JoséA. Fuentes

Antidepressants selectively antagonize the hyperactivity induced in rats by long-term isolation

Rats isolated at 16--18 days of age showed after 10--12 months a complex behavioural syndrome in which locomotor activity was markedly increased when compared to that of group-housed controls. The hyperactivity of the socially deprived animals was selectively blocked by clinically effective antidepressants but not by other classes of psychotropic drugs. The present animal model may be of value for the detection of new antidepressants and contribute to elucidate the aetiology of depression.

Chronic antidepressant treatment increases enkephalin levels in n. accumbens and striatum of the rat.

Chronic (21 consecutive days) and not acute administration of typical (clomipramine, desipramine, amitriptyline) or atypical (iprindole, nomifensin) antidepressant drugs was found to provoke a selective increase in [Met5]enkephalin-like immunoreactivity ([Met5]ELI) in striatum and nucleus accumbens of rat brain. In parallel experiments, following chronic treatment with clomipramine, iprindole and nomifensin striatal [Leu5]enkephalin-like immunoreactivity ([Leu5]ELI) was also significantly enhanced. No variations in enzymatic activity of either enkephalinase or aminopeptidase were detected when assayed in several brain parts of animals chronically treated with antidepressants. Elevation of ELI in discrete regions of the brain might play a part in the mechanism of action of these centrally acting agents.

Further studies on the antagonism of stereotyped behaviour induced by amphetamine

Abstract High doses of d -amphetamine cause stereotyped behaviour in rats and an absence of many normal activities such as exploratory motor activity. The antagonism of these two effects of amphetamine was studied by pretreatment with several neuroleptic, adrenolytic and cholinergic drugs. It was found that some neuroleptic drugs antagonized, within a certain dose range, abnormal behaviour with a concomitant increase of exploratory motor activity. The most active drugs in this sense were chlorpromazine and perphenazine. No significant effect was observed with the adrenolytic or cholinergic drugs studied. Some possible implications of the motor reversal by neuroleptic drugs are discussed.

Evidence for a central but not adrenal, opioid mediation in hypertension induced by brief isolation in the rat

Naloxone was found to provoke a hypotensive effect related to the dose on high blood pressure (BP) induced by short-term isolation in young rats. Another opiate antagonist, nalorphine, also reduced the arterial pressure of socially deprived rats. In contrast, naltrexone methylbromide that selectively blocked peripheral opiate receptors did not alter the elevated BP. To investigate whether adrenomedullary opioids were somehow implicated in the development of isolation-induced hypertension, bilaterally adrenalectomized rats were kept under social deprivation for 7 consecutive days. The data obtained indicated that high systolic BP developed in the same manner as in intact rats run in parallel. In conclusion, central opioids appear to be involved in BP elevation due to the stress generated by brief social deprivation in young rats.

Central mediation of the antihypertensive effect of pargyline in spontaneously hypertensive rats

The monoamine oxidase (MAO) inhibitor pargyline induced a moderate (about 20 mm Hg) but persistent (48 h) decrease of systolic blood pressure in unanesthetized adult spontaneously hypertensive rats (SHR) but not in normotensive rats. The fall of blood pressure correlated with the blockade of norepinephrine (NE) deamination by brain homogenates. After an intracerebroventricular (icv) injection of 6-hydroxydopamine, which lowered brain NE content by about 70%, pargyline was unable to diminish arterial pressure. Blockade of central alpha-adrenoceptors by treatment with phentolamine (100 microgram icv) could either prevent or reverse the fall of blood pressure in SHR induced by pargylline. Moreover, a low dose of pargyline injected directly into the brain lowered arterial pressure. We conclude that the hypotensive action of pargylline in SHR appears to be the consequence of NE accumulating at an inhibitory alpha-adrenoceptor in brain.

Hypotensive effect of naloxone on high blood pressure induced by stress in the rat

A naloxone-reversible enhancement of systolic blood pressure (BP) was induced in rats by application of three different types of stressor, i.e. intense light and sound, cold and foot-shock. In the case of labile high BP provoked by short-term isolation, the opiate antagonist naloxone (1 mg/Kg, i.p.) was also found to reverse hypertension. Naltrexone (2.5 mg/Kg, i.p.) also diminished high BP readings of briefly isolated rats. Conversely, blockade of the opiate receptor with naloxone did not alter elevated BP in cases of established hypertension (spontaneously hypertensive rats, deoxycorticosterone (DOCA)-salt rats and long-term isolated rats). These data can be taken as an evidence of opioid involvement at the onset of high BP readings induced by stress. However, once hypertension becomes established, the opioid system appears to recover its silent features.

β-Endorphin: A common factor in the antihypertensive action of clonidine-type imidazolines in spontaneously hypertensive rats

1. n1. The hypotensive action of two novel imidazolinic α-adrenergic agonists (ICI-106270 and UK-14304) with similar pharmacological properties to clonidine was shown in spontaneously hypertensive (SH) rats. n n2. n2. The antihypertensive effect of the clonidine-type agents was prevented by either peripheral administration of the opiate antagonist naloxone or by intracerebroventricular (i.c.v.) injection with a specific antibody against human β-endorphin (BEN). n n3. n3. A dose-response relationship was found for the hypotensive effect of i.c.v. given BEN in SH rats, the low blood pressure being significantly reversed by further treatment with either naloxone or anti-βh-endorphin. n n4. n4. These data confirm and extend the notion of a BEN mediation in the antihypertensive action of clonidine-type α-adrenergic agonists in SH rats.

Effect of selective monoamine oxidase inhibitor drugs on morphine tolerance and physical dependence in mice

Abstract Clorgyline and Lilly 51641, given at dose levels that inhibited selectively brain type A monoamine oxidase (MAO), significantly lowered the incidence of stereotyped jumping produced by naloxone in mice rendered dependent on morphine by subcutaneous implantation of a pellet of the drug. In contrast, selective inhibition of brain type B MAO by deprenyl or pargyline, or nonspecific inhibition of both type A and type B MAO by high doses of Lilly 51641 or pargyline did not modify the abstinence syndrome. Tolerance to the analgesic effect of morphine was unchanged regardless of the enzyme form blocked. The attenuation of withdrawal jumping by low doses of clorgyline or Lilly 51641 does not seem related to changes in brain dopamine. which was found to be deaminated by both enzyme types. The results suggest the possible implication of different and interrelated neurochemical systems in the development of morphine dependence in mice.

Potentiation of morphine analgesia in mice after inhibition of brain type b monoamine oxidase

Abstract Morphine analgesia in mice was significantly potentiated by deprenyl and pargyline, selective inhibitors of brain type B monoamine oxidase (MAO). Clorgyline and Lilly 51641, selective inhibitors of type A MAO, did not modify the morphine effect. Morphine analgesia was also potentiated by increasing the dose of Lilly 51641 so as to block type B MAO by about 70%, or by inhibiting unspecifically both enzyme forms after either tranylcypromine or high doses of pargyline. No general correlation was found between an increased brain concentration of morphine and the enhancement of morphine analgesia induced by some of the MAO inhibitors tested. 2-Phenylethylamine, a specific substrate of type B MAO, was also found to potentiate morphine analgesia. It is suggested that endogenous substrates of type B MAO may modulate the opiate receptor binding.

Striatal homovanillic acid levels in rats after combined treatments with amphetamine and neuroleptics

Abstract Dextro-amphetamine, 10 mg/kg, antagonized the rise of striatal homovanillicacid induced by chlorpromazine, 4 mg/kg, and potentiated the rise induced by triperidol, 0.25 mg/kg. Te results suggest that different mechanisms may be involved in the mode of action of these two neuroleptics at the level of brain dopaminergic receptors.