Evidence that 5-HT agonist-induced rotational behaviour in the rat is mediated via 5-HT1 receptors

The rotational behaviour induced by 5-HT agonists has been investigated in rats with lesions of the dorsal raphe' nucleus (DRN). We have previously reported that 5-methyoxy-N,N-dimethyl-tryptamine (5-MeODMT) caused dose-related contralateral rotation in rats with 5,7-dihydroxytryptamine (5,7-DHT) lesions of the DRN. Similar findings are now presented for the 5-HT₁ agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) (1H indole) (RU24969). In this model, in agreement with the behavioural studies, both agonists were shown to have a greater affinity for the 5-HT₁ binding site when compared with the 5-HT₂ binding site. Antagonist studies using selective 5-HT₂ antagonists (ketanserin and pirenperone) at non-sedative doses failed to inhibit this behaviour. In contrast, the classical 5-HT antagonist methysergide caused significant inhibition of the rotational behaviour. These results suggest that 5-HT agonist-induced rotation in the rat is mediated via 5-HT₁ receptors, probably located in the substantia nigra.     

Does tolerance develop to low doses of d- and l-amphetamine on locomotor activity in rats?

An observational study of the behavioural effects of chronic regimens of d- and l-amphetamine was designed to investigate possible mechanisms underlying any parallel behavioural changes: (1) Accumulation of p-hydroxynorephedrine in noradrenergic nerve terminals; (2) Altered sensitivity of dopaminergic receptors. The study revealed that locomotor activity seen with low doses of both isomers (2.0 mg/kg d- and 6.0 mg/kg l-) decreased with chronic once daily treatment. However, this was accompanied by an increase in directed sniffing activity and the behaviour came to resemble that seen with higher doses of amphetamine (8.0 mg/kg d- and 16.0 mg/kg l-). Nonsignificant decreases in locomotor activity and increases in directed sniffing to apomorphine administration were observed during chronic amphetamine treatment. These findings suggest that (1) p-hydroxynorephedrine, a metabolite of d- but not 1- amphetamine, does not play an important role in these alterations in behaviour with chronic treatment and (2) the tolerance to amphetamine observed under these conditions is due to an increased, rather than decreased, sensitivity of the rats to amphetamine.     

Supersensitivity to apomorphine following destruction of the ascending dopamine neurons: quantification using the rotational model

A new surgical preparation is described with which it is possible to quantify the degree of supersensitivity to dopamine receptor-stimulating agents using the rotational model. One group of rats received a unilateral injection of 6-hydroxydopamine which destroys the dopamine-containing neurons in one hemisphere, followed by a diencephalic electrocoagulation which interrupts both afferents and efferents of the striato-pallidal complex in the opposite hemisphere. Another series of animals received only the unilateral electrocoagulation. When given appomorphine both groups of animals rotated toward the side of the electrocoagulation. However, the 6-hdroxydopamine-treated animals were 10-40 times more sensitive to the behavioral effect of the drug. These results contrast with previous reports in which behavioral sensitivity to apomorphine was increased 2- to 7-fold following partial degeneration of central dopamine neurons of following the chronic adminstration of dopamine synthesis inhibitors of receptor blocking agents. The extent of loss of dopamine appears to be a critical factor in determining the degree of supersensitivity which will develop.     

Inhibition of neuroleptic-induced dopamine receptor supersensitivity by cyclo (Leu-Gly)

Behavioral supersensitivity of dopamine receptors was induced in mice by chronic administration of haloperidol (1 mg/kg/day for 21 days) and its subsequent withdrawal for 48 hr. This was evidenced by enhanced spontaneous locomotor activity and hypothermic responses to a dopamine agonist, apomorphine. Concurrent administration of cyclo (Leu-Gly), the enzymatically resistant diketopiperazine, an analog of melantropin release inhibiting factor, blocked haloperidol-induced dopamine receptor supersensitivity as evidenced by the blockade of apomorphine induced responses. Since many studies have linked the development of neuroleptic induced tardive dyskinesias with enhanced sensitivity of brain dopamine receptors, and the latter was blocked by cyclo (Leu-Gly), this agent may be of value in preventing the development of symptoms of neuroleptic-induced tardive dyskinesias.     

Adrenergic and cholinergic drug effects of rabbit eyes after sympathetic denervation

The effects of adrenergic and cholinergic drugs on pupillary diameter and intraocular pressure of conscious rabbits were studied one week after surgical removal of the left superior cervical ganglion. In a first series of experiments, changes in pupil size were measured after topical application of each drug at progressively increasing doses to left eyes of control and experimental animals. After administration of either epinephrine, norepinephrine, or isoproterenol in this manner, denervated eyes showed an enhanced responsiveness, or supersensitivity, to the mydriatric actions of these durgs. After administration of either pilocarpine or carbachol, on the other hand, marked subsensitivity to the miotic effects of these cholinomimetics became evident. In a second series of experiments, changes in ocular tension were measured after drug application to both eyes of control and experimental animals. Doses of sympathomimetics exerting no significant effects on intraocular pressure in the control rabbits, i.e., 0.1% epinephrine, 1% norepinephrine, and 1% isoproterenol, caused a significant lowering of ocular tension in the denervated eyes. While doses of carbachol or echothiophate amounting to 3.2% and 0.25%, respectively, had no significant effect on ocular tension in eyes of control animals, these same doses increased intraocular pressure in the denervated eyes by 4–8 mm Hg. These results indicate that changes in responsiveness of the rabbit eye to cholinergic drugs accompany the development of supersensitivity to adrenergic amined after sympathetic denervation.     

Sensitization of the Submaxillary Gland of the Rat after Sympathetic Denervation

Abstract The sensitivity of the submaxillary gland of the rat to chemical stimuli was examined 1, 4 and 6 weeks after sympathetic denervation. The gland was found to have developed a supersensitivity not only to noradrenaline but also, in contrast to previous reports, to adrenaline and metacholine. The supersensitivity remained unaltered throughout the period of observation.     

The striatonigral GABA pathway: Functional and neurochemical characteristics in rats with unilateral striatal kainic acid lesions

Rats with unilateral striatal kainic acid (KA) lesions showed ipsilateral rotation to subcutaneous apomorphine, contralateral rotation to intranigral muscimol and reductions in striatal glutamic acid decarboxylase (GAD) activity and nigral γ-aminobutyric acid (GABA) concentration. Rotational responses to apomorphine were highly correlated with nigral GABA depletions, and were a sensitive index of the functional integrity of striatonigral GABA neurons. Rotational responses to muscimol were also correlated with nigral GABA depletions, consistent with supersensitivity of denervated nigral GABA receptors. Striatal GAD was not correlated with either behavioural measure or with nigral GABA, and was a poor index of striatonigral function. These results are discussed in terms of (i) the functional role and adaptive capacity of striatonigral GABA neurons in linking the striatum with its effector mechanisms, (ii) parallels between parameters in GABA-dependent and DA-dependent rotational models and (iii) the status of the striatal KA lesion as a model for Huntington's disease and other extrapyramidal movement disorders.     

Differential effects of reserpine and alpha-methyl-p-tyrosine on norepinephrine and dopamine induced behavioral activity

The locomotor activity of rats was monitored during the intraventricular infusion of either dopamine or norepinephrine after intraperitoneal pretreatment with saline, reserpine (5.0 mg/kg), or acute and chronic alpha-methyl-p-tyrosine (125 mg/kg-1 or 8 days). While the hyperactivity produced by norepinephrine was potentiated 24 h after reserpine, the response to dopamine was reduced by reserpine. Chronic, but not acute, alpha-methyl-p-tyrosine enhanced the effect of norepinephrine without altering the dopamine-induced activity. These results indicate: 1. dopamine-induced hyperactivity is due to its conversion to norepinephrine, and 2. prolonged depletion of central catecholamines may result in post-synaptic receptor supersensitivity.This research was supported by NIMH Grant No. MH18065 and No. MH23209.The authors gratefully acknowledge the surgical assistance of P. Josephine Branson and Edward Forney.This study is part of a dissertation submitted by the first author in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of California, San Diego.     

Relation between the amount of smooth muscle of venous tissue and the degree of supersensitivity to isoprenaline caused by inhibition of catechol-O-methyl transferase

Summary The relation between the smooth muscle cell mass of dog saphenous vein strips and the degree of supersensitivity to isoprenaline caused by U-0521 (3,4-dihydroxy-2-methyl propiophenone), an inhibitor of the catechol-O-methyl transferase (COMT), was studied. For the quantitative determination of smooth muscle mass, the thickness of the muscle layer as determined by light microscopy and the maximal shortening induced by supramaximal concentration of phenylephrine were used.After the strips had been contracted by 3×10^–6 M phenylephrine, a concentration which was able to produce an about 90% maximal contraction, dose-response curves to the relaxant effect of isoprenaline were determined in the absence and in the presence of U-0521 (10^–4 M).It was observed that U-0521 caused marked supersensitivity to the relaxant effect of isoprenaline (varying between 3 and 81 times), as well as an increase of the maximal relaxation caused by this amine (varying between 7 and 120%). The correlation between these data and the smooth muscle cell mass shows that there was a direct proportionality between these parameters.Oxytetracycline (10^–4 M), an inhibitor of binding of catecholamines to collagen, did not produce any enhancement of the effects of isoprenaline.It is concluded that COMT is related to smooth muscle cells in this tissue.This study was supported by a grant from Instituto de Alta Cultura (PMC-2).Preliminary results of this study were presented to the Joint Meeting of German, Hungarian, Portuguese and Yugoslav Pharmacological Societies (Graz, 2–5 September, 1974).     

Hypophysectomy does not prevent development of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment

Hruska et al. (1980) reported that hypophysectomy prevented the onset of dopamine receptor supersensitivity. We have repeated this investigation administering haloperidol (0.75 mg/day) or sulpiride (2 X 15 mg/day) or saline for 17 days, followed by a 3 day drug washout period, to sham-operated or hypophysectomised rats. Haloperidol or sulpiride pretreatment caused an enhancement of apomorphine-induced stereotyped behaviour and increased the number of specific striatal [3H]spiperone binding sites (Bmax) in both hypophysectomised and sham-operated animals compared to their respective saline controls. We conclude that hypophysectomy does not prevent the onset of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment in the rat.