Effects of scopolamine,d-amphetamine and other drugs affecting catecholamines on spontaneous alternation and locomotor activity in mice

Locomotor activity and Y-maze spontaneous alternation were examined in three strains of inbred mice (A/J, DBA/2J and C57BL/6J) following various drug treatments. Although the strains exhibited different levels of locomotor activity, the level of spontaneous alternation was comparable among the strains. Scopolamine produced dose dependent increases in locomotor activity in the A and DBA/2 strains, but produced a transient inhibitory effect upon locomotor activity in C57BL/6. Nevertheless, spontaneous alternation was eliminated equally, regardless of strain. d-Amphetamine increased locomotor activity and reduced alternation significantly below chance levels (perseveration). -Methyl-p-tyrosine (-MpT) and FLA-63 reduced the locomotor stimulating effects of d-amphetamine; however, the effectiveness of these agents was found to be strain dependent. Neither -MpT nor FLA-63 reduced the perseverative behavior. A subsequent study employing Swiss-Webster mice revealed that with pretreatment of reserpine, both -MpT and FLA-63 eliminated the amphetamine-induced perseverative behavior. Results were interpreted in terms of (a) the role of cholinergic and catecholaminergic systems in modulating alternation behavior, (b) qualitative differences in the behavioral effects elicited by scopolamine and d-amphetamine, (c) strain-specificity regarding pharmacological effects, and (d) role of newly synthesized norepinephrine and dopamine in subserving amphetamine-induced locomotor activity and perseveration.     

Deficits of escape performance following catecholamine depletion: Implications for behavioral deficits induced by uncontrollable stress

Following exposure to inescapable shock, mice exhibit deficits of escape performance, which are progressively more pronounced as training continues. Comparable effects were produced by DA and NE depletion by -MpT and reserpine, NE depletion by FLA-63, and DA receptor blockade through haloperidol. Treatment with PCPA or 5-HTP did not influence performance. The disruptive effects of reserpine and -MpT, as well as haloperidol and FLA-63, were additive. Unexpectedly, mice that received both reserpine and FLA-63 exhibited escape latencies that were significantly lower than those of mice that received either treatment alone. Consistent with the view that increased DA synthesis in the reserpine plus FLA-63 condition prevented the escape interference, L-DOPA antagonized the effects of both -MpT and FLA-63. The results suggest that DA and NE act in a serial fashion to produce the escape deficits. Moreover, although both newly synthesized and previously stored amines contribute to the interference, the short latency responses seen during initial test trials could not be ascribed to previously stored amines.     

Catalepsy induced by α-methyl-p-tyrosine and d-amphetamine: The rÔle of catecholamine metabolism

The effect of inhibition of monoamine oxidase (MAO), catechol-O-methyltransferase (COMT) and Dopa-decarboxylase on the catalepsy induced by d-amphetamine in -methyl-p-tyrosine (-MpT) treated rats has been investigated.Administration of an MAO inhibitor concomitant with -MpT slightly antagonized the cataleptic state, but when given 2 h later was without an appreciable effect. Only when an inhibitor was injected at an extremely high dose level 18 h prior to -MpT did catalepsy fail to develop.Following COMT inhibition the cataleptic state was enhanced. After Dopa decarboxylase inhibition the catalepsy developed as usual for the first 3 h post-amphetamine, but then declined in intensity.It is concluded that neither deaminated nor O-methylated products are responsible for the development of catalepsy. In fact, the indication is that the catalepsy may be antagonised by an O-methylated derivative. A possible explanation for the action of the Dopa decarboxylase inhibitor is discussed.     

α-Adrenoceptor activity of arylalkylimidazoles is improved byα-methylation and impaired byα-hydroxylation

Summary To investigate the effects of hydroxyl and methyl substitution of the alkyl bridge bond on the-adrenoceptor activity of arylalkylimidazole derivatives, the cardiovascular effects of the molecules were studied in anaesthetized and pithed rats. The compounds studied were 4(5)-substituted imidazole derivatives with a methano, ethano or etheno bridge between the imidazole and the 2-, 2,3- or 2,6-methyl substituted phenyl rings. The hypotensive and bradycardic activities of the molecules in the anaesthetized rat were always reduced by-hydroxylation and usually augmented by-methylation of the bridge between the imidazole and phenyl rings. Hydroxylation was associated with a consistent, marked decrease in vasopressor and sympatho-inhibitory activity in the cardiovascular system of the pithed rat, but a methyl moiety as a bulky substituent in the-position of the alkyl bridge did not decrease but even caused an increase in-adrenoceptor activity in this test system. The detrimental effect of-hydroxylation of the compounds at ₁- and ₂-adrenoceptors supports the notion that the interaction of the imidazoles at-adrenoceptor is different from that of the classical, noradrenaline-like phenethylamines. The results also suggest that the alkyl bridge between the phenyl and imidazole rings of the imidazoles may contribute directly to the binding process.     

Role of catecholamines in the anorectic effects of amphetamine in rats

Inhibition of catecholamine synthesis with -methyl-p-tyrosine antagonized amphetamine-induced anorexia. This effect of -methyl-p-tyrosine was reversed by l-Dopa administration. Comparison of the anorectic potencies of the stereoisomers of amphetamine yielded a d-amphetamine to l-amphetamine ratio of 2.751. It is concluded that amphetamine produces anorexia through an action on catecholamines, with dopamine playing a major role.This work was supported in part by National Institute of Mental Health Grants MH01562 and MH08501 to Byron A. Campbell.     

Effects of antipsychotic drugs on the long-term effects of amphetamine on nigro-striatal dopamine neurons in iprindole-treated rats

Summary The decrease in striatal dopamine (DA) at 1 week after the administration of a single injection of (+)-amphetamine sulfate (9.2 mg/kg) to iprindole-treated (10 mg/kg of iprindole hydrochloride) rats was prevented by haloperidol (0.2 mg/kg), sulpiride (32 mg/kg), pimozide (2 mg/kg), chlorpromazine hydrochloride (3.5 mg/kg), fluphenazine 2-hydrochloride (0.25 mg/kg) and (+)-butaclamol hydrochloride (1 mg/kg) but not by (–)-butaclamol hydrochloride (1 mg/kg) or clozapine (40 mg/kg). The same dose of sulpiride did not significantly attenuate the rotational behavior induced by the administration of (+)-amphetamine sulfate (9.2 mg/kg) to iprindole-treated rats with unilateral aspiration lesions of the striatum. The concentration of amphetamine in the brains of iprindole-treated rats at 8 h after (+)-amphetamine sulfate (9.2 mg/kg) administration was not altered by the coadministration of haloperidol (1 mg/kg), sulpiride (32 mg/kg), pimozide (2 mg/kg) or clozapine (40 mg/kg). Recovery of striatal DA after depletion by -methyl-m-tyrosine (MMT) (50 mg/kg) was facilitated by haloperidol (0.2 mg/kg) and sulpiride (32 mg/kg) but not by clozapine (40 mg/kg). The possibility that neuroleptic drugs antagonize both the shortterm depletion of striatal DA produced by MMT and the long-term depletion of striatal DA produced by amphetamine in iprindole-treated rats by an effect on the nerve impulsemediated release of vesicular transmitter is discussed.     

Effects of alpha-methyl tyrosine and adrenergic blocking agents on the facilitating action of amphetamine and nicotine on learning in rats

dl-amphetamine sulphate (2 mg/kg) and nicotine (0.2 mg/kg) showed a facilitatory action on the acquisition of a conditioned response in a shuttle-box by rats and this was reversed by pretreatment with -MT (30 mg/kg).Pretreatment with dibenamine (10 mg/kg) impaired the action either of amphetamine or nicotine. Nethalide (5–10 mg/kg) exerted a partial protection on the depressant effect produced by the interaction between dibenamine and nicotine.Animals treated with -MT (30 mg/kg) and kept in the cold (4–6° C for 3 h) also showed a depressed learning capacity. dl-Dopa (200 mg/kg) provided a partial protection on the depressive effects caused by the interaction of -MT with amphetamine, nicotine or cold. It is suggested that the facilitatory learning action of amphetamine and nicotine involves a common adrenergic mechanism. The depressant effects of amphetamine, nicotine or cold after -MT treatment are attributed to depletion of functional pools of catecholamines.This work was supported by grant N 2911/67 from the Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina (O. A. Orsingher).     

Comparison of tyrosine hydroxylase and dopamine-Β-hydroxylase inhibition with the effects of various 6-hydroxydopamine treatments on d-amphetamine induced motor activity

The significance of central noradrenergic and dopaminergic neural systems for the locomotor stimulant effects of d-amphetamine were investigated in rats with depletions of norepinephrine, dopamine, or both catecholamines produced by treatment with either reserpine, L--methyl-tyrosine (-MPT), 6-hydroxydopamine (6-OHDA), or the dopamine--hydroxylase inhibitor 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624). In animals pretreated with reserpine, amphetamine-stimulated locomotor activity was blocked by -MPT but not by U-14,624 when amphetamine was given l h after these catecholamine synthesis inhibitors. In rats with chronic depletions of brain norepinephrine, dopamine, or both catecholamines produced by different 6-OHDA treatments, both amphetamine-stimulated motor activity and stereotyped behavior were antagonized by treatments reducing dopamine or both catecholamines but not in animals in which brain norepinephrine was reduced. Results are consistent with the view that the locomotor stimulation and stereotyped behaviors produced by d-amphetamine are dependent upon functional dopaminergic neural systems in brain.     

The effect of lithium on amphetamine-induced locomotor stimulation

Rats were treated chronically with -methyl-p-tyrosine methyl-ester HCl (-MT) twice daily for 0–14 days. At 1 h after the (last) -MT injection, d-amphetamine sulphate was given and motor activity was measured in an ANIMEX activity meter for 4 h. Amphetamine-induced excitatory and stereotyped behaviour was scored according to a rating scale in a separate experiment. A single dose of -MT markedly reduced the activity response after amphetamine. After 1–3 days of -MT treatment, tolerance to its amphetamine-antagonistic affect started to develop, reaching a maximal degree after 7–14 days. The pattern of the amphetamine response, monophasic in control rats, became biphasic in the -MT tolerant rats with an early (at 0–1 h) and a late (2–4 h) peak of motor activity. The late peak appeared within 3 days, while the early peak appeared after 7 days of -MT treatment. The results on amphetamine-induced excitatory and stereotyped behaviour in essence agreed with the motor-activity data. It is concluded that tolerance to the amphetamine-antagonistic action of -MT is not complete. Its rate of development varies in a complex pattern, indicating the presence of more than one mechanism of tolerance.     

Evidence for monoaminergic involvement in triadimefon-induced hyperactivity

Triadimefon is a triazole fungicide that produces hyperactivity in both mice and rats similar to that seen following administration of compounds with catecholaminergic activity (e.g., d-amphetamine). To determine whether the triadimefon-induced hyperactivity is due to an action on CNS catecholaminergic systems, we evaluated the effects of combined treatment of triadimefon with either the tyrosine hydroxlase inhibitor d,l--methyl-p-tyrosine methyl ester HCl (MPT) or the amine depletor reserpine. Adult male Long-Evans hooded rats, approximately 70 days of age were used. Dosage-effect functions were determined for MPT (0–200 mg/kg IP), reserpine (0–2.5 mg/kg IP), d-amphetamine (0–3 mg/kg IP), and methylphenidate (0–40 mg/kg IP). Motor activity was measured as photocell interruptions in figure-eight mazes. The interaction between triadimefon and MPT was determined with the following groups: 1) vehicle control; 2) 200 mg/kg triadimefon PO; 3) 100 mg/kg MPT; and 4) both MPT and triadimefon. A similar design was used to determine the interaction between triadimefon and reserpine (0.62 mg/kg), MPT and d-amphetamine (1.5 mg/kg), and reserpine and methylphenidate (5.0 mg/kg). In the first experiment MPT did not block the increased motor activity produced by triadimefon (i.e., both triadimefon alone and MPT in combination with triadimefon produced significant increases in motor activity). MPT did, however, block d-amphetamine-induced hyperactivity. Since MPT did not antagonize the effect of triadimefon, these data suggest that increased motor activity produced by triadimefon is not mediated through release of newly synthesized catecholamines. In contrast, pretreatment with reserpine blocked the hyperactivity induced by both triadimefon and methylphenidate, which suggests that triadimefon-induced hyperactivity may be due to an interaction with CNS catecholamines stored in reserpine-sensitive pools.The research described in this article has been reviewed by the Health Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. Presented in part at the Annual Meeting of the Society for Neuroscience, New Orleans, LA, November, 1987     

Two distinct adrenoceptor-biophases in the vasculature: One for α-and the other for β-agonists

Summary Strips of two canine vessels with different patterns of sympathetic innervation were used: the mesenteric artery which has an adventitio-medial plexus and the saphenous vein in which nerve terminals are distributed throughout the media.The pD₂ of (–)-adrenaline for -and -adrenoceptors was determined for both vessels (in the presence of 0.5 M propranolol and 7 M phentolamine, respectively; in the latter case the strips were contracted by 0.28 M prostaglandin F2) and found to be very similar: 6.96 and 7.01 in the saphenous vein and 6.77 and 6.91 in the mesenteric artery, respectively. The similarity of pD₂ for adrenaline acting on -and -adrenoceptors in both preparations allowed us to compare the effect of inhibition of neuronal uptake by 12 M cocaine with that of inhibition of COMT by 50 M dihydroxy-2-methyl propiophenone (U-0521) on: a) the potency of adrenaline (noradrenaline was used in the saphenous vein only) acting on -and -adrenoceptors and b) the time required by the strips to recover 50% in oil (t ₅₀) after contractions or relaxations caused by 0.23 M adrenaline. In the saphenous vein cocaine increased the potency of both adrenaline and noradrenaline for -effects more than for -effects (2.8 times vs. no increase for adrenaline; 7.1 vs. 1.9 times for noradrenaline) and U-0521 increased the potency of both adrenaline and noradrenaline for -effects more than for -effects (4.1 vs. 2.6 times for adrenaline; 1.8 times vs. no increase for noradrenaline); regarding the termination of action of adrenaline, cocaine prolonged the t ₅₀ 1.6 times after contraction and did not change it after relaxation, whereas U-0521 prolonged the t ₅₀ 6.9 times after relaxation and only 1.8 times after contraction.In the mesenteric artery only sensitivity experiments were done. Cocaine increased the potency of adrenaline by a factor of 2.1 for the -effects while there was no influence on its potency with regard to its -effects, and U-0521 increased the potency of adrenaline for the -effects more than for -effects (3.9 vs. 1.8 times, respectively).These results show that there are two different biophases for sympathomimetic agonists in the vasculature: one for -adrenoceptors which is more under the influence of the neuronal uptake and one for -adrenoceptors which is more under the influence of COMT activity. We conclude that -adrenoceptors are situated close to the nerve endings and -adrenoceptors close to COMT sites. Since these results do not differ qualitatively in two vessels with different patterns of innervation, we conclude that this asymmetry in the distribution of -and -adrenoceptors may be due to either an uneven distribution of cells with only one type of receptors each or due to an uneven distribution of receptors on the same cell.     

Comparative behavioral characterization of the neuroactive steroids 3α-OH,5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents

Pregnan steroids have been shown to possess anesthetic, hypnotic, anticonvulsant and anxiolytic properties. In this study, two endogenous neuroactive steroid isomers, 3-hydroxy-5-pregnan-20-one (3,5-P) and 3-hydroxy-5-pregnan-20-one 3,5-P), were studied for differences in their pharmacological properties using behavioral assays. 3,5-P and 3,5-P were similar in their potencies and efficacies in blocking pentylenetetrazol-induced seizures in mice (ED₅₀: 3,5-P=2.8 mg/kg and 3,5-P=3.0 mg/kg). Similarly, both neuroactive steroids produced roto-rod deficits within the same range of potency (TD₅₀:3,5-P=18.8 mg/kg and 3,5-P=21.2 mg/kg). However, in animal models of anxiety, subtle differences were observed between the two isomers. In both the light/dark transition test and elevated plus-maze, 3,5-P was more efficacious than 3,5-P, though both compounds had similar potencies. In the Geller-Seifter test, 3,5-P was more potent and efficacious than 3,5-P. Neither compound had significant effects on unpunished responding within the dose range tested. Both compounds produced similar biphasic curves in the locomotor test. All together, the data indicate that 3,5-P and 3,5-P have similar anticonvulsant activity, but the 5-isomer possesses more potent and efficacious anxiolytic properties than the 5-isomer.     

Noradrenergic and dopaminergic interactions in escape behavior: Analysis of uncontrollable stress effects

The effects of norepinephrine receptor blockade on the deficits of escape behavior induced by haloperidol and by inescapable shock were evaluated. Phenoxybenzamine, the -norepinephrine receptor blocker, was found to enhance escape behavior and to eliminate the disruptive effects of both inescapable shock and haloperidol. In contrast, the -norepinephrine receptor antagonist, propranolol, was without effect on behavior under any of these conditions, while the dopamine--hydroxylase inhibitor, FLA-63, disrupted performance. Like phenoxybenzamine, the norepinephrine receptor stimulant, clonidine, was found to eliminate the behavioral disruption produced by haloperidol. These somewhat paradoxical findings were discussed in terms of the contribution of DA-NE interactions in determining behavioral change in aversive paradigms.     

Release-inhibiting α2-adrenoceptors at serotonergic axons in rat and rabbit brain cortex: evidence for pharmacological identity with α2-autoreceptors

The pharmacological properties of the presynaptic ₂-adrenoceptors modulating the release of serotonin in rat and rabbit brain cortex (₂-heteroreceptors) were compared with the properties of presynaptic ₂-autoreceptors in the same brain area. Brain cortex slices were preincubated with [³H]-serotonin or [³H]-noradrenaline and then superfused and stimulated by brief high-frequency pulse trains.The ₂-adrenoceptor agonist bromoxidine reduced the electrically evoked overflow of tritium in experiments with both [³H]-noradrenaline and [³H]-serotonin and in brain slices from either species. The antagonists phentolamine, idazoxan, (+)-mianserin, rauwolscine, 5-chloro-4(1-butyl-1,2,5,6-tetrahydropyridin-3-yl)-thiazole-2-amine (ORG 20350), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), (–)-mianserin and corynanthine caused parallel shifts of the concentration-inhibition curves of bromoxidine to the right. Negative logarithms of antagonist dissociation constants pK_d were calculated from the shifts. In the rat, the ₂-autoreceptor pK_d value of each single antagonist was similar to its ₂-heteroreceptor pK_d value, maximal difference 0.4, giving a close correlation, r = 0.97 (P<0.001). In the rabbit equally, the ₂-autoreceptor pK_d value of each single antagonist was similar to its ₂-heteroreceptor pK_d value, maximal difference 0.4, again yielding a close correlation, r = 0.96 (P < 0.001). However, antagonist pK_d values at rat ₂-autoreceptors differed from those at rabbit ₂-autoreceptors, r = 0.70 (P > 0.05), and antagonist pK_d values at rat ₂-heteroreceptors differed from those at rabbit ₂-heteroreceptors, r = 0.64 (P > 0.05). Comparison with radioligand binding experiments from the literature indicated that, in the rat, both auto- and heteroreceptors conformed best to the _2D subtype (r 0.97, P < 0.01 for pK_d correlation with binding sites in rat submaxillary gland) whereas, in the rabbit, they conformed best to the _2A subtype (r 0.93, P < 0.01 for pK_d correlation with binding sites in HT29 cells).It is concluded that, in both the rat and the rabbit, the ₂-adrenoceptors modulating the release of serotonin are pharmacologically identical with the presynaptic ₂-autoreceptors. However, rat ₂-autoreceptors and -heteroreceptors differ pharmacologically from rabbit ₂-autoreceptors and -heteroreceptors. Presynaptic ₂-auto-as well as -heteroreceptors are _2D in the rat and _2A in the rabbit. Correspondence to: N. Limberger at the above address     

The relationship between amphetamine antagonism and depletion of brain catecholamines by alpha-methyl-p-tyrosine in rats

Summary The time-course and the dose-response relationship for the antagonistic effect of alpha-methyl-p-tyrosine methyl ester HCl H 44/68 (-MT) on damphetamine (10.6 moles/kg) induced increase in motor activity was studied. The effect of amphetamine was gradually reduced from 30–60 min to a minimum at 1–4 h after the administration of 0.407 mmoles/kg of -MT. From (4-) 8 h the amphetamine response started to reappear and the original response was restored completely at 16 h after -MT. The dose-response curve showed, that between 0.051–0.41 mmoles/kg of -MT, given 1 h before amphetamine, there was a gradual reduction of the amphetamine response; doses above 0.41 mmoles/kg did not cause any further effect.The antiamphetamine action of -MT was compared with its time-and dose-dependent effects of inhibition of synthesis and reduction of stores of brain catecholamines. It was found, that the antiamphetamine action was more closely correlated with the reduction of the levels of brain dopamine, than with the brain noradrenaline levels. Further, the inhibition of catecholamine synthesis per se did not appear to be a sufficient condition for -MT induced antagonism of amphetamine These finding support the view that amphetamine is dependent on a substantial portion of the brain pool of dopamine and possibly noradrenaline rather than on very small, newly synthesized pools of these neurotransmitters.     

Further evidence for a change in central α-adrenergic receptor sensitivity after withdrawal from long-term haloperidol treatment

Summary Phenoxybenzamine, FLA-63 and -MT produced less locomotor depression in mice withdrawn for 4 days from a 21 day treatment with haloperidol than that produced in vehicle-treated animals. There were no differences between the two groups when challenged with yohimbine or phentolaminé. The data support the hypothesis that central -adrenergic receptors had become supersensitive and suggest that the sensitivity changes are restricted to post-synaptic receptors.     

Motor disturbance induced by tremorine and oxotremorine

Summary The action of tremorine and oxotremorine on spinal motor activity was studied in the rat. Both tremorogenio agents increased a reflex activity and spontaneous activity. The increase in spontaneous activity consisted of rhythmic bursts of discharges. The increase in a reflex activity was accompanied by rigidity, which manifested itself by the appearance of tonic muscle activity.Tremorine and oxotremorine-induced tremor was depressed by the antitremor agents metixene and Kr 339, the antiparkinson drugs atropine and biperiden, and the adrenergic receptor blocking agents propranolol and pronethalol. The adrenergic. receptor blocking agents azapetine, dihydroergotamine, haloperidol, phenoxybenzamine and phentolamine failed to inhibit tremor activity. Chlorpromazine, however, as well as procaine, verapamil and DOPA, diminished the intensity of tremor activity without blocking the generation of tremor bursts.Drugs which depressed tremor activity also antagonized the effect of oxotremorine on and motor activity, whereas the drugs, which only diminished tremor intensity, depressed the increased reflex discharge without reducing spontaneous activity. Rigidity disappeared when reflex discharge was normalized.It is concluded that experimental parkinsonlike rigidity may be interpreted in terms of a disturbed balance between monoaminergic and cholinergic mechanisms in the brain.The authors are grateful to KnolI-Ludwigshafen for the support of the investigation.     

The effect of intracerebroventricular administration of catecholamines and their antagonists on rectal temperature of Mastomys natalensis

Summary Noradrenaline (NA), adrenaline (ADR), isoprenaline (ISO) and dopamine (DA) were given through a chronically implanted cannula in the lateral cerebral ventricle of Mastomys natalensis. Low doses of NA (0.05–0.25 g) reduced rectal temperature while larger doses (0.35 g upwards) produced dose-dependent hyperthermia. The hypothermic effect was antagonised by -adrenceptor and the hyperthermia by -adrenoceptor antagonists. -Methyl noradrenaline produced less hyperthermia but it antagonised the hyperthermic effect of NA. Adrenaline (0.1–10 g) was ineffective per se but when given after tolazoline it produced hyperthermia and after propranolol it produced hypothermia. The dose-dependent hyperthermia with isoprenaline (0.1–10 g) was blocked by propranolol and MJ-1999. Dopamine (0.5–20 g) and its agonists apomorphine, amantadine and BS 9641 produced hyperthermia which was antagonised by haloperidol and pimozide but not by - or -adrenoceptor antagonists. Noradrenaline (1.0 g) produced hypothermia at ambient temperature of 10°C and 16°C. It had no effect at 20°C which seems to be the thermoneutral zone for mastomys. The hyperthermic effect at 33°C was less than at 24°C. Dopamine (10 g) response was attenuated at 33°C and unaffected at other ambient temperatures. It is concluded that - and -adrenoceptors and DA-receptors exist in the central thermoregulatory mechanism in mastomys. The -receptors are concerned with lowering the body temperature whereas the -receptors and DA-receptors are involved in raising it.Communication No. 2841 from the Central Drug Research Institute, Lucknow     

α1- and α2-Adrenoreceptor antagonists differentially influence locomotor and stereotyped behaviour induced byd-amphetamine and apomorphine in the rat

The importance of dopamine (DA) in mediating locomotor, exploratory and stereotyped behaviour in rodents is well established. Evidence also indicates a modulatory role for noradrenaline (NA) although, due to non-specificity of previously available agents, a precise role remains undefined. The effects of the specific and selective -adrenoreceptor antagonists idazoxan (₂) and prazosin (₁) on behaviour induced by amphetamine and apomorphine have been investigated in the rat.d-Amphetamine (2 mg/kg) induced hyperactive locomotion and exploration. Pretreatment with prazosin (1 mg/kg) markedly reduced these responses. In contrast, pretreatment with idazoxan (20 mg/kg) only marginally alteredd-amphetamine hyperactivity. Apomorphine (0.5 mg/kg) induced biphasic locomotor and exploratory activity. Neither -antagonist affected the initial burst of activity (60 min), although prazosin inhibited whereas idazoxan potentiated the secondary phase (90–180 min). At higher dosage, amphetamine (6 mg/kg) and apomorphine (2 mg/kg) induced stereotyped behaviours. Prazosin pretreatment enhanced stereotyped gnawing and decreased sniffing and locomotion, whereas idazoxan increased locomotion and decreased amphetamine-induced mouth movements. These data indicate that DA-induced locomotor and stereotyped behaviours are differentially influenced (in opposite directions) by both ₁- and ₂-adrenoreceptor antagonists. NA may thus modulate the expression and character of behaviour by influencing DA function in certain brain areas.     

Effect of haloperidol on reflex activation of rat α-motoneurones

Summary Effects of haloperidol on rat flexor and extensor -motoneurones were studied in ventral roots of laminectomized rats under halothane anesthesia. The -motoneurones were activated by tetanic stimulation of low-threshold afferents (group I and II), either of the ipsilateral peroneal nerve (flexor -motoneurones) or gastrocnemius-soleus nerve (extensor -motoneurones).Haloperidol, given in the doses of 0.075, 0.15 and 0.30 mg/kg i.p. inhibited the reflex activation of flexor -motoneurones; higher doses seemed to be more effective than lower ones. Apomorphine (2 mg/kg s.c.) partially antagonized the inhibitory action of haloperidol with some latency. Higher doses of haloperidol (0.15–0.60 mg/kg i.p.) also inhibited the reflex activation of extensor -motoneurones; this inhibitory effect was, at least for a short time, antagonized by apomorphine (2 mg/kg s.c.).The threshold for reflex activation both of flexor and extensor -motoneurones was raised by haloperidol and lowered by a subsequent administration of apomorphine.Our results suggest that akinesia and catalepsy, induced in rats by haloperidol might be, at least in part, due to a decrease in sensitivity of -motoneurones to proprioceptive stimuli.