Andrew B. Norman

The quinolinic acid model of Huntington's disease: Locomotor abnormalities

In contrast to other excitotoxins, such as kainic acid, quinolinic acid (QA) may spare a specific population of striatal neurons that is also spared in Huntingtons disease (HD). Although several histological and biochemical experiments support the use of QA as a model for HD, to date no behavioral experiments have been performed to examine the suitability of this model. The present study explored the behavioral effects of bilateral intrastriatal microinjections of four doses (75, 150, 225, 300 nmol) of QA in the male rat. Using a multidimensional analysis of spontaneous locomotion (Digiscan activity) and a record of metabolic indicators, such as weight loss, a dose-dependent effect was found. The 75-nmol dose had no significant effect on locomotion or feeding behavior. In contrast, the 150- and 225-nmol doses induced hyperactivity and weight loss, whereas the 300-nmol dose was lethal. The results obtained suggest that striatal injections of 150-225 nmol of QA induce behavioral deficits qualitatively similar though quantitatively less than those which are seen after similar injection of 3 nmol of kainic acid and which have been reported to be comparable to the symptomatology of HD. Together with QAs possible greater histological selectivity, the present results support the use of QA-induced striatal lesions as a behavioral model of Huntingtons disease.

Nicotine potentiates the effects of haloperidol in animals and in patients with Tourette syndrome

Nicotine was found to markedly potentiate haloperidol-induced hypokinesia in rats. Nicotine alone was without effect. Subsequently, concurrent administration of 2 mg nicotine gum to 10 Tourette syndrome patients being treated with haloperidol produced a substantial decrease in tics and improvement of concentration and attention span. Nicotine gum alone was without effect. While 80% of children showed improvement with nicotine gum, 70% completely discontinued the gum because of side-effects, primarily involving nausea and bitter taste. Nicotine may prove useful for treating other neuroleptic responsive disorders, such as schizophrenia and Huntingtons disease.

OLFACTORY RECEPTOR NEURONS EXPRESS D2 DOPAMINE RECEPTORS

The role of the dopamine (DA) in the olfactory bulb (OB) was explored by determining which of the potential target cells express dopamine receptors (DARs). Previously, it was reported that D2‐like DAR (D2, D3, and D4 subtypes) radioligand binding is restricted to the outer layers of the OB. The neuronal elements present only in these layers are the axons of the olfactory receptor neurons (ORNs) and the juxtaglomerular (JG) neurons of the glomerular layer. Based on this pattern of D2‐like ligand binding, it was suggested that D2‐like receptors might be located presynaptically on ORN terminals. The present study was undertaken to investigate this hypothesis. In the outer bulb layers of rats in which the ORNs were destroyed by nasal lavage with ZnSO4, D2‐like radioligand binding was reduced severely. The receptor subtype D2 mRNA, but not D3 mRNA, was detected in adult rat olfactory epithelial tissue. By using in situ hybridization, this D2 mRNA was located preferentially in epithelial layers that contain ORN perikarya. D2 mRNA was eliminated after bulbectomy, a manipulation known to cause retrograde degeneration of the mature ORNs. Taken together, the surgical manipulations indicate that mature ORNs express D2 DARs and are consistent with the hypothesis that functional receptors are translocated to their axons and terminals in the bulb. This suggests that dopamine released from JG interneurons could be capable of presynaptically influencing neurotransmission from the olfactory nerve terminals to OB target cells through the D2 receptor. J. Comp. Neurol. 411:666–673, 1999.

Olfactory bulb DA receptors may be located on terminals of the olfactory nerve.

The glomerular layer of the olfactory bulb contains a substantial population of dopaminergic neurons. We determined the quantity and location of D1 and D2 dopamine receptors which are the presumed targets of these neurons. Binding of the D1 selective ligand [3H]SCH23390 was slightly above background and was distributed through all layers of the bulb except the olfactory nerve layer. In contrast there were relatively high levels of [3H]spiperone binding to D2 DA receptors in the glomerular and olfactory nerve layers. The presence of relatively high concentrations of D2 DA receptors in both the nerve layer and glomerular layer suggests the novel hypothesis that these receptors may be localized on terminals of the olfactory nerve.

Magnetic resonance imaging of neural transplants in rat brain using a superparamagnetic contrast agent.

Rat fetal brain tissue was incubated in vitro with superparamagnetic ferrite particles covalently coupled to the lectin wheat germ agglutinin (WGA) and transplanted into the adult rat striatum. At 6 days and at 3 weeks post-surgery the transplants were observed on T1 weighted magnetic resonance (MR) images of the rat head as an area of relatively low signal intensity which could be clearly differentiated from the higher signal intensity produced by the host brain. Histological analysis revealed that the ferrite particles were largely restricted to the transplant in a patchy distribution. The ferrite particles were associated with cells having an apparent normal morphology. Superparamagnetic ferrite particles act as potent MR contrast agents and can be used to label transplanted cells. The labeled cells are apparently not adversely affected by the WGA-ferrite particles and can be monitored for at least three weeks in vivo using noninvasive MR imaging.

Priming threshold: a novel quantitative measure of the reinstatement of cocaine self-administration

The intravenous injection of cocaine has been reported to reliably reinstate (prime) the self-administration of cocaine in animals. We report herein that there is a cocaine priming threshold in rats trained to self-administer cocaine. The cocaine priming threshold is defined as the minimum level of cocaine in the body that will reinstate maintained cocaine self-administration. The mean cocaine priming threshold in rats was calculated to be approximately 186 to 212 microg kg(-1). Therefore, any injection, series of injections or continuous infusion that result in a level of cocaine equivalent to that produced by a single intravenous injection of this range of doses, will reinstate cocaine self-administration. The priming threshold was significantly increased by the D(1) dopamine receptor antagonist SCH23390 (10 microg kg(-1), i.v.), indicating a role for dopaminergic neurotransmission. The priming threshold, but not the inter-injection interval of maintained self-administration, was increased following withdrawal from a 7-day infusion of D-amphetamine. In addition, there was no correlation between the cocaine priming threshold and the inter-injection intervals of maintained cocaine self-administration. Therefore, the mechanisms underlying the reinstatement of cocaine self-administration are distinct from the mechanisms underlying the maintenance of cocaine self-administration and they are differentially regulated. It is possible that the priming threshold may represent a distinct target for medications development.

Striatal tissue transplants attenuate apomorphine-induced rotational behavior in rats with unilateral kainic acid lesions

Four to six weeks following unilateral striatal kainic acid (KA) lesions, challenge with apomorphine (0.5-0.75 mg/kg s.c.) elicited rotational behavior. Gestational day 17-19 rat fetal striatal tissue was implanted into the lesioned striatum, and rats were rechallenged with apomorphine 10 weeks post-transplant. There was a significant reduction in the maximal rate of rotations and an alteration in the topography of locomotor activity in response to apomorphine. These data indicate that the transplanted material may possess similar pharmacological properties as the original host tissue and is capable of functionally repairing damage to a complex neurochemical system.

Quinolinic acid lesions of rat striatum abolish D1- and D2-dopamine receptor-mediated catalepsy

The selective D1-dopamine receptor antagonist SCH23390 and the more D2-selective antagonist haloperidol produced marked catalepsy in rats. The novel excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol and 225 nmol per side) abolished the cataleptic response to both SCH23390 and haloperidol. These data indicate that the D1- and/or D2-dopamine receptors which mediate the cataleptic response are restricted to QA-sensitive neurons in the rat striatum.

Nicotine potentiates haloperidol-induced catalepsy and locomotor hypoactivity

Nicotine was found to potentiate the catalepsy and reduced locomotion following the administration of haloperidol. The ability of various doses of nicotine (0.1, 0.2, or 0.3 mg/kg) to potentiate the catalepsy produced by haloperidol (0.1, 0.2 or 0.4 mg/kg) was investigated. Nicotine potentiated the cataleptic effects of both the 0.2 and 0.4 mg/kg doses of haloperidol, but had no effect following the lowest (0.1 mg/kg) dose of haloperidol. The nicotine potentiation of catalepsy produced by the highest dose of haloperidol was independent of the dose of nicotine used. Nicotine alone did not produce catalepsy. A second experiment evaluated the ability of nicotine to potentiate the decreases in spontaneous locomotor activity produced by haloperidol. Animals received nicotine (0.1 mg/kg) alone or in conjunction with haloperidol (0.1 or 0.4 mg/kg) and were tested in Digiscan Animal Monitors. Haloperidol produced a dose-related decrease in locomotion. Nicotine significantly potentiated the hypoactivity produced by both doses of haloperidol. These results indicated that: 1) nicotine produces a significant potentiation of both the catalepsy and locomotor decreases following haloperidol and 2) the Digiscam Animal Activity Monitors may provide a more sensitive assessment of the interaction between nicotine and haloperidol than the catalepsy bat test. These data suggest that adjunct treatment with nicotine may prove useful for treating neuroleptic responsive disorders such as Tourette Syndrome, schizophrenia and Huntingtons disease.

The topography of MK-801-induced locomotor patterns in rats

Locomotor patterns in rats given systemic injections of the novel, noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 were characterized using Digiscan Animal Activity Monitoring System. At low systemic doses, MK-801 produced an activity pattern most similar to patterns previously described for less potent noncompetitive NMDA antagonists; this was typified by hyperactive locomotor behavior, with increases in distance travelled, speed, and clockwise/anticlockwise locomotion, and a marked decrease in rearing behavior. Although MK-801 elicited some motor patterns similar to those previously described for sympathomimetic agents, including hyperactivity and increased stereotypy, it did not produce increased rearing behavior, the most prominent sympathomimetic effect. These results demonstrated that the topography of locomotion elicited by low systemic doses of MK-801 is most similar to locomotor patterns previously described for noncompetitive NMDA receptor antagonists.