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The effect of repeated s.c. administration of various neuroleptics (haloperidol, sulpiride and cis-flupentixol) on the in vivo release and metabolism of dopamine (DA) was studied in freely moving rats using trans striatal dialysis coupled to reverse-phase high-pressure liquid chromatography with electrochemical detection. Acute administration of neuroleptics dose-dependently but transiently stimulates DA release whereas lastingly stimulating DA metabolism. Administration of a second dose of neuroleptic, 4 to 12 hr after a priming dose, fails to stimulate DA release or stimulates it less effectively than in normal rats. A normal stimulatory response of DA release is reinstated when at least a 24-hr delay between the two doses is allowed. In contrast, the ability of the second neuroleptic dose to affect DA metabolism is unchanged. The results indicate that rapid tolerance takes place to neuroleptic-induced stimulation of DA release but not of DA metabolism.

The effect of unilateral 6-hydroxydopamine lesions of the medial forebrain bundle on the specific binding of [125I]iodosulpride and [125I]SCH 23982 in the rat substantia nigra was determined by quantitative autoradiography of adjacent sections. The specific binding of [125I]iodosulpride was reduced by 40-70% on the lesioned side in the substantia nigra pars compacta, reticulata, lateralis and in the ventral tegmental area. In contrast, the specific [125I]SCH 23982 binding was unchanged in all subdivisions of the substantia nigra. The results indicate that dopamine autoreceptors are present in the substantia nigra and in the ventral tegmental area and that they are exclusively of the D2 type.

The D-1 receptor agonist, SKF 38393 (2 mg/kg s.c.), failed to elicit contralateral turning when administered to drug-naive rats 17 days after unilateral 6-hydroxydopamine (6-OHDA) lesioning of the medial forebrain bundle, while it elicited intense contralateral turning 90 days post-lesioning. On the other hand the D-1/D-2 receptor agonist, apomorphine (0.1 mg/kg s.c.), induced contralateral turning in drug-naive rats lesioned 14 days earlier and made the administration of SKF 38393 (2 mg/kg s.c.) 3 days later effective to evoke contralateral turning ('priming'). The effectiveness of apomorphine as a primer of SKF 38393-induced turning depended critically on the interval between the administration of the two agonists. Effectiveness was minimal after 3 h and increased after 6-12 h, peaked at 72 h and was reduced after 10 days. The D-2 receptor agonist, LY 171555 (0.2 mg/kg s.c.), was also effective as a primer of SKF 38393-induced contralateral turning and this effect also was dependent upon the interval between priming and SKF 38393 administration. Moreover, priming was dependent on the dose of drug used as primer and on the dose of SKF 38393 used as a challenge. In contrast to SKF 38393, priming was unable to make effective a dose of LY 171555 that was ineffective in drug-naive rats, suggesting that LY 171555 affects D-1-dependent turning to a greater extent than D-2-dependent turning. The results indicate that the priming phenomenon is rather strictly time- and dose-dependent.

The method of trans-striatal dialysis has been applied here to the study of the release and metabolism of dopamine (DA) in the awake rat. DA and its acidic metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), present in the dialysates were separated by high performance liquid chromatography on reverse phase columns and estimated by electrochemical detection. In the awake rat, DA, DOPAC, and HVA could be recovered and quantitated in the dialysates for at least 4 days from the time of implantation of the dialysis tube. At a constant 2-microliters/min flow of Ringer in the dialysis tube, the output of the substances recovered in 20-min samples 24 hr after the implantation was as follows: DA, 0.318 +/- 0.035; DOPAC, 41.3 +/- 4.84; HVA, 32.98 +/- 3.79 (mean picomoles +/- SEM of six 40-microliters samples). The output of DA, DOPAC, and HVA decreased slowly so that 4 days after the implantation the output of DA was reduced by about 35% in respect to the 24-hr values. After a 24-hr recovery, drugs were administered and their effect on DA release and metabolism was investigated. Drugs of different chemical structure and spectrum, but having in common the property of blocking DA receptors and being effective neuroleptics such as haloperidol, sulpiride, and flupentixol, stimulated DA release and DOPAC and HVA output. Threshold doses for this effect were very low, being 0.012 mg/k, s.c., for haloperidol, 2.5 mg/kg, s.c., for (-)-sulpiride, and 0.025 mg/kg, s.c., for cis-flupentixol. This effect was stereospecific as the (+) form of sulpiride and the trans- form of flupentixol were at least 10 to 100 times less potent than their enantiomer. The stimulation of DA release was shorter-lasting than the stimulation of DA metabolism and sedation or catalepsy. Moreover, whereas DA release did not increase by more than 100% over basal values, DOPAC and HVA increased by more than 3 times after maximally effective doses of neuroleptics. gamma-Butyrolactone (200 mg/kg, i.p.) reversed haloperidol (0.1 mg/kg, s.c.), and sulpiride (20 mg/kg, s.c.) induced stimulation of DA release while it potentiated the stimulation of DOPAC and HVA output. These data indicate that stimulation of DA release by neuroleptics is strictly dependent upon stimulation of DA firing and that different mechanisms underline their effects on DA release and on DA metabolism.

The effect of apomorphine on the EEG of freely moving rats was studied. Apomorphine at the dose of 1 mg/kg caused stereotypy and a marked reduction of total sleep. On the contrary, acute subcutaneous administration of apomorphine at the dose of 100 microgram/kg, or less, markedly increased the amount of total sleep (corresponding mostly to synchronized sleep). Moreover, the infusion of apomorphine (80 microgram/kg/h) for 4 h doubled the duration of slow and REM sleep. The hypnotic effect of apomorphine was prevented by neuroleptics, such as pimozide, benzperidol and L-sulpiride, at doses which, per se, did not modify the EEG of the animals. These results suggest the existence in the CNS of DA receptors mediating sleep.