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Exercise exerts antidepressant effects in humans and rodent models of affective disorders. These effects may be mediated by the upregulation of endogenous factors that exert antidepressant actions. The physiological functions and behavioral actions of the neuropeptide galanin (GAL) suggest antidepressant activity. Previous studies have shown that various modes of exercise elevate GAL gene expression in the locus coeruleus (LC) in rats. The present experiments examined the interaction between voluntary exercise and antidepressant pharmacotherapy. Male Sprague-Dawley rats were provided access to activity wheels (exercise condition) or inoperative wheels (sedentary condition) for 28 days. Rats in each group were injected with clomipramine (10mg/kg/day) or vehicle throughout this period (for 3 weeks). Prepro-GAL mRNA in the LC was measured by in situ hybridization histochemistry. Exercise and clomipramine treatment significantly elevated GAL gene expression, though prepro-GAL mRNA levels in rats receiving both interventions did not differ from sedentary controls that received vehicle. Prepro-GAL mRNA levels were significantly correlated with running distance. The results further implicate a role for GAL in the antidepressant effects of exercise and pharmacotherapy, though the mechanisms through which these treatments influence GAL gene expression appear to differ significantly.

The syndrome of behavioral, physiological, and neurochemical changes caused by ablation of the olfactory bulbs (OBX) in rats serves as a reliable and well-validated model of depression. Previous experiments have demonstrated that OBX leads to increased expression of the preproenkephalin (ENK) gene in the olfactory tubercle (OT) portion of the ventral striatum in rats. The aim of the present experiments was to investigate the role of OBX-induced ENK overexpression in the OT in the behavioral abnormalities exhibited by bulbectomized rats. A recombinant herpes virus carrying human preproENK cDNA was used to manipulate ENK gene expression in the OT of bulbectomized and sham-operated rats. Motivational deficits were assessed by the sucrose preference test, and 'agitation-like' behaviors were measured with the novel open field and footshock-induced freezing tests. ENK gene transfer in sham-operated rats mimicked some of the effects of OBX; it decreased freezing behavior in response to mild footshock and produced behavioral activation in the open field. In another experiment, virally mediated ENK gene transfer into the OT of intact rats decreased footshock-induced freezing, and this effect was reversed by naltrexone administration. PreproENK gene transfer into the OT did not produce analgesic effects in the tail-flick test. No effects on freezing behavior were observed following preproENK gene transfer into the frontal cortex. An additional experiment revealed that naltrexone administration attenuated the OBX-induced abnormality in freezing behavior. The results indicate that overexpression of the preproENK gene in the ventral striatum may mediate the 'agitation-like' behavior exhibited by bulbectomized rats.

The effects of treadmill exercise training on prepro-galanin (GAL) and tyrosine hydroxylase (TH) gene expression in the locus coeruleus (LC) were examined. Male Fischer-344 rats (n=9) were assigned to 6 weeks of treadmill running. An additional group of animals comprised the sedentary home cage control group (n=9). Levels of GAL and TH messenger RNA (mRNA) in the LC were measured using in situ hybridization histochemistry with autoradiography. Levels of GAL mRNA were higher in treadmill trained animals compared to sedentary animals, but there was no effect of treadmill running on TH mRNA. These results suggest that gene expression for galanin is responsive to repeated exercise stress and may have a neuromodulatory role in LC-noradrenergic adaptation to treadmill exercise training.

The effects of bilateral olfactory bulbectomy (OBX) on prepro-enkephalin, thyrotropin-releasing hormone, and D-2 receptor mRNA levels in the ventral striatum were examined by in situ hybridization histochemistry. Pre- pro-enkephalin mRNA levels were significantly increased in the olfactory tubercle (OT), but not in the nucleus accumbens, 14 days following bilateral OBX. Levels of D-2 receptor mRNA were also increased in the OT, though to a lesser degree. Prepro-thyrotropin-releasing hormone mRNA was unaffected by OBX. A separate experiment revealed no effect of OBX on enkephalin gene expression 7 days following surgery but a comparable elevation in pre- pro-enkephalin mRNA 14 and 28 days post-surgery. The findings are consistent with previously-reported effects of dopamine lesions on striatal gene expression, suggesting that the observed effects may be mediated by deafferentation-induced alterations in dopaminergic transmission in the OT. Altered dopaminergic function in the OT may be particularly relevant to the 'anhedonia' that has been associated with the olfactory bulbectomized rat model of depression., (Copyright 1999 Harcourt Publishers Ltd.)

Bilateral olfactory bulbectomy in the rat produces a well-characterized syndrome that is independent of anosmia. This syndrome is reversed by chronic antidepressant administration, which provides the basis for the olfactory bulbectomy model of depression. The present experiments focused on neuropeptide plasticity in central olfactory/limbic structures following olfactory bulbectomy in rats. Male Sprague-Dawley rats received bilateral surgical ablation of the olfactory bulbs, sham surgery, or no surgery and were killed either three, seven, 14 or 28 days later. Relative levels of messenger RNA encoding neuropeptide Y, somatostatin, thyrotropin-releasing hormone, and corticotropin-releasing factor precursors in the forebrain were measured by quantitative in situ hybridization histochemistry using oligonucleotide probes. Prepro-neuropeptide Y messenger RNA levels in the piriform cortex and dentate gyrus were significantly elevated in bulbectomized rats 14 and 28 days after surgery compared to sham-operated and surgically naive rats. Prepro-somatostatin messenger RNA levels in the piriform cortex were marginally increased in bulbectomized rats at these time-points. Thyrotropin-releasing hormone and corticotropin-releasing factor precursor messenger RNA levels were not altered in the brain regions studied. The results indicate that olfactory bulbectomy causes long-term increases in the expression of the neuropeptide Y gene. These findings suggest that neuropeptide Y plasticity in the olfactory/limbic system may contribute to the olfactory bulbectomy syndrome in rats, and they provide further evidence of a role for neuropeptide Y in the pathophysiology of depression.

Enkephalins are endogenous opioid peptides that are derived from a pre-proenkephalin precursor protein. They are thought to be vital in regulating many physiological functions, including pain perception and analgesia, responses to stress, aggression and dominance. Here we have used a genetic approach to study the role of the mammalian opioid system. We disrupted the pre-proenkephalin gene using homologous recombination in embryonic stem cells to generate enkephalin-deficient mice. Mutant enk-/- animals are healthy, fertile, and care for their offspring, but display significant behavioural abnormalities. Mice with the enk-/- genotype are more anxious and males display increased offensive aggressiveness. Mutant animals show marked differences from controls in supraspinal, but not in spinal, responses to painful stimuli. Unexpectedly, enk-/- mice exhibit normal stress-induced analgesia. Our results show that enkephalins modulate responses to painful stimuli. Thus, genetic factors may contribute significantly to the experience of pain.

The effects of olfactory bulbectomy (OBX) on galanin (GAL) gene expression in the locus coeruleus (LC) were examined with quantitative in situ hybridization histochemistry. OBX increased prepro-GAL levels 3 and 14 days after surgery, as compared to sham-operated controls. Levels of mRNA encoding prepro-neuropeptide Y (NPY) were unchanged, and levels of mRNA encoding tyrosine hydroxylase (TH) were elevated in the LC only on day 3. The results indicate that GAL gene expression in the LC increases after lesioning a terminal field.

Galanin is a 29 amino acid neuropeptide that coexists with norepinephrine in approximately 80% of locus coeruleus (LC) neurons in the rat. The effects of chronic, naturalistic stress on preprogalanin mRNA in the LC was studied. The visible burrow system (VBS) served as the stress paradigm. Long-Evans rats (three males and two females) were housed together in the VBS for 13 days. The males established dominance hierarchies during this period. On day 14, preprogalanin mRNA in the LC was significantly elevated in subordinate rats compared to dominant and control rats, as measured by quantitative in situ hybridization. Levels of mRNA were positively correlated with the number of wounds by day 7 and day 14 and negatively correlated with body weight gain by day 14. These results suggest that the neuropeptide galanin may be overexpressed during chronic stress in rats.