptors. Adrenal weight was significantly increased, and thymus weight decreased in CRH-infused animals, indicating activation of the pituitary adrenal axis. However, in contrast to the responses following chronic stress, the increases in plasma ACTH in response to an injection of 10 micrograms/kg CRH or acute stress were significantly lower in CRH- and CRH-plus-VP-infused rats. Furthermore the content and release of ACTH from quartered pituitaries were also decreased in chronically treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Depressive Characteristics of FSL Rats ☆: Involvement of Central Nicotinic Receptors

Antidepressant effects of acute or chronic nicotine treatments in swim test immobility of Flinders sensitive line (FSL) rats, an animal model of depression, were recently demonstrated (Tizabi et al. Psychopharmacology 142:193, 1999). In the present study we sought to determine whether the antidepressant effects of nicotine could be blocked by the nicotinic antagonist, mecamylamine (MEC). Moreover, the effects of chronic nicotine treatment on [3H]cytisine binding in discrete brain regions of FSL and their control Flinders resistant line (FRL) rats were also evaluated. Adult male FSL rats were treated with MEC (0.5 mg/kg) 20 min prior to an acute or chronic nicotine administration. MEC by itself did not affect the immobility in swim test. However, it completely blocked the acute or chronic nicotine effects. Daily nicotine injection (0.4 mg/kg/day for 14 days) resulted in an increase in [3H]cytisine binding primarily in the FRL rats. An increase in nicotinic receptor binding following chronic nicotine administration is believed to reflect desensitization of these receptors. These findings, coupled with previous observation of higher basal nicotinic receptors in FSL rats, further support the involvement of central nicotinic receptors in depressive characteristics of these rats. Moreover, the data suggest therapeutic potential for selective nicotinic receptor agonists in depressive disorders.

Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression

Affective disorders often occur in combination with disrupted sleep-wake cycles and abnormal fluctuations in hypothalamic neurotransmitters. Hypocretin (orexin) is a hypothalamic neuropeptide linked to narcolepsy, a sleep-related disorder characterized by profound disturbances in the normal sleeping pattern and variable degrees of depression. Wistar-Kyoto (WKY) rats exhibit depressive characteristics and patterns of sleep disruption similar to that observed in depressed human patients. In this study we sought to determine whether the total number or the size of hypothalamic hypocretin neurons in WKY rats differ from their control, Wistar (WIS) rats. Immunocytochemical and stereological methods were applied to quantify hypocretin-1 containing neurons in the hypothalamus. The study revealed 18% fewer hypocretin-1 positive neurons as well as a 15% decrease in average neuronal soma size of hypocretin-1 producing cells in the hypothalamus of WKY rats compared to WIS rats. These findings support the view that reduced number or size of hypothalamic hypocretinergic neurons may underlie the disrupted sleep pattern associated with depressive characteristics in WKY rats.