Mechanism of action of clozapine-induced modification of motor behavior in an animal model of the "super-off" phenomenon.

We tested the effects of clozapine, and "atypical" neuroleptic with high affinity for the D4 (dopaminergic), and the 5-HT1c and 5-HT2 (serotonergic) receptor subtypes on locomotor activity in an animal model of Parkinson's disease showing a bimodal response curve to increasing doses of a D2 agonist. Sulpiride (D2 antagonist) and ritanserin (5-HT1c and 5-HT2 antagonist) were used for comparison. The D1 agonist SKF 38393 at a dose of 8 mg/kg significantly reversed the akinesia induced by chronic reserpine treatment (1 mg/kg for 5 days) and alpha-methyl-p-tyrosine pretreatment (300 mg/kg). In this model, the addition of a low dose of a D2 agonist, LY 171555 (quinpirole, 1 microgram/kg), inhibited the effects of SKF 38393, whereas the same drug at higher doses (5-50 microgram/kg) restored and potentiated the stimulatory response to D1 stimulation. Clozapine inhibited the inhibitory phase and potentiated the stimulatory phase of the curve. Sulpiride inhibited both phases of the dose-response curve (inhibitory/stimulatory), whereas ritanserin had no effect. We believe these results may reflect a disinhibition phenomenon possible mediated by the blockade by clozapine of a subpopulation of inhibitory, dopamine (DA) receptors belonging to the D2 "family."

Threshold of dopamine content and D1 receptor stimulation necessary for the expression of rotational behavior induced by D2 receptor stimulation under normo and supersensitive conditions.

We measured the minimum amount of endogenous dopamine (EDA), necessary for the expression of rotational behavior induced by D2 receptor stimulation in striatal or medial forebrain bundle (MFB) lesioned rats. We correlated these results with the minimum dose of D1 receptor agonists needed to substitute EDA in its permissive role for D2 motor effects to take place. Rats with unilateral quinolinic acid (QA) striatal or 6-hydroxydopamine (6-OHDA) MFB lesions were given increasing doses of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT) in combination with a fixed dose of the D2 receptor agonist quinpirole (trans-(-)-4aR-4,4a,5,6,7,8,8a,9-Octahydro-5-propyl-1H-pyrazolo(3, 4-g) quinoline hydrochloride) and tested for rotational behavior. The animals were later sacrificed and striata removed; EDA was measured by high performance liquid chromatography (HPLC). Rotational responses were abolished by increasing doses of AMPT inducing a stepwise depletion of EDA. EDA content and rotational behavior to D2 stimulation showed a high degree of correlation. There was an abrupt reduction in rotational behavior at dopamine levels of 50-60% of controls in both animal models. In addition, striatal or MFB lesioned rats which were maximally depleted of dopamine by AMPT pretreatment received a fixed dose of quinpirole and then challenged with increasing doses of a D1 receptor agonist SKF 38393 ((+/-)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride). Rotational behavior was restored by SKF 38393 in both animal models in a dose-dependent fashion. Our results confirm the need for simultaneous D1/D2 stimulation in the generation of rotational behavior in both animal models. Moreover, they demonstrate the existence of a threshold level of D1 stimulation necessary to exert its permissive role on D2 mediated responses.

Adaptive mechanisms of striatal D1 and D2 dopamine receptors in response to a prolonged reserpine treatment in mice.

Mice receiving reserpine (1 mg/kg/day) during 5 days develop behavioral supersensitivity. To study the possible molecular correlates of these adaptive changes we compared binding parameters of D1 and D2 receptors and adenylate cyclase activity in striata from normal and reserpinized mice. Saturation curves using [3H]SCH 23390 showed no changes in maximum binding capacity (Bmax) or Kd of striatal D1 receptors taken from control or 5 days reserpine-treated mice. However, [3H]spiperone saturation curves showed a 31% increase in D2 receptors Bmax with no changes in Kd. Dopamine competition of [3H]SCH 23390 and [3H]spiperone binding in mouse striatum was also performed. Analysis of data by LIGAND showed that dopamine recognizes two subpopulations for D1 and for D2 receptors. The proportion of receptors in the high affinity state (D1high and D2high) were increased in reserpine-treated animals. The addition of 100 microM GTP produced a complete conversion of D1high and D2high receptors into their low-affinity states in striata from control and reserpinized mice. Five days of reserpine treatment increased basal adenylate cyclase activity of mouse striatum in the presence of Mn++ or Mg++ ions. Concentration curves with dopamine, NaF or forskolin revealed shifts to the left and higher maximum responses without changes in EC50 values in striata from reserpinized mice. Thus, a prolonged reserpine treatment produces marked changes in D1 and D2 receptors increasing the proportion of high affinity state subpopulations and the total Bmax of D2 receptors. Also, dopamine function may be enhanced through an increment of the catalytic component of striatal adenylate cyclase.

Physiological role of alpha-adrenoceptors in salivary secretion.

The submaxillary gland (SM) of rat is innervated by both branches of the autonomic nervous system. Secretion is mediated by the activation of both muscarinic-cholinergic and alpha/beta adrenergic receptors. Studies of the relative affinity of pharmacological agonists and antagonists have warranted a subclassification of alpha adrenoceptors into types alpha 1 and alpha 2. Our studies involve an analysis of the physiologic role of both types of alpha adrenoceptors in salivary secretion. Dose response curves (DRC) to noradrenaline (NA) following administration of alpha adrenoceptor antagonists, i.e. prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) and phentolamine (alpha 1-alpha 2 antagonist) were constructed. Our results demonstrate that prazosin is 100 times more effective than yohimbine in blocking NA-induced salivary secretion. The alpha 2 agonist clonidine (10 micrograms/Kg) blocked the DRCs to methacholine, noradrenaline and substance P-but failed to modify the DRC to isoproterenol. Our results reveal that the subtypes of alpha adrenergic receptors play antagonistic roles in salivary secretion. Alpha 1 stimulation elicits profuse salivary secretion whereas alpha 2 stimulation inhibits salivary secretion induced by 3 different types of agonists, i.e. alpha 1, muscarinic-cholinergic and neurokininergic without affecting beta receptor mediated responses.

Physiological role of alpha-adrenoceptors in salivary secretion

The submaxillary gland (SM) of rat is innervated by both branches of the autonomic nervous system. Secretion is mediated by the activation of both muscarinic-cholinergic and alpha/beta adrenergic receptors. Studies of the relative affinity of pharmacological agonists and antagonists have warranted a subclassification of alpha adrenoceptors into types alpha 1 and alpha 2. Our studies involve an analysis of the physiologic role of both types of alpha adrenoceptors in salivary secretion. Dose response curves (DRC) to noradrenaline (NA) following administration of alpha adrenoceptor antagonists, i.e. prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) and phentolamine (alpha 1-alpha 2 antagonist) were constructed. Our results demonstrate that prazosin is 100 times more effective than yohimbine in blocking NA-induced salivary secretion. The alpha 2 agonist clonidine (10 micrograms/Kg) blocked the DRCs to methacholine, noradrenaline and substance P-but failed to modify the DRC to isoproterenol. Our results reveal that the subtypes of alpha adrenergic receptors play antagonistic roles in salivary secretion. Alpha 1 stimulation elicits profuse salivary secretion whereas alpha 2 stimulation inhibits salivary secretion induced by 3 different types of agonists, i.e. alpha 1, muscarinic-cholinergic and neurokininergic without affecting beta receptor mediated responses.

Physiological role of alpha-adrenoceptors in salivary secretion.

The submaxillary gland (SM) of rat is innervated by both branches of the autonomic nervous system. Secretion is mediated by the activation of both muscarinic-cholinergic and alpha/beta adrenergic receptors. Studies of the relative affinity of pharmacological agonists and antagonists have warranted a subclassification of alpha adrenoceptors into types alpha 1 and alpha 2. Our studies involve an analysis of the physiologic role of both types of alpha adrenoceptors in salivary secretion. Dose response curves (DRC) to noradrenaline (NA) following administration of alpha adrenoceptor antagonists, i.e. prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) and phentolamine (alpha 1-alpha 2 antagonist) were constructed. Our results demonstrate that prazosin is 100 times more effective than yohimbine in blocking NA-induced salivary secretion. The alpha 2 agonist clonidine (10 micrograms/Kg) blocked the DRCs to methacholine, noradrenaline and substance P-but failed to modify the DRC to isoproterenol. Our results reveal that the subtypes of alpha adrenergic receptors play antagonistic roles in salivary secretion. Alpha 1 stimulation elicits profuse salivary secretion whereas alpha 2 stimulation inhibits salivary secretion induced by 3 different types of agonists, i.e. alpha 1, muscarinic-cholinergic and neurokininergic without affecting beta receptor mediated responses.

Positive interaction between alpha-1 adrenergic and dopamine-2 receptors in locomotor activity of normo and supersensitive mice.

In normosensitive mice either the D1 antagonist SCH 23390 or the D2 antagonist sulpiride inhibited the reversion of reserpine-induced akinesia elicited by the mixed D1/D2 agonist pergolide. In mice rendered supersensitive by a five days' reserpine treatment, sulpiride did not prevent the pergolide-induced reversal of akinesia while SCH 23390 disclosed two subpopulations of mice. One population responded to pergolide with marked locomotor activity whereas in the other subpopulation this response was absent. However, all mice challenged with pergolide failed to reverse reserpine-akinesia after alpha-methyl-p-tyrosine (AMPT) pretreatment. The alpha 1/alpha 2 agonist clonidine restored the ability of pergolide to overcome reserpine akinesia in supersensitive mice pretreated with SCH 23390. Clonidine reversed the akinesia in supersensitive mice but in normal animals it did not. However, in these last conditions, the combined use of clonidine plus the D2 agonist LY 171555 was effective to induce locomotion. Neither AMPT nor SCH 23390 inhibited this response whereas the alpha-adrenergic antagonists prazosin and yohimbine did prevent it. The alpha 2 agonist B-HT 920 failed to induce locomotor responses when given together with LY 171555. The same occurred with the D1 agonist SKF 38393 when given together with clonidine. The combined use of SCH 23390 plus prazosin in chronic reserpinized mice prevented pergolide-induced locomotion. Adrenergic stimulation, acting on alpha 1 receptors, could be an alternative to D1 stimulation as a necessary factor to obtain D2-induced motor responses under normo and supersensitive conditions.

Amphetamine antagonizes the presynaptic inhibitory effect of clonidine through an interaction at the level of the alpha 2-adrenoceptors.

1. In the whole rat vas deferens 20 microM noradrenaline (NA) and 0.011 microM clonidine decreased (36 +/- 7.4% and 80 +/- 6.0% respectively) the motor response induced by hypogastric nerve stimulation. These effects were reverted by 1 microM yohimbine. Amphetamine 5.4 microM failed to antagonize the inhibitory effect of NA and attenuated clonidine effect. 2. The effect of amphetamine was not altered by preincubation with either cocaine 1 microM, (-)-propranolol 0.3 microM or cocaine plus prazosin 0.028 microM. 3. In reserpine pretreated animals amphetamine 5.4 microM shifted to the right the concentration-response curve (CRC) to clonidine 0.62 +/- 0.05 log units with a KB value of 1.83 +/- 0.30 microM. 4. Binding of [3H]clonidine and [3H]prazosin were inhibited by amphetamine. Amphetamine was 90 times more potent to inhibit [3H]clonidine binding. 5. The results obtained suggest a possible direct interaction between clonidine and amphetamine on alpha-adrenoceptor.

Potassium-evoked efflux of [3H]purines from the rat submaxillary gland.

1. Normal, atrophied and denervated submaxillary glands were incubated with [3H]adenine for 1 h. The accumulation of [3H]adenine, expressed as microCi/g tissue, did not differ significantly when the sympathetically denervated glands were compared with the control group. The radioactivity retained in both control and denervated tissues was also similar. 2. In atrophied glands 3H-accumulation as well as 3H-retention were 2-fold higher than these obtained in controls per unit weight, but 30% lower when expressed per gland. 3. The spontaneous efflux of radioactivity, expressed as fractional release, from normal, atrophied and denervated glands prelabelled with [3H]adenine was similar. 4. The outflow of radioactivity was enhanced by exposure of the tissues to 60 mM K+ during 2.5 min. 5. In all three groups, the purine release induced by K+ was the same. 6. Phentolamine 3.1 microM enhanced the K+-induced release of [3H]purine compounds in control and atrophied glands but not in denervated glands. 7. Propranolol 0.3 microM produced no changes among the three experimental groups. 8. Atropine 1 microM and phentolamine 3.1 microM plus atropine 1 microM did not modify the release of tritiated purine compounds in control and denervated glands. 9. Our results cannot discriminate between neuronal or non-neuronal elements as the source of purines released by depolarization but suggest that classical pharmacological tools such as phentolamine and atropine may affect purine metabolism in a complex fashion.

Pharmacological activity of novel alkylsulfonylaryl-1-substituted-1,4-benzodiazepine derivatives.

A series of 1-alkylsulfonylaryl-1,4-benzodiazepine derivatives were synthesized and assayed for their pharmacological profile. All the compounds tested exhibited a competitive antagonism of 3H-diazepam binding in cerebellum, cerebrum and submaxillary gland. Compound II (rec. INN tolufazepam) had a Ki of 12.7 nM in cerebrum and 400 nM in the submaxillary gland. It was very potent in preventing convulsions elicited by pentylenetetrazol (ED50 p.o.: 16.5 and ED50 i.v.: 20 mg/kg). This anticonvulsant action was suppressed by previous administration of Ro 15-1788. Compound II was also active in inhibiting suppressive behaviour in the test of Vogel. This compound has a relative low hypnogenic activity as well as a low potency to produce motor incoordination. Our results show that tolufazepam has a potential clinical usefulness.

Different roles of D-1 and D-2 dopamine receptors involved in locomotor activity of supersensitive mice.

Simultaneous stimulation of both D-1 and D-2 receptors is necessary to reverse reserpine-induced akinesia in mice. The effect of supersensitivity on locomotor function was studied in mice after treatment with reserpine for five days. The response of these animals to a mixed D-1/D-2 agonist, pergolide, or to a presynaptic dopamine (DA) releaser, amphetamine, was increased 3-fold, indicating behavioural supersensitivity. Under these conditions, both selective D-1 and D-2 dopamine receptor agonist (SKF 38393 and LY 171555, respectively), given separately, induced locomotor activity. The D-1 antagonist, SCH 23390, inhibited the effect of both SKF 38393 and LY 171555, whereas the DA synthesis inhibitor, alpha-methyl-p-tyrosine (AMPT), and the D-2 antagonist, sulpiride, only abolished the effect of LY 171555. Moreover, AMPT increased the response to SKF 38393 by 80%. The amphetamine-mediated responses were abolished by SCH 23390 whereas sulpiride did not block them. Thus, stimulation of the D-1 receptor seems crucial in supersensitive animals. In another set of experiments, AMPT was administered to mice pretreated with reserpine for five days in order to fully deplete DA stores. Low doses of LY 171555 reduced the response of these animals to SKF 38393 by 60% whereas higher doses potentiated it. This bimodal effect of LY 171555 was blocked by sulpiride. Since amphetamine was unable to reverse the reserpine-induced akinesia in these mice, we can conclude that the inhibitory effect of LY 171555 is not related to presynaptic inhibition of DA release.

Exocrine secretion of immunoreactive erythropoietin from the rat submaxillary gland.

The physiological role of immunoreactive erythropoietin (iEp) in rodent submaxillary glands (SMG) is largely unknown. We studied in vivo the effects of cholinergic and adrenergic agents in male rats with respect to exocrine secretion of iEp into saliva. Intravenous administration of metacholine (20 micrograms/kg), norepinephrine (30 micrograms/kg), and isoproterenol (30 micrograms/kg) resulted in equal volumes of saliva over 1 h. None of the drugs altered circulating plasma levels and kidney concentrations of iEp. Salivary secretions induced by either norepinephrine or isoproterenol, both adrenergic agonists, contained high levels of iEp and a significant depletion of gland content was observed, suggesting that SMG exocrine iEp secretion is mediated by adrenergic receptors. In contrast, metacholine-stimulated glands retained their full iEp content and iEp was undetectable in saliva, indicating that cholinergic activity is not associated with exocrine secretion of iEp from SMGs.

Postsynaptic bimodal effect of sulpiride on locomotor activity induced by pergolide in catecholamine-depleted mice.

In reserpinized (5 mg/kg, s.c.) mice treated with alpha-methyl-p-tyrosine (200 + 100 mg/kg, i.p.), increasing doses of the D-2 antagonist sulpiride had varying effects on locomotor activity induced by the mixed D-1/D-2 agonist pergolide (2 mg/kg, s.c.). Low doses of sulpiride (1 mg/kg, i.p.) significantly enhanced this activity whereas at higher doses (50 mg/kg) an inhibitory effect was observed. Amphetamine (3 mg/kg, i.p.) failed to reverse akinesia in this animal model, precluding the possibility of a presynaptically mediated phenomenon; in contrast, mice receiving reserpine alone showed a high degree of locomotor activity when challenged with amphetamine. The bimodal effect of sulpiride is thought to be mediated either by two different D-2 receptors located on the same cell or by the same receptor with different topographical localization on postsynaptic neurons mediating opposite functions.

Interaction between amphetamine and alpha 2-postsynaptic adrenoreceptors in the rat submaxillary gland.

1 The interaction between amphetamine and the alpha 2-adrenoreceptor agonists, clonidine and guanabenz, was studied in the submaxillary gland of anaesthetised rats. 2 Low doses of clonidine (10 micrograms/kg) and guanabenz (10 micrograms/kg) inhibited the secretory responses induced by methacholine and substance P, respectively. 3 Amphetamine (300 micrograms/kg) antagonized the inhibitory effects of both alpha 2-agonists. This dose of amphetamine alone did not show sialagogic effects. 4 Atropine (1 micrograms/kg) diminished the secretory responses to methacholine as much as clonidine (10 micrograms/kg). Amphetamine did not modify the blockade by atropine. 5 Guanabenz (10 micrograms/kg) markedly decreased the secretory responses to substance P, an effect that was also prevented by amphetamine. 6 Reserpine pretreatment (5 mg/kg, i.p., 18 h) did not alter the effect of amphetamine. 7 These results indicate that the interaction between amphetamine and alpha 2-adrenoreceptor agonists is unrelated to the indirect effect of this amine and suggest a direct interaction between the drug and postsynaptic inhibitory alpha 2-adrenoreceptors.

Sympathetic and parasympathetic nerves regulate postsynaptic alpha-2 adrenoceptor in salivary glands.

The effects of sympathetic denervation or parasympathetic decentralization on the inhibitory effects of postsynaptic alpha-2 adrenoceptors were studied in the submaxillary and the sublingual gland of the rat. Chronic sympathetic denervation enhanced by a factor of 10 the potency of clonidine to inhibit the secretory responses of the submaxillary gland to either norepinephrine or methacholine. In denervated glands, clonidine (1 microgram/kg), reduced markedly the response to norepinephrine, but potentiated this response in control glands. Blockade of postsynaptic alpha-2 adrenoceptors with idazoxan (3 micrograms/kg) enhanced the secretory responses of denervated glands to norepinephrine. Parasympathetic decentralization also potentiated the inhibitory effects of the alpha-2 agonists. In the submaxillary gland the potency of guanabenz to decrease the secretory response to methacholine was increased by a factor of 30. Supersensitivity to the inhibitory effects of clonidine was also observed in parasympathetically decentralized sublingual glands. Parasympathetic decentralization increased the maximum binding site of [3H]clonidine binding by about 50% in both the submaxillary and sublingual glands. No changes in KD were detected. This surgical procedure also increased the maximum binding site of [3H]prazosin binding in submaxillary glands. The present findings show clearly that interruption of either branch of the autonomic nervous system induces supersensitivity of the inhibitory response mediated through postsynaptic alpha-2 adrenoceptors. The enhanced inhibitory activity could mask alpha-1 adrenoceptor supersensitivity after postganglionic sympathetic denervation.

Blockade of postsynaptic alpha 2-adrenoceptors enhances responses to mixed alpha 1/alpha 2-agonists in rat submaxillary gland.

The effects of selective blockade of alpha 2-adrenoceptors with idazoxan on salivary secretion elicited by several alpha-adrenoceptor agonists known to differ in their alpha 1/alpha 2 potency ratios were studied in the submaxillary gland. Doses of idazoxan ranging between 0.01 to 10 000 micrograms/kg did not produce secretion in anaesthetized rats. Idazoxan (3 micrograms/kg) effectively blocked the inhibitory action of clonidine, 10 micrograms/kg, on the responses to methacholine but did not change the sialagogic responses to either phenylephrine or isoprenaline. On the other hand, idazoxan enhanced the secretion elicited by other agonists known to have mixed alpha 1/alpha 2-agonistic properties. The degree of augmentation of the responses observed after alpha 2 blockade was: clonidine much greater than alpha-methyl-norepinephrine greater than norepinephrine. Guanabenz did not elicit secretory responses in either the presence or absence of idazoxan. These results argue that two components determine the magnitude of the sialagogic response induced by agonists with mixed alpha 1/alpha 2 activity: (a) an alpha 1-mediated secretory effect and (2) an alpha 2-mediated inhibitory effect, both being localized at postsynaptic level.

Inhibition by dopamine of the neurotransmission in the rat vas deferens.

The effects of alpha-adrenoceptor and dopaminoceptor agonists and antagonists were investigated on presynaptic receptors in the prostatic portion of rat vas deferens. The variable studied was the early component (250 msec) of the motor response elicited by field stimulation (single pulses). All the experiments were carried out in the presence of cocaine 30 mumol/l and hydrocortisone 28 mumol/l so as to block the sites of amines loss and 1-propranolol 0.3 mumol/l to block beta-adrenoceptors. Clonidine, noradrenaline (NA) and dopamine (DA) inhibited the motor response in a concentration-dependent manner. DA was 10 and 10(4) times less potent than NA and clonidine respectively. The selective D2 agonist, LY 141865, failed to inhibit the motor response even at a high concentration (30 mumol/l). Yohimbine (0.1, 0.3 and 1 mumol/l) antagonized competitively the effect of clonidine, NA and DA showing similar - log KB values (7.57; 7.68 and 7.09 respectively). Likewise, idaxozan (0.03 mumol/l) blocked the inhibitory effect of DA in the same order of potency (- log KB = 7.81). On the other hand, pimozide 0.21 mumol/l and Schering 23390 3 mumol/l antagonized the inhibitory effect of DA, showing a lower potency than the other antagonists. Taken together, these findings do not support the hypothesis that DA activates a specific population of prejunctional dopaminoceptors to inhibit the motor response elicited by field stimulation in the presence of cocaine, hydrocortisone and 1-propranolol in the prostatic portion of the rat vas deferens. Instead, the population of prejunctional alpha 2-adrenoceptor may be involved.

Inhibition by dopamine of the neurotransmission in the rat vas deferens.

The effects of alpha-adrenoceptor and dopaminoceptor agonists and antagonists were investigated on presynaptic receptors in the prostatic portion of rat vas deferens. The variable studied was the early component (250 msec) of the motor response elicited by field stimulation (single pulses). All the experiments were carried out in the presence of cocaine 30 mumol/l and hydrocortisone 28 mumol/l so as to block the sites of amines loss and 1-propranolol 0.3 mumol/l to block beta-adrenoceptors. Clonidine, noradrenaline (NA) and dopamine (DA) inhibited the motor response in a concentration-dependent manner. DA was 10 and 10(4) times less potent than NA and clonidine respectively. The selective D2 agonist, LY 141865, failed to inhibit the motor response even at a high concentration (30 mumol/l). Yohimbine (0.1, 0.3 and 1 mumol/l) antagonized competitively the effect of clonidine, NA and DA showing similar - log KB values (7.57; 7.68 and 7.09 respectively). Likewise, idaxozan (0.03 mumol/l) blocked the inhibitory effect of DA in the same order of potency (- log KB = 7.81). On the other hand, pimozide 0.21 mumol/l and Schering 23390 3 mumol/l antagonized the inhibitory effect of DA, showing a lower potency than the other antagonists. Taken together, these findings do not support the hypothesis that DA activates a specific population of prejunctional dopaminoceptors to inhibit the motor response elicited by field stimulation in the presence of cocaine, hydrocortisone and 1-propranolol in the prostatic portion of the rat vas deferens. Instead, the population of prejunctional alpha 2-adrenoceptor may be involved.

Effects of guanabenz and guanfacine on postsynaptic alpha 2-adrenoceptors in the rat submaxillary and parotid glands.

The effects of two alpha 2-agonists (guanfacine and guanabenz) on both the submaxillary and parotid gland of the rat were studied. Whereas guanfacine in doses ranging between 1,000 and 30,000 micrograms/kg i.v. produced an immediate and persistent secretion of saliva from the submaxillary gland, guanabenz in doses as high as 40,000 micrograms/kg did not induce measurable secretion either from the parotid or the submaxillary gland. Secretion elicited by guanfacine was not modified by yohimbine (300 micrograms/kg) but was abolished by prazosin (100 micrograms/kg). In both glands, low doses of either guanabenz (10 micrograms/kg) or guanfacine (100 micrograms/kg) markedly inhibited the secretory responses induced by noradrenaline, methacholine and substance P, but not that induced by isoprenaline. The inhibition caused by the alpha 2-agonists was greater for noradrenaline than for either methacholine or substance P. Blockade of alpha 2-adrenoceptors with yohimbine (300 micrograms/kg) did not modify the response to noradrenaline, methacholine or substance P in either gland. However, the same dose of yohimbine injected 5 min before the alpha 2-agonists prevented the inhibitory effects of guanfacine and guanabenz on the response induced by either one of the three sialagogic agents. Guanabenz (10 micrograms/kg) did not modify the increase in mean blood pressure observed after the different doses of noradrenaline employed to induce salivary secretion. Guanabenz (10 micrograms/kg) and guanfacine (100 micrograms/kg) did not change the time course of the secretion elicited by either noradrenaline, methacholine or substance P, since the degree of inhibition was of similar magnitude at all the periods of time analyzed.(ABSTRACT TRUNCATED AT 250 WORDS)