Adrenergic involvement in the locus ceruleus and adjoining regions in the facilitation of predatory attack behavior as induced by hypothalamic stimulation in cats.

The present study was carried out in five cats which did not attack the rats spontaneously. Predatory attack on an anaesthetized rat was elicited by electrical stimulation of extreme lateral regions of hypothalamus. These sites were stimulated at a current strength from 300-700 microa to evoke a predatory attack on an anaesthetized rat. The attack was accompanied by minimal affective display such as alertness, pupillary dilatation, and culminated in beck biting at higher current strength. A scoring system allowed the construction of stimulus response curves, which remained fairly constant when repeated over a period of 3-4 weeks. Microinfusions of norepineprine and clonidine in 4.0 and 5.0 microg dose respectively in locus ceruleus and adjoining tegmental fields facilitated the predatory attack and there was a significant reduction in the threshold current strength for the elicitation of affective and somatomotor components. Microinfusions of yohimbine, an alpha-2 blocker, in 5 microg dose completely blocked the predatory attach response as indicated by an increase in the threshold current strength for the affective components. The somatomotor components were completely inhibited and could not be elicited even when the current strength was increased to 1000 microA. The predatory attack behavior remained completely inhibited for almost two hours following microinfusion of yohimbine. During this period, the animal was extremely drowsy and reacted very slowly even to a painful stimulus such as pinching of tail. Microinfusions of propranalol (beta-blocker), practalol (beta-1 blocker), prazosin (alpha-1 antagonist), propylene glycol as well as saline in similar volumes (0.5 microl) as control failed to produce any blocking effect, thus indicating the involvement of alpha-2 adrenoceptive mechanisms in the modulation of predatory attack in this region of midbrain. The facilitatory effects of norepinephrine and clonidine were significant at P<0.01 and P<0.05 respectively with Wilcoxon's signed rank test. The inhibitory effects of yohimbine were significant at P<0.05. The present study indicates the involvement of alpha-2 adrenoceptive mechanisms in the facilitation of hypothalamically elicited predatory attack.

Enkephalinergic involvement in substantia nigra in the modulation of hypothalamically-induced predatory attack behavior.

The present study was carried out in five cats which did not attack the rats spontaneously. Predatory attack on an anaesthetized rat was elicited by electrical stimulation of lateral hypothalamus at a mean current strength of 650 microA. The attack was accompanied by minimal affective display and culminated in neck biting. Microinfusions of DAME (delta-alanine methionine enkephaline) in 500 ng dose in substantia nigra facilitated the predatory attack and there was a significant reduction in the threshold current strength for affective display as well as somatomotor components. Microinfusions of naloxone, an opioid antagonist in 1.0 microg dose when DAME effect was at its peak reversed the facilitatory effects and the threshold returned to the control levels within 10 minutes of naloxone infusion at the same locus. Microinfusions of naloxone alone in similar dosage completely blocked the predatory attack response as indicated by an increase in the threshold current strength for somatomotor as well as affective display components. The somatomotor were completely inhibited and could not be elicited even when the current strength was increased to 1000 microA. Control injections of saline in similar volumes (0.5 microl) failed to produce any response Microinfusions of naloxone in lower dose (250 ng) failed to produce any blocking effect. These findings indicate that hypothalamically elicited predatory attack is facilitated by enkephalinergic mechanisms operating at the midbrain level.

Enkephalinergic mechanisms in midbrain (dPAG) in modulation of hypothalamically-induced predatory attack behaviour.

Present study was carried out in nine cats which did not attack the rats spontaneously. Predatory attack on an anaesthetized rat was elicited by electrical stimulation of lateral hypothalamus at a mean current strength of 690 microA. The attack was accompanied by minimal affective display and culminated in neck biting. Microinjections of delta-alanine methionine enkephaline (DAME) in 250 ng dose in dorsal periaqueductal gray completely suppressed the predatory attack. There was a significant increase in the threshold current strength for affective display components while the somatic components were completely inhibited even when the current strength was increased to 1000 microA. Microinjections of naloxone, an opioid antagonist in 1 microgram dose reversed the DAME blocking effect and the thresholds returned to control levels within 10 min of microinjections. Microinjections of naloxone alone in similar dose facilitated the response as indicated by a decrease in threshold current strengths for both affective display and somatomotor components. Control injections of saline in similar volumes (0.5 microliter) failed to produce any change. These findings indicate that hypothalamically induced predatory attack is inhibited by enkephalinergic mechanisms operating at the dPAG level in the midbrain.

Role of midbrain ventro-lateral tegmental area (VTA) enkephalinergic mechanisms in the facilitation of hypothalamically-induced predatory attack behaviour.

Bipolar concentric electrodes were implanted in five cats in extreme lateral regions of hypothalamus. These sites were electrically stimulated using biphasic square wave pulses at a current strength ranging from 300-800 microA to evoke predatory attack on an anaesthetized but live rat. At lower current strength (300 microA) only alertness with pupillary dilatation was produced. Gradual increase in the current strength led to the recruitment of somatic and affective components and a predatory attack was exhibited at a mean current strength of 700 microA. A scoring system allowed the construction of stimulus response curves, which remained fairly constant when repeated over a period of 3-4 weeks. Bilateral microinjections of delta-alanine methoinine enkephaline (DAME) (500 ng in 0.5 microliter saline) in ventrolateral tegmental area (VTA) elevated the mean threshold current strength for affective components while somatomotor components were totally inhibited. The blocking effect of DAME persisted for 1 hour. Microinjections of naloxone (1 microgram) in similar volumes facilitated the response as indicated by a reduction in threshold current strength for somatomotor and affective components. Microinjections of naloxone (1 microgram) in similar volumes facilitated the response as indicated by a reduction in threshold current strength for somatomotor and affective components. Microinjections of naloxone (1 microgram) also reversed the blocking effect of DAME and the thresholds returned to the control level within 10 min while microinjection of normal saline as control had no effect. The excitatory effects of naloxone and inhibitory effects of DAME were statistically significant at P < 0.01 and P < 0.05 respectively with Wilcoxon's signed rank test. The present study indicates that enkephalinergic as well as opioidergic mechanisms operating at the midbrain (VTA) level are involved in the inhibition of predatory attack as elicited from lateral hypothalamus.

Role of midbrain ventro-lateral tegmental area (VTA) adrenergic mechanisms in facilitation of hypothalamically-induced predatory attack behaviour.

Bipolar concentric electrodes were implanted in extreme lateral regions of hypothalamus having coordinates (A12.5 mm, L 3.5-3.7 mm, V 3.0-3.7 mm). These sites were electrically stimulated using biphasic square wave pulses (1 ms, 60 Hz) at a current strength ranging from 300-800 microA to evoke predatory attack on an anaesthetized rat. At lower current strengths of 300 microA only altertness with pupillary dilatation was produced. Gradual increase in the current strength led to recruitment of somatic and affective components and a full blown predatory attack on a rat was produced at a mean current strength of 700 microA. A scoring system allowed the construction of stimulus response curve, which remained fairly constant when repeated over a period of 3-4 weeks. In ventrolateral tegmental area (VTA), bilateral microinjections of norepinephrine (NE 10 micrograms in 0.5 microliter saline, pH 7.4) lowered the mean threshold current strength to 100 microA while predatory attack was produced at 500 microA. Clonidine (5 micrograms in 0.5 microliter propylene glycol, pH 7.4) an alpha-2 agonist similarly lowered the mean threshold to 100 microA and predatory attack threshold to 400 microA. The effects of clonidine appeared within 20 min of microinjection and persisted up to 6 hr. Yohimbine, an alpha-2 antagonist (4 micrograms in 0.5 microliter propylene glycol. pH 7.4) when microinjected into the same locus (VTA), completely blocked predatory attack behaviour for 3 days, the peak period of the blocking effects were between 3-8 hr, after microinjection. Isoproterenol (beta agonist), propranolol (beta blocker), prazosin (alpha-1 antagonist) and phenoxybenzamine (alpha antagonist) failed to produce any effect. Normal saline and propylene glycol in similar volumes served as controls. The excitatory effects of NE and clonidine and inhibitory effects of Yohimbine were significant at P < 0.01 and P < 0.05 respectively with Wilcoxon's signed rank test. The present study indicates the involvement of alpha-2 adrenoceptive mechanisms operating at the midbrain (VTA) level in the elicitation of predatory attack from lateral hypothalamus.

Electrical and chemical stimulation of the same hypothalamic loci in relation to agressive behaviour in cats: a comparison study.

Chemitrodes which permit electrical and chemical stimulation of the same hypothalamic loci were implanted in anterior hypothalamic and preoptic regions. These sites were stimulated electrically using biphasic square wave pulse (1 ms, 60 Hz) at a current strength ranging from 150-800 microA to evoke an aggressive response. At lower current strength of 150-200 micro A, defence response, a sort of non-specific response can be elicited from these regions. Increasing the current strength to 400 microA led to the recruitment of affective and somatic components and changed the response pattern either to affective attack or flight. The loci producing affective attack response were localized more laterally and ventrally while the loci producing flight response were located in the dorsomedial regions of the hypothalamus. In this response the animal made a goal-directed attempt to escape through an escape route. Increasing the current strength to 500 microA in the dorsomedial regions changed the flight response to violent flight, which involved vigorous running with unsheathed claws and attacking objects if obstructed. Similar increase in current strength at loci producing affective attack only led to a decrease in the latency of response and made the attack more vigorous. Microinfusion of carbachol in graded doses of 2-15 microgram at all these loci produced a profound affective display. At lower doses of 2 and 5 microgram, only some components of affective display like alertness, pupillary dilation and ear flatness were exhibited. Increasing the dose to 10 micrograms and 15 micrograms led to the recruitment of other affective components like piloerection, salivation, hissing and baring of teeth. Microinfusion of carbachol at all loci producing affective attack on electrical stimulation produced a prononced affective display while microinfusion of carbachol at loci producing flight response led to the development of defence posture. At six loci a typical flight response was obtained while violent flight was never exhibited at any of these sites. Microinfusion of atropine (10 microgram in 1.0 microliter saline) at these loci completely blocked the carbachol induced response. Both somatomotor and affective components were completely inhibited. However, the responses obtained on electrical stimulation were not totally blocked following atropine infusion and some of the somatomotor and affective components could be elicited with higher current strength. These studies indicate the involvement of cholinoceptive mechanisms in the elicitation of hypothalamically induced aggresive behaviour. Microinfustion of hexamethonium bromide, a nicotinic blocker in 50 micrograms doses did not affect the aggressive response.

Midbrain adrenergic mechanisms modulating flight behaviour induced by hypothalamic stimulation.

The present study was carried out in ten cats of either sex. Flight response was obtained by electrical stimulation of dorsomedial regions of preoptic area (A13-14.5, L3.5 V-3.5 to -3.7) and lateral hypothalamic regions (A12.5, L2.5-3.5, V-3.7). It consisted of a goal directed attempt to get out of the cage with a vigorous leaping to foot. Norepinephrine when microinjected in 10 micrograms doses into pretectal area of midbrain (A3.5, 3.0, V+1.0 to +1.5 mm) significantly lowered the mean current strength from 640uA to 420uA; clonidine, an alpha-2 agonist in 5 micrograms dose when microinjected into the same locus also significantly lowered the mean current strength to the same level. On the other hand yohimbine, an alpha-2 blocker in 5 micrograms dose when microinjected in to the same locus significantly increased the mean current strength from 640 to 970 uA. These results indicate that hypothalamically induced flight response is mediated via the alpha-2 adrenoceptive mechanism operating at the midbrain level. Control microinjection of normal saline and propylene glycol in similar volumes failed to produce any changes in current strength.

Midbrain adrenergic mechanism modulating predatory attack behaviour induced by hypothalamic stimulation.

The present study was carried out in ten cats which did not attack the rats spontaneously. Predatory attack on a rat was produced by lateral hypothalamic stimulation using mean current strength of 340-690uA. This attack was accompanied by minimal affective display and culminated in neck biting. It was found that norepinephrine (NE) when microinjected into dorsal periaqueductal gray (dPAG) region in doses of 2, 4 and 10ug significantly lowered the mean current strength required for the elicitation of predatory attack by hypothalamic stimulation. Microinjection of propranolol (Prop), a beta-blocker, within the same region in similar doses significantly blocked the response as indicated by the increase in current strength required to produce the response. Control injections of normal saline and propylene glycol failed to produce any change. These findings indicate that hypothalamically induced aggressive responses involves beta adrenoceptive mechanisms located in the dPAG.

Comparative bioavailability of slow release diclofenac (Voveran SR) with enteric coated tablet and internationally used Voltaren Retard.

The objective of the study was to compare the enteric coated diclofenac sodium (Voveran), the slow release formulation developed in India (Voveran SR) and the internationally marketed formulation Voltaren Retard. Ten healthy volunteers were administered 100 mg each of the three formulations in a three-way crossover fashion. Blood samples were collected over 24 hours following administration of the drug; plasma levels of unchanged drug were determined by gas chromatography. Pharmacokinetic parameters for the three formulations were compared. The extent of the drug available from the three formulations was the same as the mean AUC values were not significantly different. Cmax and MRT values for the two slow release formulations were comparable but were significantly different from the values obtained with the enteric coated formulation. Tmax values for the two slow release formulations were similar while the enteric coated tablet had faster time to peak. Voveran SR is comparable to Voltaren Retard and has the distinct advantage of a slow release formulation in that its Cmax is much lower and levels are maintained over 12 hours and detectable upto 24 hours. This slow release formulation will offer clinical advantages of better compliance, relief of early morning symptoms and better tolerability over long term usage.