Evidence for cholinergic regulation of basal norepinephrine release in the rat olfactory bulb.

The effects of locally infused cholinergic agonists on extracellular levels of norepinephrine in the olfactory bulb of anesthetized rats were determined using in vivo microdialysis coupled with high-performance liquid chromatography and electrochemical detection. Using chronically implanted microdialysis probes, the basal norepinephrine level in the olfactory bulb was 0.55 pg/10 microl dialysate. Local infusion of K+ (30 mM) or the norepinephrine re-uptake inhibitor desipramine (1 microM) through the dialysis probe significantly increased basal norepinephrine levels. Focal activation of noradrenergic locus coeruleus neurons, the sole source of norepinephrine innervation of the olfactory bulb, increased norepinephrine levels by 247% of control. Local infusion of the acetylcholinesterase inhibitor soman (0.4 mM) into the olfactory bulb increased basal norepinephrine levels by 134% of control, suggesting that endogenously released acetylcholine modulates norepinephrine release. Intrabulbar infusion of acetylcholine (40 mM) or nicotine (40 mM) increased norepinephrine levels (317% and 178% of control, respectively), while infusion of the muscarinic receptor agonist pilocarpine (40 mM) reduced norepinephrine levels (54% of control). These results demonstrate that basal norepinephrine release in the olfactory bulb is potently modulated by stimulation of local cholinergic receptors. Nicotinic receptors stimulate, and muscarinic receptors inhibit, norepinephrine release from locus coeruleus terminals.

Nicotine potentiation of haloperidol-induced catalepsy: striatal mechanisms.

Nicotine potentiated the catalepsy produced by haloperidol. The excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol) significantly reduced the catalepsy produced by haloperidol as well as the ability of nicotine to potentiate haloperidol-induced catalepsy. A second experiment examined whether the ability of nicotine to potentiate haloperidol-induced catalepsy was associated with a potentiation of dopamine turnover following haloperidol. Nicotine alone produced a mild increase in dopamine turnover relative to saline treated controls while haloperidol produced a marked increase in dopamine turnover relative to saline- and nicotine-treated controls. However, the combined administration of haloperidol and nicotine did not further elevate dopamine turnover over that observed following haloperidol alone. The results indicated that: 1) nicotine could not potentiate haloperidol-induced catalepsy without an intact striatum and 2) the behavioral effect of nicotine and haloperidol cotreatment was not due to any change in dopamine turnover.

Pilocarpine-induced convulsions in rats: evidence for muscarinic receptor-mediated activation of locus coeruleus and norepinephrine release in cholinolytic seizure development.

We recently reported that systemic administration of the anticholinesterase, soman, caused rapid depletion of forebrain norepinephrine (NE) in convulsive but not in nonconvulsive rats. As neurons in nucleus locus coeruleus (LC) provide the bulk of NE innervation to most of the forebrain and the sole source of NE input to the cortex and the olfactory bulb, soman-induced NE depletion was hypothesized to result from activation of LC neurons. This activation was thought to be due to inhibition of acetylcholinesterase by soman, leading to rapid, sustained accumulation of acetylcholine in LC, causing these cells to fire at a high sustained rate. Support for this hypothesis was provided by neurophysiological findings showing that: (i) Systemic administration of soman in anesthetized rats caused a sustained, fivefold increase in the mean firing rate of LC neurons and (ii) microinjections of soman directly into LC caused a similar increase in the firing rate of LC neurons. Soman-induced activation of LC occurred prior to and even in the absence of seizures. As systemic administration of the muscarinic receptor antagonist, scopolamine, rapidly and completely reversed soman-induced activation of LC, it was further hypothesized that activation of LC neurons following soman administration is due to muscarinic receptor stimulation. The rapid release of NE by cholinolytic agents, thus, may play an important role in the initiation and/or maintenance of convulsions. To further test the hypothesis that NE release in soman-intoxicated rats is due to muscarinic activation of LC, we have investigated the effects of the muscarinic receptor agonist, pilocarpine, on NE release and LC discharge. In one set of experiments, rats were injected with a periconvulsive dose of pilocarpine (300 mg/kg, ip); both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h and monoamine levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. NE levels declined substantially only in convulsive rats; forebrain NE levels in convulsive rats rapidly decreased to 50% of control levels at 1 h and to 37% of controls level between 2 and 4 h. The time course and magnitude of these changes were similar to those observed following soman administration in our previous study. Recovery of forebrain NE began at 8 h and was complete by 96 h following pilocarpine administration. Neither dopamine (DA) nor serotonin (5-HT) levels were changed in the forebrain and olfactory bulb of either convulsive or nonconvulsive rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain norepinephrine reductions in soman-intoxicated rats: association with convulsions and AChE inhibition, time course, and relation to other monoamines.

The organophosphate chemical nerve agent, soman, causes convulsions, neuropathology, and, ultimately, death. A major problem in treating soman intoxication is that peripherally acting pharmacological agents which prevent death do not prevent seizures. Although a primary cause of these symptoms is the excess of acetylcholine which follows acetylcholinesterase (AChE) inhibition, centrally acting muscarinic blockers, such as atropine, alleviate, but do not block, the convulsive actions of soman. Moreover, there is a relatively weak relationship between CNS reductions of AChE and the incidence of convulsions. There is evidence suggesting that soman intoxication stimulates the release of norepinephrine (NE) in the brain. Recent evidence has implicated NE in the induction and/or maintenance of seizures. Thus, in the present study the relations among soman-induced convulsions, AChE inhibition, and brain NE and other monoamine changes were examined. The time course of brain NE recovery was also determined. Rats were injected (im) with a single dose (78 micrograms/kg) of soman. At this dose 68% of the injected rats developed convulsions. Both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h following soman injection and NE levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. In all convulsive rats NE levels declined substantially. Forebrain NE levels were decreased by 50% at 1 h and 70% at 2 h following soman injection. Recovery of NE began at 8 h and was complete by 96 h following soman administration. Although nonconvulsive rats showed other signs of intoxication, NE levels in these rats were unchanged. Dopamine (DA) and serotonin (5-HT) levels were not significantly affected in either convulsive or nonconvulsive rats. However, 5-hydroxyindoleacetic acid, the major metabolite of 5-HT, and homovanillic acid and 3,4-dihydroxyphenylacetic acid, the two major metabolites of DA, were increased significantly in the forebrain of convulsive, but not nonconvulsive rats, indicating an increase in 5-HT and DA turnover. However, in contrast to the abrupt decline in NE, these increases in DA and 5-HT metabolites were slow and progressive. Taken together, the present results and other recent findings suggest that rapid, sustained NE release could play a role in the induction and/or maintenance of soman-induced convulsions, whereas increased release of 5-HT and DA may be a consequence of seizures. Further investigation of the role of NE in soman-induced convulsions may lead to improved treatment of soman intoxication and a better understanding of the role of NE in other forms of seizures, including human epilepsy.

The effect of prenatal treatment with MPTP or MPP+ on the development of dopamine-mediated behaviors in rats.

Systemic exposure to the neurotoxin MPTP produces a Parkinsonian syndrome in man and primates, but not in adult rats. However, embryonic rat dopamine neurons in cell cultures are selectively destroyed by MPTP. This study examined whether similar effects on dopamine neurons occur in vivo, by studying dopamine-mediated behaviors in rats prenatally treated with MPTP or its active metabolite MPP+. Pregnant rats were injected daily with MPTP, MPP+, or vehicle from gestational day (E)13 until birth. There were time-dependent increases in spontaneous locomotor and rearing activity. Offspring of both the MPTP and MPP+ groups were hyporesponsive to d-amphetamine (1 mg/kg IP) at postnatal day 21. This hyporesponsiveness persisted at postnatal day 50 in the pups from MPTP-treated mothers. However, the striatal concentration of dopamine and its metabolites DOPAC and HVA were not significantly affected by the prenatal MPTP or MPP+ treatments. Both MPTP and MPP+ groups had significantly increased stereotypic responses to apomorphine (0.2 mg/kg SC) on both postnatal days 21 and 50. These results demonstrated persistent postsynaptic supersensitivity to dopaminergic agonists following prenatal MPTP/MPP+ treatment. That fetal rats develop long-term sequelae after prenatal exposure to MPTP/MPP+ suggests a different sensitivity of the immature rat dopamine neurons than in adult rats. Understanding this difference may provide useful information in the development of animal models of Parkinson's Disease.