Biomedical subjects
Publications and source records attributed to G M De Montis.
B-HT 920, a selective DA autoreceptor agonist, reduced motor activity in rats. Chronic, but not acute, treatment with imipramine (IMI) reversed this effect. The mechanism by which chronic IMI reverses the B-HT 920 effect is discussed.
The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D2 receptor agonist, SKF 38393, a selective D1 receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed by L-sulpiride, a D2 antagonist, and by a combination of reserpine with alpha-methyltyrosine (alpha-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D1 antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D2 receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D1 receptor level.
Repeated electroconvulsive shock (ECS) exposure produced a decrease of [3H]SCH 23390 binding sites and a reduced response of adenylate cyclase activity to dopamine D-1 receptor stimulation in the rat limbic area analogous to that previously observed in rats chronically treated with imipramine. These effects were completely prevented by the repeated administration of a small dose of alpha-methyl-p-tyrosine (alpha-MPT), associated with the tricyclic compound. Increased dopaminergic transmission seems to be involved in the mechanism of antidepressant action. Rats chronically treated with imipramine showed a decrease of dihydroxyphenylacetic acid (DOPAC) concentration restricted to the limbic area. Finally, both imipramine and desipramine blocked the uptake of [3H]dopamine in the limbic system with a 100-fold greater potency than that observed in the basal ganglia.
Long-term administration of imipramine to rats produced an increase in the Vmax of forskolin- or guanylylimidodiphosphate (Gpp(NH))p-activated adenylate cyclase only in the limbic area. This effect was prevented by the daily administration of alpha-methyl-p-tyrosine (alpha-MPT), given together with imipramine, at a dose (50 mg/kg) which had no effect on adenylate cyclase activity per se. The time course of the effects of chronic imipramine on dopaminergic transmission in the limbic area showed that the decrease in both D-1 receptor number and adenylate cyclase stimulation by dopamine (DA) reached significance on day 8 of treatment and were maximal on day 15. The Vmax of the enzyme started to increase on day 15 and was further increased on day 21. Possible mechanisms underlying these effects are discussed.
[3H]SCH 23390 binding and dopamine (DA)-stimulated adenylate cyclase activity were measured in brain membrane preparations from rats chronically treated with imipramine (10 mg/kg twice daily for 14 days). [3H]SCH 23390 binding sites were decreased by 27% in the limbic system but only 14% in the striatum. The responsiveness of adenylate cyclase to DA was reduced by 38% in the limbic system but was not modified in the striatum. Concomitant treatment with alpha-methyltyrosine (alpha-MPT) (50 mg/kg daily for 14 days) prevented the imipramine-induced reduction in both [3H]SCH 23390 binding sites and the responsiveness of adenylate cyclase to DA.
Rats made tolerant to morphine show neither a change in brain opiate receptor number nor altered sensitivity to the inhibitory effect of opiates on striatal adenylate cyclase (AC) activity. Interestingly, SCH 23390, a selective blocker of D1 dopamine (DA) receptors which, given chronically to rats, induces a 32% increase in D1 receptor number and increases the Vmax of D1-stimulated striatal AC, resulted in marked resistance to acute morphine effects. In particular, rats chronically treated with SCH 23390 failed to show muscular rigidity and increased striatal dihydroxyphenylacetic acid (DOPAC) concentration after morphine. Moreover, basal striatal AC activity in these animals had a significantly reduced sensitivity to opiate inhibition. On the other hand, decreased AC sensitivity to acetylcholine (ACh) inhibition observed in the striatum of rats chronically treated with DFP, an irreversible blocker of acetylcholinesterase, appeared to be secondary to the downregulation of muscarinic receptors and thus did not modify the opiate inhibitory capacity. It was concluded that although a potentiation of striatal AC impairs opiate action, such mechanism is not involved in morphine tolerance.
D-Ala2, D-Leu5-enkephalin (DADLE) and dynorphin1-13 (Dyn1-13) inhibited striatal adenylate cyclase activity, both basal and dopamine-stimulated (DA), in rats and guinea pigs. The kappa-agonists bremazocine (BRZ), U-50,488 (trans-3,4-dicloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), and U-69,593 (5 alpha, 7 alpha 8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl-1-oxaspiro (4.5)dec-8yl) benzeneacetamide inhibited only the basal adenylate cyclase activity, and such an effect was restricted to guinea pig striatum, an area known to contain a high density of kappa-binding sites. Moreover, BRZ was found to antagonize the inhibitory effect of both DADLE and Dyn1-13 in rat striatum.
Female rats were made dependent to high doses of morphine (400 mg/kg per day) or methadone (60-80 mg/kg per day) and subsequently exposed to adult males. None of the morphine-dependent rats became pregnant while there were no differences in the gestation time and number of young in the litter born to each rat in the methadone and the control groups. The values for muscarinic, serotonergic and opiate receptors measured in the whole brain of the offspring at 1 and 7 days after birth were similar in the control and in the methadone-exposed animals. Brain beta-receptors were lower in rats exposed in utero to methadone at 1 and 7 days. [3H]IMI binding sites were steadily and significantly lower in the whole brain of rats born to methadone-dependent animals than in the brain of controls. In 2 month old animals, the decrease of [3H]IMI binding capacity was associated with a decrease of [3H]5HT uptake. In the light of these findings the authors propose a unifying hypothesis to explain the altered reactivity to morphine of animals treated with opiates during gestation.
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The perikarya of the dopaminergic and non-dopaminergic neurons contained in the substantia nigra were selectively destroyed by a proper, local injection of 6-hydroxydopamine or kainic acid, respectively. Both lesions resulted in a marked decrease of the nigral GABA-binding sites. The effect of 6-hydroxydopamine was restricted to the high affinity receptors, while kainic acid specifically decreased the low affinity ones.
The intranigral injection of kainic acid (k.a.) (3.5 nM/s.n.) produced a lesion which resulted in a decreased muscarinic receptor binding capacity and in a decreased choline acetyl transferase (CAT) activity confined to the pars reticulata. The unilateral, intranigral injection of carbachol in the substantia nigra (s.n.) produced turning, ipsilateral to the injected side, of dose-related intensity, which was antagonized by scopolamine given either i.p. or intranigrally together with carbachol. The bilateral, intranigral injection of carbachol produced rigid catalepsy, highly resistant to apomorphine administration and antagonized by scopolamine. On the other hand, the catalepsy produced by intranigral picrotoxin was much more sensitive to apomorphine and was disrupted by systemic scopolamine administration. Intranigral scopolamine per se produced either contralateral turning or stereotyped movements consistently, when injected unilaterally or bilaterally, respectively. In addition, scopolamine injected bilaterally in the s.n. but not in the caudate nucleus (c.n.), at the concentration of 64 nM side, was able to antagonize the haloperidol-induced catalepsy and to prevent the tremors and the muscular rigidity produced by arecoline. This effect of scopolamine was surmountable with a higher dose of arecoline. Finally, intranigral muscimol (0.44 nM/s.n.) prevented the occurrence of the parkinsonian syndrome produced by systemic arecoline. It is concluded that the muscarinic receptors present in the s.n. pars reticulata play a role in the control of posture opposite to that of the nigral GABA receptors.
The unilateral, intranigral administration of kainic acid (k.a.) produced a syndrome characterized by early sequelae of contra- and ipsilateral circling and by a chronic contralateral turning associated with moderate loss of neurons in the pars reticulata. The acute contralateral circling seems to be related to dopaminergic nigro-neostriatal neuron stimulation, since it was prevented by previous intranigral injections of 6-OHDA. The acute ipsilateral circling and the chronic contralateral turning, on the other hand, seem to be independent of the integrity of the dopaminergic system and may be due to an initial stimulation, followed by destruction, of a nigral neuronal system which mediates turning behavior in a manner opposite to that of nigro-striatal dopamine. Treatment with D-amphetamine or apomorphine changed the contralateral into ipsilateral turning, while haloperidol potentiated the contralateral turning. Bilateral injection of k.a. into the nigra resulted in chronic stereotyped sniffing and gnawing, which were not inhibited by haloperidol. Moreover, haloperidol did not produce catalepsy in these animals. It is suggested that the intranigral k.a. injection destroyed a neuronal system antagonistic to dopamine and resulted in a reduction of the response to DA-receptor stimulation of the c. striatum.
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Morphine given to rats fed ad libitum increased the striatal levels of DA and DOPAC while naloxone had no effect. Conversely, after prolonged fasting, morphine failed to increase both DA and DOPAC, while naloxone markedly decreased striatal DOPAC concentration. Intermediate sensitivity to the DOPAC increasing effect of morphine and to the DOPAC decreasing effect of naloxone was present in rats trained to eat their daily meal within 2 h, at different times after feeding. It is concluded that striatal DA synthesis in fasted rats is sustained by an increased endorphin-like activity.
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