Clinical studies with dopamine-receptor stimulants

Abstract

Oral administration of ET-495 was found to cause worsening of psychiatric status in 4 out of 7 schizophrenic patients, and to induce a paranoid state and a syndrome of auditory hallucinosis in 2 non-schizophrenics. These observations were compatible with the hypothesized role of dopamine in schizophrenia. However, these psychotogenic effects were far less dramatic than those noted in other studies with amphetamine, methylphenidate or L-Dopa. Possible explanations for this differing psychotogenic potency of receptor stimulators versus presynaptic agonists are presented. Intravenous ET-495 and apomorphine did not show psychotogenic effects.

Dopamine Receptor Stimulation in the Treatment of Depression: Piribedil (ET-495)

“…The present findings with regard to a definite but only transient antidepres sant efficacy in a group of individuals nonresponsive to other conventional drug treatment modalities would, at first glance, appear consistent with the hypothe sis that postsynaptic agonist stimulation can activate an inhibiting feedback loop to the presynaptic neuron leading to self-limiting clinical effects (Angrist et aL, 1975). However, presynaptic agonists such as amphetamines may also be capable of activating this regulatory feedback; the stimulant-euphoric effects of these latter compounds are even more transient (self-limiting), characteristically lasting only hours.…”

“…We have previously recorded our findings that oral ET-495 was found to cause worsening of psychiatric status in 4 out of 7 schizophrenics and to induce a paranoid state as well as a syndrome of auditory hallucinosis in 2 nonschizo phrenics (Angrist et al, 1975). These observations are consistent with the hypothesized role of dopamine in schizophrenia {Snyder, 1973).…”

“…It is likely that the effects of drugs such as amphetamine and L-dopa on the one hand and ET-495 on the other may be intrinsically different qualitatively and mediated by different mechanisms. The sedation seen after intravenous ET-495 (Angrist et aL, 1975) particularly contrasts with the stimulant effects of amphetamine and ¿-dopa. More specific evidence for intrinsic differences in the mechanisms of action between ¿-dopa and ET-495 are suggested by Chase and Shoulson's (1975) observations that ET-495 caused improvement in tardive dyskinesia, while ¿-dopa causes exacerbation of this condition.…”

“…The administration of haloperidol 10 mg orally 3 times daily for 2 days led to suppression of the voices which did not recur after haloperidol was discontinued. This clinical effect has been described (Angrist et al, 1975).…”

New detection of brain dopamine receptors with (3H)dihydroergocryptine.

“…Before using, the samples were thawed, resuspended in the glass-Teflon homogenizer and homogenized by hand (10 upand-down passes), and centrifuged at 39,000 X g for 15 min at 40; the supernatant was discarded and the pellet was resuspended in 10 ml of buffer. The suspension was finally homogenized by a Polytron homogenizer (Brinkman Instrument Co.) at a setting of 7 (full range = 10) for 20 sec, by using a PT-10 homogenizer probe and a 50-ml polycarbonate tube to contain the suspension. Homogenization at settings higher than 7 led to a loss of protein through the glass fiber GF/B filters used in the radioreceptor assays.…”