Galanin mediates features of neural and behavioral stress resilience afforded by exercise.

Exercise promotes resilience to stress and increases galanin in the locus coeruleus (LC), but the question of whether changes in galanin signaling mediate the stress-buffering effects of exercise has never been addressed. To test the contributions of galanin to stress resilience, male Sprague Dawley rats received intracerebroventricular (ICV) cannulation for drug delivery and frontocortical cannulation for microdialysis, and were housed with or without a running wheel for 21d. Rats were acutely injected with vehicle or the galanin receptor antagonist M40 and exposed to a single session of either footshock or no stress. Other groups received galanin, the galanin receptor antagonist M40, or vehicle chronically for 21d prior to the stress session. Microdialysis sampling occurred during stress exposure and anxiety-related behavior was measured on the following day in the elevated plus maze. Dendritic spines were visualized by Golgi impregnation in medial prefrontal cortex (mPFC) pyramidal neurons and quantified. Exercise increased galanin levels in the LC. Under non-stressed conditions, anxiety-related behavior and dopamine levels were comparable between exercised and sedentary rats. In contrast, exposure to stress reduced open arm exploration in sedentary rats but not in exercise rats or those treated chronically with ICV galanin, indicating improved resilience. Both exercise and chronic, ICV galanin prevented the increased dopamine overflow and loss of dendritic spines observed after stress in sedentary rats. Chronic, but not acute M40 administration blocked the resilience-promoting effects of exercise. The results indicate that increased galanin levels promote features of resilience at both behavioral and neural levels.

Indirect assessment of dihydropyrimidine dehydrogenase activity in cats.

Use of 5-fluoropyridimine antimetabolite drugs, specifically 5-fluorouracil (5-FU), has been discouraged in cats because of adverse events including neurotoxicity and death. Causes of toxicity have never been elucidated. In humans, toxicity has been associated with ineffective metabolism secondary to deficiencies in dihydropyrimidine dehydrogenase (DPD). Direct assessment of DPD activity is challenging; determination of uracil:dihydrouracil (U:UH2 ) in plasma using high performance liquid chromatography (HPLC) has been reported as an indirect measurement. U:UH2 was measured in the plasma of 73 cats. Mean U:UH2 for all cats was 1.66 ± 0.11 (median 1.53, range 0.24-7.00). Seventeen (23%) cats had U:UH2 >2, a value associated with decreased DPD activity in humans. Spayed female cats had significantly lower U:UH2 as compared with intact females, and age and U:UH2 were weakly but significantly negatively correlated (r = -0.26). Studies correlating U:UH2 and 5-FU tolerability are required to further determine the validity and use of this test in cats.

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice.

Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine beta-hydroxylase knockout (Dbh-/-) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh-/- mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh-/- mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh-/- mice. Finally, striatal levels of phospho-ERK-1/2 and DeltaFosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh-/- mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.

Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception.

The effects of neurotoxic destruction of catecholaminergic projections to the spinal cord on cannabinoid antinociception were examined in models of acute and tonic nociception. High performance liquid chromatography was used to quantify monoamine levels in sham-operated and lesioned rats. Intrathecal administration of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) induced a selective depletion of norepinephrine (by approximately 85% of control) in rat lumbar spinal cord without altering levels of dopamine or serotonin. By contrast, brain levels of monoamines did not differ in sham-operated and lesioned rats. Pain behavior was similar in sham-operated and lesioned rats receiving vehicle in models of both acute and tonic nociception. The cannabinoid agonist WIN55,212-2 (5 or 10 mg/kg, i.p.) produced antinociception in the tail-flick test in sham-operated rats. The antinociceptive effect of WIN55,212-2 was attenuated relative to control conditions in rats depleted of spinal norepinephrine. WIN55,212-2 suppressed tonic pain behavior in the formalin test in sham-operated rats during phase 2 (15-60 min post formalin) of nociceptive responding. By contrast, in lesioned rats, WIN55,212-2 suppressed pain behavior during phase 1 (0-9.9 min) and phase 2A (10-39.9 min), but not during phase 2B (40-60 min). The cannabinoid agonist suppressed formalin-evoked Fos protein expression, a marker of neuronal activity, in the lumbar dorsal horn of sham-operated rats, but no suppression was observed in lesioned rats. The number of formalin-evoked Fos-like immunoreactive (FLI) cells was greater in lamina I and II of lesioned rats relative to sham-operated rats. These data indicate that the suppressive effect of the cannabinoid on formalin-evoked Fos protein expression in the superficial dorsal horn was attenuated following destruction of descending noradrenergic pathways. Our data are consistent with the hypothesis that cannabinoids produce antinociception, in part, by modulating descending noradrenergic systems and support a differential involvement of noradrenergic projections to the spinal cord in cannabinoid modulation of acute versus tonic nociception.