Michael J. Zigmond

Neurobiology of Exercise

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinsons disease, Alzheimers dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.

Compensations after lesions of central dopaminergic neurons: some clinical and basic implications

Parkinsons disease is associated with degeneration of the dopaminergic component of the nigrostriatal pathway. However, the neurological symptoms of this disorder do not emerge until the degenerative process is almost complete. A comparable phenomenon can be observed in animal models of Parkinsons disease produced by the administration of the selective neurotoxin, 6-hydroxydopamine (6-OHDA). Studies using such models suggest that the extensive loss of dopaminergic neurons is compensated, in large part, by increased synthesis and release of dopamine (DA) from those DA neurons that remain, together with a reduced rate of DA inactivation. These findings may have important implications for the diagnosis and treatment of a variety of neurological and psychiatric diseases, as well as for our understanding of plasticity in monoaminergic systems.

Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: Effects of diazepam

We have examined the effects of diazepam on the stress-induced increase in extracellular dopamine and norepinephrine in the medial prefrontal cortex using in vivo microdialysis. In naive rats, acute tail pressure (30 min) elicited an increase in the concentrations of dopamine and norepinephrine in extracellular fluid of medial prefrontal cortex (+54 and +50%, respectively). Diazepam (2.5 mg/kg, i.p.) decreased the basal concentration of extracellular dopamine and norepinephrine. Diazepam also attenuated the stress-evoked increase in the absolute concentrations of extracellular dopamine (+17%), but did not alter the stress-induced increase in norepinephrine (+41%). However, when the drug-induced decrease in basal dopamine and norepinephrine concentration was taken into account, the stress-induced net increase in dopamine above the new baseline was equivalent to that obtained in vehicle pretreated rats, whereas the net increase in norepinephrine was almost twice that obtained in control subjects. In rats previously exposed to chronic cold (three to four weeks at 5 degrees C), tail pressure again produced an increase in the concentrations of dopamine and norepinephrine in the medial prefrontal cortex (+42% and +92%, respectively). However, in these chronically stressed rats, diazepam no longer decreased basal dopamine or norepinephrine in extracellular fluid, nor did it affect the stress-induced increase in the concentrations of these catecholamines. These data indicate that diazepam has complex effects on the extracellular concentrations of dopamine and norepinephrine which vary depending upon whether the rat is undisturbed or stressed during the period of drug exposure as well as the rats prior history of exposure to stress. Moreover, these data raise questions regarding the role of catecholamines in the mechanism by which diazepam exerts its anxiolytic properties.

Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: Pharmacological and behavioral studies

The release of endogenous norepinephrine in hippocampus was studied in freely moving rats with microdialysis perfusion. Using a loop-style dialysis probe, the basal amount of norepinephrine collected in 15-min fractions averaged 12 pg/25 microliters. Correcting for recovery (21%), the concentration of norepinephrine in the extracellular fluid of hippocampus under resting conditions was estimated to be approximately 14 nM. The alpha 2 adrenoceptor antagonist yohimbine (5.0 mg/kg, i.p.) increased norepinephrine efflux to 230% of basal levels. Clonidine (0.3 mg/kg, i.p.), an alpha 2 adrenoceptor agonist, decreased norepinephrine efflux to 56% of baseline. Addition of the reuptake blocker desipramine (1.0 microM) to the perfusate had no significant effect on norepinephrine efflux. However, increasing the K+ concentration of the perfusate to 30 mM increased norepinephrine efflux to 196% of baseline, and this effect was increased nearly two-fold by the addition of desipramine to the perfusate (364% of baseline). Restraint stress and intermittent tailshock increased norepinephrine efflux to 213% and 234% of baseline, respectively. The results suggest that microdialysis is a useful way to study norepinephrine release in hippocampus and they permit several conclusions to be drawn. First, the data obtained with systemic administration of alpha 2 adrenoceptor drugs emphasize the fact that a variety of regulatory mechanisms exist that may affect transmitter levels in the extracellular fluid. Second, the ratio of extracellular to intracellular norepinephrine in hippocampal tissue is considerably higher than that reported for dopamine in striatum. Coupled with the small effect of norepinephrine uptake blockade, this suggests that nerve terminal density is an important factor in determining the concentration of catecholamines in the extracellular fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects ofl-DOPA on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats

In vivo microdialysis was used to examine the effect of L-3,4-dihydroxyphenylalanine (L-DOPA) administration upon dopamine (DA) in extracellular fluid both in intact striatum and in striatum of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine (6-HDA). Basal extracellular levels of DA were not significantly altered by 6-HDA unless the DA content of striatal tissue was reduced to less than 20% of control. Peripheral aromatic amino acid decarboxylase (AADC) inhibition (RO4-4602, 50 mg/kg i.p.) followed by L-DOPA treatment (100 mg/kg i.p.) elevated extracellular DA in striatum of control rats from 37 +/- 5 to 68 +/- 11 pg/sample (n = 7; values corrected for recovery of the dialysis probe). In animals with severe bilateral depletions of DA in striatal tissue (mean depletion 87%; n = 6), L-DOPA increased extracellular DA in striatum from 8 +/- 3 to 266 +/- 60 pg/sample. In animals with large unilateral depletions of DA in striatal tissue (mean depletion 96%; n = 6), the increase in extracellular DA in striatum after L-DOPA was greater on the lesion side (from 7 +/- 4 to 245 +/- 67 pg/sample) than on the intact side (from 28 +/- 11 to 61 +/- 8 pg/sample). Animals with unilateral DA depletions showed contralateral circling behavior after L-DOPA. Increases in extracellular DA approaching the magnitude of those occurring in DA-depleted striata were observed when intact animals were treated with nomifensine (5 mg/kg i.p.; n = 5), an inhibitor of high-affinity DA uptake, in addition to L-DOPA.

Recovery of feeding and drinking by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions.

Rats given intraventricular injections of 6-hydroxydopamine after pretreatment with pargyline become aphagic and adipsic, and show severe loss of brain catecholamines. Like rats with lateral hypothalamic lesions, these animals gradually recover ingestive behaviors, although catecholamine depletions are permanent. Both groups decrease food and water intakes markedly after the administration of α-methyltyrosine, at doses that do not affect the ingestive behaviors of control rats. Thus, both the loss and recovery of feeding and drinking behaviors may involve central catecholamine-containing neurons.

Apparent sprouting of striatal serotonergic terminals after dopamine-depleting brain lesions in neonatal rats

Near-total dopamine-depleting brain lesions produced in 3-day-old rats by intracerebroventricular injection of the neurotoxin 6-hydroxydopamine led to pronounced increases in striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid contents 1-8 months later. This effect was associated with an increase in in vitro high affinity 5-HT uptake, suggesting that proliferation of new serotonergic terminals had occurred within the striatum. No such effect was obtained when comparable brain lesions were produced in adult rats.

Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF

Unilateral administration of 6‐hydroxydopamine (6‐OHDA) into the medial forebrain bundle (MFB) causes a loss of dopamine (DA) in the ipsilateral striatum and contralateral motor deficits. However, if a cast is placed on the ipsilateral limb during the first 7 days following 6‐OHDA infusion, forcing the animal to use its contralateral limb, both the behavioral and neurochemical deficits are reduced. Here, we examine the effect of forced reliance on a forelimb during the 7 days prior to ipsilateral infusion of 6‐OHDA on the deficits characteristic of this lesion model. Casted animals displayed no behavioral asymmetries as measured 14–28 days postlesion and a marked attenuation in the loss of striatal DA and its metabolites at 30 days. In addition, animals receiving a unilateral cast alone had an increase in glial cell‐line derived neurotrophic factor (GDNF) protein in the striatum corresponding to the overused limb. GDNF increased within 1 day after the onset of casting, peaked at 3 days, and returned to baseline within 7 days. These results suggest that preinjury forced limb‐use can prevent the behavioral and neurochemical deficits to the subsequent administration of 6‐OHDA and that this may be due in part to neuroprotective effects of GDNF.

Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex.

Abstract: Noradrenergic and dopaminergic projections converge in the medial prefrontal cortex and there is evidence of an interaction between dopamine (DA) and norepinephrine (NE) terminals in this region. We have examined the influence of drugs known to alter extracellular NE on extracellular NE and DA in medial prefrontal cortex using in vivo microdialysis. Local application of the NE uptake inhibitor desipramine (1.0 µM) delivered through a microdialysis probe increased extracellular DA (+149%) as well as NE (+201%) in medial prefrontal cortex. Furthermore, desipramine potentiated the tail shock‐induced increase in both extracellular DA (stress alone, +64%; stress + desipramine, +584%) and NE (stress alone, +55%; stress + desipramine, +443%). In contrast, local application of desipramine did not affect extracellular DA in striatum, indicating that this drug does not influence DA efflux directly. Local application of the α2‐adrenoceptor antagonist idazoxan (0.1 or 5.0 mM) increased extracellular NE and DA in medial prefrontal cortex. Conversely, the α2‐adrenoceptor agonist clonidine (0.2 mg/kg; i.p.) decreased extracellular NE and DA in medial prefrontal cortex. These results support the hypothesis that NE terminals in medial prefrontal cortex regulate extracellular DA in this region. This regulation may be achieved by mechanisms involving an action of NE on receptors that regulate DA release (heteroreceptor regulation) and/or transport of DA into noradrenergic terminals (heterotransporter regulation).

Estimating Hydroxyl Radical Content in Rat Brain Using Systemic and Intraventricular Salicylate: Impact of Methamphetamine

Abstract: Free radicals have been implicated in the etiology of many neurodegenerative conditions. Yet, because these species are highly reactive and thus short‐lived it has been difficult to test these hypotheses. We adapted a method in which hydroxyl radicals are trapped by salicylate in vivo, resulting in the stable and quantifiable products, 2,3‐dihydroxybenzoic acid (DHBA) and 2,5‐DHBA. After systemic (100 mg/kg i.p.) or intraventricular (4 µmol) administration of salicylate, the amount of DHBA in striatal tissue correlated with tissue levels of salicylate. After systemic salicylate, the ratio of total DHBA to salicylate in neostriatum was at least 10‐fold higher than that observed after central salicylate. In addition, systemic salicylate resulted in considerably higher concentrations of 2,3‐ and 2,5‐DHBA in plasma than in brain. Therefore, a large portion of the DHBA present in brain after systemic salicylate may have been formed in the periphery. A neurotoxic regimen of methamphetamine increased the concentration of DHBA in neostriatum after either central or systemic administration of salicylate. The increase in 2,3‐DHBA after the central administration of salicylate was significant at 2 h, but not at 4 h, after the last dose of methamphetamine. These results suggest that (1) when assessing specific events in brain, it is preferable to administer salicylate centrally, and (2) neurotoxic doses of methamphetamine increase the hydroxyl radical content in brain in a time‐dependent manner.