Compulsive sexual activity induced by p-chlorophenylalanine in normal and pinealectomized male rats.

p-Chlorophenylalanine depletes brain serotonin and induces longlasting sexual excitation in male rats. The effect of p-chlorophenylalanine is potentiated by pargyline. Administration of 5-hydroxytryptophan to rats treated with p-chlorophenylalanine plus pargyline blocks the sexual excitation. p-Chlorophenylalanine also elicits sexual excitation in pinealectomized rats; this effect is not mediated by the lack of indole hormones in the pineal but may be the consequence of depletion of 5-hydroxytryptophan in the brain and the resulting imbalance between 5-hydroxytryptophan and catecholamine activity in the central nervous system.

Amphetamine: differentiation by d and l isomers of behavior involving brain norepinephrine or dopamine.

d-Amphetamine is markedly more potent an inhibitor of catecholamine uptake by norepinephrine neurons in the brain than is 1-amphetamine, whereas the two isomers are equally active in inhibiting catecholamine uptake by the dopamine neurons of the corpus striatum. In behavioral studies, d-amphetamine is ten times as potent as 1-amphetamine in enhancing locomotor activity, while it is only twice as potent in eliciting a compulsive gnawing syndrome. This suggests that the locomotor stimulation induced by amphetamine involves central norepinephrine, while dopamine neurons play an important role in the induced compulsive gnawing behavior. Assessment of differential actions of d- and 1-amphetamine may be an efficient method to differentiate behaviors involving norepinephrine or dopamine in the brain.

Compulsive gnawing in rats after implantation of drugs into the ventral thalamus. A contribution to the mechanism of morphine action.

1 Implantation of morphine into various parts of the corpus striatum of rats evokes only weak gnawing responses.2 Deposition of apomorphine, morphine or methadone in the region of the nucleus ventralis thalami produces a biphasic response, i.e. general excitation, followed by a period of intense gnawing.3 The effect of both apomorphine and morphine is blocked by chlorpromazine, haloperidol and pimozide. However, pretreatment with alpha-methyltyrosine methyl ester or alpha-methyldopa prevents only the gnawing response to morphine, but not to apomorphine.4 Systemic nalorphine, morphine or pethidine suppress the gnawing response, evoked by thalamic implants of apomorphine or morphine.5 Systemic amphetamine potentiates the effect of thalamic deposits of morphine.6 Compulsive gnawing, following implantation of morphine into the ventral region of the thalamus, probably results from enhanced production and release of catecholamines.

Influence of pheniramine and chlorpheniramine on apomorphine induced compulsive gnawing in mice.

In mice, apomorphine (10 mg/kg s.c.) does not induce a compulsion to gnaw, but pretreatment with antihistamines, viz. pheniramine, chlorpheniramine and mepyramine, in doses ranging from 30 to 60 mg/kg i.p. caused gnawing activity. Mepyramine showed significantly less effect when compared to the other two agents. Antihistamines are known to influence the activity of biogenic amines in central nervous system. The potentiation of apomorphine-induced gnawing by antihistamines might depend upon the reciprocal balance between dopaminergic and cholinergic systems. This was tested by blocking biosynthesis of biogenic amines or by blocking their receptors. The potentiation of gnawing was antagonised by physostigmine (0.25 mg/kg) or blocked by pretreatment with alpha-methyl-p-tyrosine (alpha-MPT) (4 X 150 mg/kg) and bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulphide (FLA) (40 mg/kg), while p-chlorophenyl alanine (p-CPA) (3 X 100 mg/kg) had no effect. Similarly, phenoxybenzamine (30 mg/kg) and haloperidol (1.0 mg/kg) inhibited gnawing activity, but methysergide (10 mg/kg) had no effect. Furthermore, pretreatment with tetrabenazine (20 mg/kg) and L-Dopa (200 mg/kg) did not affect gnawing activity. It is concluded that both pheniramine and chlorpheniramine potentiate apomorphine gnawing by upsetting the cholinergic and dopaminergic balance in favour of dopaminergic dominance.

Central muscarinic activation elicits compulsive drinking behaviour in the rat.

Injection of bethanechol into the lateral cerebral ventricle of the rat induces a marked increase in drinking, within 30 min from administration. The response is dose-related, maximal water intake (6.1 +/- 0.55 mL; mean +/- s.e.) occurring at 10 micrograms of bethanechol. Peripheral administration of the agonist (up to 3 mg kg-1 i.p.) fails to elicit drinking. Among several specific antagonists only antimuscarinic drugs produced a significant inhibition of the response, suggesting that the compulsive drinking behaviour in the rat is caused by activation of central muscarinic receptors. The drinking behaviour emerges as a reliable test to assess central muscarinic activity of both agonists and antagonists.

Dopamine receptor blocking activity of sulpiride in the central nervous system.

Effects of sulpiride on the central nervous system were studied in catalepsy induction (I) and antagonism to gnawing behaviour (II) induced by apomorphine and methamphetamine in normal rats, and in antagonism to rotational behaviour (III) induced by apomorphine and methamphetamine in rats with substantia nigra unilaterally lesioned chronically by microinjection of 6-hydroxydopamine. Sulpiride was administered orally and intraventricularly, and the effects of sulpiride were compared to those of haloperidol and chlorpromazine administered through the same routes. In oral administration, sulpiride was almost inactive in (I), and was several hundreds to a thousand times less potent than haloperidol in (II) and (III), while chlorpromazine was 20 to 150 times stronger than sulpiride. In intraventricular administration, sulpiride was almost equipotent to haloperidol in (I), and was equally effective to or 2 to 3 times more effective than halopridol in (III), although several times less in all respects. These findings suggest that sulpiride is essentially a potent inhibitory substance on dopamine receptors in the central nervous system and the rather weak central effects of peripherally given sulpiride are due to poor penetration through the blood brain barrier.

Dual action of morphine and related drugs on compulsive gnawing of rats.

Rats received daily i.p. injections of p-chlorophenylalanine (PCPA) for 3 days, before morphine and related drugs were implanted into the lateral thalamus or injected systemically. PCPA enhanced the stereotyped response to morphine, methadone, and apomorphine, as expressed by compulsive gnawing, but abolished the antagonistic effect of large doses of i.p. morphine. Thus, suppression of gnawing by large doses of systemic morphine and related analgesics may be mediated by a serotoninergic pathway. PCPA also brought to light the ability of pethidine to cause gnawing, which is otherwise suppressed by the strong antagonistic effect of this drug. Morphine and related analgesic drugs exert a dual effect: stimulation of gnawing via a catecholaminergic mechanism and inhibition of gnawing by a serotoninergic mechanism.

Dl-phenylalanine in depressed patients: an open study.

In an open study dl-phenylalanine in doses from 75-200 mg/day was administered to 20 depressed patients for 20 days. Patients were classified according to the International Classification of Diseases (ICD). The AMP system, the Hamilton depression scale and the von Zerssen self rating questionnaire were used for documentation of psychopathological, neurologic and somatic changes. In addition a global clinical impression was agreed upon by experienced psychiatrists. At the end of the trial 12 patients (8 with complete, 4 with good response) could be discharged without any further treatment. 4 patients with partially untypical depressions experienced mild to moderate responses, whereas 4 patients did not respond at all to the phenylalanine administration. Depressive "core symptoms" as depressed mood, retardation and/or agitation were preferentially, anxiety and sleep disturbances moderately and hypochondriasis and compulsiveness were not influenced. It is concluded that dl-phenylalanine might have substantial antidepressant properties and that further more controlled investigations are warranted.