Behavioural and biochemical effects of subchronic treatment with raclopride in the rat: tolerance and brain monoamine receptor sensitivity

Male Sprague-Dawley rats were treated with the dopamine (DA) D2 receptor blocking agent raclopride 0.5 or 8.0 mg kg-1 subcutaneously (1.0 and 16.0 mumol kg-1, respectively), twice daily for 21 days. The animals treated with raclopride gained weight at the same rate as saline controls, and gross observation did not indicate any behavioural abnormalities due to the subchronic raclopride treatment. Possible changes in brain DA receptor sensitivity due to prolonged blockade of DA receptors were evaluated in behavioural and biochemical models. There were no effects on locomotor activity, as observed by means of photobeam-equipped activity cages, 24 hr or 72 hr after withdrawal of 0.5 or 8.0 mg kg-1 subchronic raclopride treatment. Twenty-four hr after withdrawal of the raclopride treatment there was an increased post-synaptic DA receptor sensitivity as evidenced by increased behavioural and biochemical responses to apomorphine, and by an attenuated response to acute raclopride treatment, 0.1 mg kg-1. Thus, there was an increase in locomotor activity by the apomorphine treatment in animals pretreated with the 8 mg kg-1 dose, as compared to the response obtained in saline controls. Furthermore, the suppression of locomotor activity in saline controls produced by acute raclopride treatment was dose-dependently antagonized by the raclopride pretreatment and this also applied to the increase in striatal DOPAC levels produced by acute raclopride treatment. Finally, there was an increased DA receptor sensitivity presynaptically as evidenced by an enhanced effect on striatal DOPA levels by apomorphine in rats treated with NSD 1015 and reserpine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of morphine on the accumulation of DOPA after decarboxylase inhibition in the rat.

Acute systemic administration of morphine (10 mg/kg s.c.) to rats increased in vivo tyrosine hydroxylation in the striatum measured as the accumulation of DOPA after decarboxylase inhibition. DOPA accumulation reached a maximum 30-60 min after morphine. The morphine antagonist naloxone (1, 10 or 100 mg/kg s.c.) did not significantly after DOPA accumulation. However, naloxone completely antagonized the effect of morphine. The DA agonist apomorphine decreased and the DA antagonist haloperidol increased DOPA accumulation. The effect of apomorphine (0.05 mg/kg) was counteracted by morphine. Naloxone did not significantly change the accumulation of DOPA after apomorphine or after haloperidol. In rats treated with gamma-butyrolactone (GBL) or with reserpine DOPA accumulation was not altered by treatment with morphine or naloxone. However, the inhibiting effect of apomorphine (0.5 mg/kg) on the accumulation of DOPA in rats treated with reserpine was weakly counteracted by morphine (0.5 mg/kg) on the accumulation of DOPA in rats treated with reserpine was weakly counteracted by morphine (10 mg/kg s.c.). Since the effects of morphine on the apomorphine-induced inhibition of DOPA accumulation were antagonized by naloxone, we suggest that the effects on striatal DOPA accumulation produced by morphine were mediated via opioid receptors and not directly via DA receptors.     

Behavioral and biochemical studies of dopamine receptor sensitivity in differentially housed mice

Group housed and individually housed mice were compared in (1) the motor activity responses to direct and indirect dopamine (DA) agonists, (2) in vivo presynaptic autoreceptor sensitivity and (3) in vitro binding of ³H-spiperone. Relative to group housed mice, individually housed mice showed an increased motor activity response to amphetamine, 1.25 and 0.625 mg/kg. Using two in vivo measures of presynaptic DA receptor sensitivity, the antagonism of spontaneous locomotor activity and the antagonism of dihydroxyphenylalanine (DOPA) accumulation by apomorphine (APO), individually housed mice showed greater activity counts and higher DOPA accumulations than group housed mice. Levels of tyrosine were significantly greater in individually housed mice. Significant effects of housing were also noted with the motor activity response to APO, 0.075–0.300 mg/kg, following pretreatment with reserpine, an in vivo measure of postsynaptic receptor sensitivity. However, there was no effect of housing on the number or affinity of ³H-spiperone binding sites in the striatum. These results are discussed in terms of the presynaptic activity of catecholaminergic neurons and the postsynaptic receptor sensitivity to APO in individually housed mice.     

Bromocriptine potentiates the behavioural effects of directly and indirectly acting dopamine receptor agonists in mice

Summary After an initial period of depression which lasted up to 90 min following injection, bromocriptine (BRC, 5–20 mg/kg, IP) produced dose-dependent and long lasting (7 h) locomotor stimulation in mice. The locomotor stimulation was antagonised by reserpine, alpha-methyl-p-tyrosine (AMPT) or haloperidol. The blockade by AMPT of BRC's locomotor stimulant effect was reversed by prior treatment of the mice with a low, behaviourally inactive dose of L-Dopa plus benserazide. In mice pretreated with reserpine, BRC enhanced the stimulant action of d-amphetamine. Moreover, in mice pretreated with reserpine plus AMPT, BRC significantly enhanced the locomotor stimulant effect of apomorphine. This ability of BRC to enhance the effect of apomorphine commenced as soon as 20 min after BRC administration and lasted for at least 8 h. The dopamine (DA) uptake inhibitor and DA receptor agonist nomifensine potentiated and prolonged the stimulant effect of BRC while inhibitor of the neuronal uptake of noradrenaline (desipramine) and 5-hydroxytryptamine (fluoxetine) were without marked effect. The results clearly show that BRC, in behavioural terms, has no efficacy per se at the postsynaptic DA receptor and that it requires either DA or the administration of an exogenous agonist such as apomorphine for the expression of its effects.     

Neurochemical and behavioral effects of acute and chronic treatment with apomorphine in rats

In three experiments, rats were injected once daily with 5.0 mg/kg apomorphine or vehicle and tested for locomotor activity for 10-14 days. In each experiment, apomorphine produced behavioral sensitization, characterized by a progressively greater increase in locomotor activity with each succeeding injection. On day 11 of testing, in an experiment designed to assess the synthesis of dopamine (DA), rats were injected with 5.0 mg/kg apomorphine or vehicle, followed by 100 mg/kg NSD-1015, an inhibitor of the enzyme l-aromatic amino acid decarboxylase. After administration of NSD-1015, concentrations of dihydroxyphenylalanine (DOPA) were determined in striatal and mesolimbic tissues by high performance liquid chromatography (HPLC) with electrochemical detection. The results revealed a significant decrease in accumulation of DOPA in both striatal and mesolimbic tissue after acute treatment with apomorphine. More important, chronic treatment with apomorphine produced a significant increase in accumulation of DOPA in both areas. In subsequent experiments, rats on day 14 of testing were sacrificed for determination of levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) or specific binding of [3H]spiperone in the striatum and mesolimbic region. Although levels of DOPAC were significantly reduced in the regions of the brain after an acute injection of apomorphine, chronic treatment with apomorphine did not significantly affect levels of DA, DOPAC or specific binding of [3H]spiperone. These findings suggest that the development of behavioral sensitization to apomorphine may be related to an alteration in the synthesis of DA.     

Effects of chlorimipramine on the synthesis and metabolism of dopamine in the rat striatum

In the rat, chlorimipramine (7.5, 15, and 60 mg/kg IP and 15 and 60 mg/kg orally) increased the rate of the striatal in vivo tyrosine hydroxylation measured as the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition. The demethylated metabolite of chlorimipramine desmethylchlorimipramine increased the DOPA accumulation only after a dose of 60 mg/kg IP, but did not significantly change the DOPA accumulation after oral administration. Protriptyline (7.5–30 mg/kg) and benztropine (25 mg/kg) decreased the DOPA accumulation. After inhibition of the impulse flow in the nigroneostriatal pathway by treatment with gammabutyrolactone (GBL), benztropine decreased the DOPA accumulation, while no significant effect was observed after chlorimipramine or protriptyline. Neither chlorimipramine nor protriptyline counteracted the decreased DOPA accumulation after apomorphine in rats treated with GBL. After treatment with reserpine, benztropine decreased the DOPA accumulation. Chlorimipramine and protriptyline did not significantly alter the DOPA accumulation after reserpine. Neither did chlorimipramine or protriptyline counteract the effect of apomorphine on the DOPA accumulation after reserpine. Chlorimipramine (15 mg/kg IP) increased the striatal 3,4-dihydroxyphenylacetic acid (DOPAC) levels, while protriptyline (15 mg/kg IP) had no significant effect. The effects of chlorimipramine on the DOPA accumulation and on the DOPAC levels in the striatum may be mediated directly via central dopamine receptors, but more probably indirectly via central 5-hydroxy-tryptaminergic mechanisms.     

Alteration of striatal dopaminergic functions implicated in methamphetamine-induced reverse tolerance in rats

Rats were injected repeatedly with methamphetamine (6 mg/kg per day, for 14 days). The effects of the repeated treatment on the change of behaviors and striatal DA metabolism induced by challenge with DA agonists were studied 10 days after the last injection. Repeated methamphetamine administration decreased the sedative effect of low dose apomorphine, and enhanced apomorphine-induced stereotyped behavior but reduced in after pretreatment with tetrabenazine. Striatal DA, HVA and DOPAC contents, and striatal gamma-butyrolactone-induced DA or DOPA accumulation were not altered by repeated methamphetamine treatment. The effect of apomorphine to decrease DA metabolite content and DA or DOPA accumulation was not changed either. As evidenced by experiments using alpha-MT, repeated methamphetamine administration increased DA utilization after methamphetamine or low dose apomorphine challenge, although it did not change DA utilization at the steady state (without drug challenge). These findings suggest that methamphetamine-induced reverse tolerance is accompanied by an increase of DA utilization resulting from the subsensitivity of DA utilization-modulating autoreceptors.     

Destruction of 5-hydroxytryptaminergic neurons and the dynamics of dopamine in nucleus accumbens septi and other forebrain regions of the rat

5,7-Dihydroxytryptamine (5,7-DHT) was injected into the lateral cerebral ventricle of rats which had been pretreated with desipramine; this treatment reduced the concentrations of 5-hydroxy-tryptamine (5-HT) but not of norepinephrine or dopamine (DA) in forebrain regions. When 5,7-DHT was injected bilaterally into the nucleus accumbens septi (NAS) of desipramine-pretreated rats, it selectively depleted 5-HT only from the NAS. Exploratory locomotor activity and the locomotor stimulation induced by f-amphetamine and apomorphine were enhanced in both NAS- and 5,7-DHT-injected rats. These locomotor effects in the 5-HT-depleted animals were not associated with changes in the activity of dopaminergic neurons, which were estimated biochemically from either the regional concentrations of dihydroxyphenylacetic acid (DOPAC) or the rate of accumulation of dihydroxyphenylalanine (DOPA) after the administration of a decarboxylase inhibitor. That is, the concentration of DOPAC and the accumulation of DOPA in the NAS, olfactory tubercle and striatum of NAS-5,7-DHT and 5,7-DHT-injected rats were the same as in controls. Furthermore, the ability of apomorphine to decrease, and of haloperidol to increase, DOPAC concentrations and DOPA accumulation were the same in control, NAS-5,7-DHT and 5,7-DHT-injected rats. These results indicate that the enhancement of spontaneous and drug-stimulated locomotor activity following destruction of 5-HT nerve terminals in the brain are not associated with changes in the activity of the major ascending DA-containing neuronal systems.     

Increase of striatal dopamine turnover by drugs: Interference with granular storage or receptor blockade?

Apomorphine completely antagonized the reserpine-induced enhancement of the striatal 3,4-dihydroxyphenylalalinine (dopa) accumulation seen after administration of the decarboxylase inhibitor 3-hydroxybenzyl-hydrazine (NSD 1015). Reserpine-like drugs, e.g. Ro 4-1284 and Ro 4-9040, markedly enhanced the striatal dopa accumulation (due to NSD 1015) in normal animals but not in rats treated with reserpine plus apomorphine. Haleoperidol enhanced the striatal dopa accumulation to a similar extent in normal and in reserpine-apomorphine-treated animals. Chlorpromazine also caused an enhancement of striatal dopa accumulation in both types of animals, but its potency was somewhat higher in normal rats than in those treated with reserpine plus apomorphine. In conclusion, reserpinized animals treated with apomorphine appear to be useful models for differentiating whether a drug enhances striatal DA turnover by interference with granular DA storage or by blockade of DA receptors. The latter seems to be the main mechanism of action of neuroletpic drugs.     

The effect of dopamine receptor agonist treatment on haloperidol-induced supersensitivity in mice

Mice were pretreated with haloperidol (HP) (3-4 mg/kg/day in drinking water) or vehicle for 21 days. On the 25th day, HP-pretreated mice were supersensitive to the locomotor stimulant effects of apomorphine (after acute premedication with reserpine and alpha-methyl-p-tyrosine). This behavioural supersensitivity was accompanied by a 25-39% increase in the number of [3H]-spiperone binding sites in the striata of HP-pretreated mice. Short-term repeated administration of the dopamine (DA) agonist drugs d-amphetamine and L-DOPA during the HP withdrawal phase (days 22, 23 and 24) had no effect on either measure of DA receptor supersensitivity. In contrast, the administration of apomorphine on days 22, 23 and 24 enhanced the HP-induced behavioural supersensitivity but decreased the HP-induced elevation of the number of [3H]-spiperone binding sites. Apomorphine treatment alone did not alter either measure. The results do not support the hypothesis that supersensitive DA receptors can be down-regulated by short-term treatment with DA agonist drugs and, moreover, indicate that important discrepancies may exist between behavioural and biochemical measures of DA receptor supersensitivity.     

Effects of continuous administration for 12 months of amine-depleting drugs and chlorpromazine on striatal dopamine function in the rat

Rats received either chlorpromazine (33-36 mg/kg/day), oxypertine (6.3-7.3 mg/kg/day), tetrabenazine (6.0-6.7 mg/kg/day) or reserpine (0.28-0.30 mg/kg/day) continuously for up to 12 months. Chlorpromazine and tetrabenazine reduced spontaneous locomotor activity of animals after 1 month of treatment. Thereafter, locomotor activity in animals treated with chlorpromazine returned to control levels, whereas treatment with tetrabenazine increased locomotion. Oxypertine enhanced spontaneous locomotor activity after 9 months of administration only, whereas treatment with reserpine did not alter this activity at any time during the study compared to age-matched controls. Treatment with tetrabenazine enhanced stereotyped behaviour induced by apomorphine (0.063-1.0 mg/kg s.c.) throughout the study. In contrast, stereotypy in animals administered chlorpromazine, oxypertine or reserpine was the same as in control animals throughout the 12 months of treatment. Levels of dopamine in the striatum were reduced after the first month of administration of chlorpromazine, but thereafter returned to control values. Treatment with oxypertine for up to 12 months did not alter concentrations of dopamine in the striatum, whereas administration of tetrabenazine and reserpine caused a decrease. All treatments with drugs consistently reduced the content of homovanillic acid in the striatum during the study. The Bmax for specific binding of [3H]spiperone in the striatum was increased by continuous treatment of animals with chlorpromazine, oxypertine or tetrabenazine, although the effects of oxypertine and tetrabenazine were only transient. Administration of reserpine did not alter the Bmax for specific binding of [3H]spiperone. The Bmax for specific binding of [3H]piflutixol in the striatum was unchanged by any treatment for up to 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic L-Dopa treatment of rats and mice does not change the sensitivity of post-synaptic dopamine receptors

Summary The effects of L-Dopa + benserazide (L-Dopa + B) treatment on pre- and postsynaptic dopamine (DA) receptors were studied. Mice treated once daily P.O. with L-Dopa (200 mg/kg)+B (50 mg/kg) or vehicle for 10 days were used on the 11th day. After premedication with reserpine and alpha-methyltyrosine (alpha-MT), apomorphine (0.5–2.0 mg/kg) produced locomotor stimulation which was of equal intensity in the 3 treatment groups, even when the treatment dose of L-Dopa was increased to 400 mg/kg per day. In contrast, low doses of apomorphine (0.1–0.5 mg/kg) produced locomotor depression in B- and vehicle-treated mice but not in L-Dopa + B-treated mice. In rats treated I.P. twice daily with L-Dopa (200 mg/kg) + (50 mg/kg), B (50 mg/kg) or vehicle for 12 days, apomorphine produced an equivalent degree of stereotypy on the 13th day in each of the 3 treatment groups. There were no treatment group differences in the binding of [³H]-spiperone or [³H]-leuenkephalin to rat striatal membranes. The data suggest that long-term L-Dopa + B treatment of mice and rats does not change the sensitivity of postsynaptic DA receptors but may affect the sensitivity of DA autoreceptors.     

Influences of diterpene sclareol glycol on some dopamine related behavior

1. The effects of the diterpene sclareol glycol (SG) of the labdane family on some dopamine (DA) related behavior (locomotor activity in mice, apomorphine-induced stereotypy in mice and rats, and haloperidol-induced catalepsy in rats) were studied. 2. The locomotion frequency of mice was significantly increased by SG (stronger effect by low and medium dose). SG antagonized the hypomotility induced by reserpine pretreatment. SG enhanced the apomorphine decreased motility (induced by small dose of apomorphine). 3. SG provoked increase of apomorphine stereotypy. The long-term SG treatment augmented the sensitivity of rats to apomorphine-induced stereotypy. 4. SG at low dose decreased haloperidol-induced catalepsy: at higher dose it increased the catalepsy. SG treatment alone did not induce catalepsy. 5. These results were discussed in the light of a possible interaction of SG with dopaminergic transmission (DA autoreceptors and postsynaptic DA receptors) at the level of the striatum and the nucleus accumbens. The interaction of SG with adenylate cyclase (stimulation of catalytic subunit) and with GABAergic transmission in realization of its effects on DA related behavior was also discussed.     

D-1 type of dopamine autoreceptors are not involved in the regulation of dopamine synthesis in the striatum

To clarify if dopamine (DA) synthesis is regulated by D-1 DA receptors located on dopaminergic nerve terminals in the striatum, we investigated effects of D-1 DA receptor agonist and antagonist on striatal 3,4-dihydroxyphenylalanine (DOPA) accumulation induced by gamma-butyrolactone in mice treated with an amino acid decarboxylase inhibitor. SKF 38393, a D-1 agonist, did not affect DOPA accumulation, whereas apomorphine that stimulates both D-1 and D-2 receptors inhibited the accumulation. SCH 23390, a D-1 antagonist, did not antagonize apomorphine-induced inhibition of DOPA accumulation, while YM-09151-2, a D-2 antagonist, reversed it. These results suggest that D-1 type of DA autoreceptors is not involved in the inhibition of in vivo DA synthesis.     

Effect of subchronic treatment with methamphetamine on apomorphine-induced changes in locomotor activity in mice

Subchronic treatment with methamphetamine (3 mg/kg, s.c., twice daily for 14 days) attenuated hypomotility produced by a low dose of apomorphine (0.1 mg/kg, s.c.) and enhanced hypermotility induced by a high dose of apomorphine (3 mg/kg, s.c.) in mice. The treatment did not affect apomorphine-induced decrease in striatal DOPA accumulation following gamma-butyrolactone plus m-hydroxybenzylhydrazine, an L-amino acid decarboxylase inhibitor, administration. These results suggest that drug sensitivity of presynaptic dopamine receptors in the striatum may not be altered after subchronic methamphetamine treatment.     

The effectiveness of yohimbine in blocking rat central dopamine autoreceptors in vivo

Summary The influence of various -adrenoceptor antagonists (10 mg/kg i.p.) upon the rate of turnover of dopamine (DA) in the rat brain was investigated. Taking the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as a measure of the rate of DA turnover, it was found that prazosin and phenoxybenzamine decreased, whereas piperoxane and yohimbine increased the turnover rate both in the corpus striatum and in the tuberculum olfactorium. Azapetine, phentolamine and tolazoline as well as the -adrenoceptor antagonist propranolol were without a significant effect, whereas the DA antagonist haloperidol increased DOPAC and HVA levels and decreased the levels of DA itself.The possibility that the yohimbine-induced increase in the DA turnover rate was produced by a direct blockade of DA autoreceptors, was investigated under conditions where influences other than those elicited via DA autoreceptors are thought to be eliminated, i.e. in rats treated with reserpine or -butyrolactone (GBL). In rats that were pretreated with reserpine, yohimbine (10 mg/kg i.p.) was found to be ineffective in antagonizing the reduction of the accumulation of 3,4-dihydroxyphenylalanine (DOPA) following decarboxylase inhibition, that was produced by the DA agonist apomorphine (2.0 mg/kg i.p.). In rats pretreated with reserpine, yohimbine (10 mg/kg i.p.) was also ineffective in antagonizing the reduction of the DOPAC and HVA levels produced by apomorphine (2.0 mg/kg i.p.), but it was effective in antagonizing the reduction of the HVA level that was produced by the selective DA autoreceptor agonist N,N-di-n-propyl-7-hydroxy-2-aminotetralin (DP-7-AT, 1.0 mg/kg i.p.). In rats treated with GBL and a decarboxylase inhibitor, apomorphine (2.0 mg/kg i.p.) and DP-7-AT (1.0 mg/kg i.p.) induced a maximal suppression of the GBL-induced increase in the accumulation of DOPA. The effects of both apomorphine and DP-7-AT were partially inhibited by yohimbine (10 mg/kg i.p.). In inhibiting the effect of DP-7-AT, yohimbine appeared to be 100–200 times less effective than the DA antagonist haloperidol when both antagonists were administered at a fixed pretreatment time (1 h). It is concluded that yohimbine does indeed possess direct central DA autoreceptor blocking properties in vivo, and that this has to be taken into consideration if yohimbine is used as a pharmacological tool in order to achieve a selective blockade of ₂-adrenoceptors.     

Striatal dopamine receptor sensitivity after subchronic fencamfamine in the rat

Dopamine (DA) receptor sensitivity was assessed in the rat striatal system following subchronic treatment with fencamfamine or saline for 7 days (10 mg/kg i.p.). Seventy-two hours after the last injection the stereotyped behaviour and general activity induced by apomorphine or saline were evaluated. Apomorphine (2.0 mg/kg s.c.) induced a decrease of the stereotypic response when fencamfamine-pretreated animals were compared to saline-treated ones while apomorphine (0.02 mg/kg s.c.) failed to alter the general activity of animals, treated with fencamfamine or not. In biochemical experiments subchronic fencamfamine did not alter the effects of apomorphine (0.02 mg/kg s.c.) in reducing homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) striatal levels, when compared to saline. In addition we observed a slight but significant reduction in the total dopamine receptor content in the striatum labelled by [3H]spiroperidol. These findings indicate that subchronic fencamfamine treatment leads to a desensitization of postsynaptic DA receptors in rat striatum.     

Effects of d-amphetamine and disruption of 5-hydroxytryptaminergic neuronal systems on the synthesis of dopamine in selected regions of the rat brain

The rate of accumulation of DOPA following the administration of a decarboxylase inhibitor was employed to estimate the in vivo rate of dopamine (DA) synthesis in rat brain regions containing the cell bodies (substantia nigra) and terminals (striatum) of nigrostriatal nerves, and the terminals of mesolimbic (nucleus accumbens, olfactory tubercle) and tuberoinfundibular (median eminence) nerves. d-Amphetamine (0.5–2 mg/kg, i.p.) caused a marked increase in DA synthesis in striatum, a modest increase in olfactory tubercle, and was without effect in nucleus accumbens and median eminence. At the largest dose, f-amphetamine slightly reduced DA synthesis in substantia nigra. The mechanism of these regional differences is currently unknown.Depletion of 5-hydroxytryptamine (5-HT) with an intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) or a systemic injection of p-chlorophenylalanine (pCPA) enhanced spontaneous and amphetamine-stimulated locomotor activity. Pretreatment with 5,7-DHT did not alter DOPA accumulation in any brain region of animals injected with d-amphetamine or its vehicle. Pretreatment with pCPA reduced DOPA accumulation only in regions containing terminals of mesolimbic DA nerves. Thus, the increased amphetamine-induced hyperactivity in 5-HT-depleted rats is not reflected in a consistent change in the rate of DA synthesis in the brains of these animals.     

The effect of LSD and 2-bromo LSD on the striatal DOPA accumulation after decarboxylase inhibition in rats.

LSD and BOL (0.125-0.5 mg/kg) were equipotent in increasing the in vivo tyrosine hydroxylation in the striatum as measured by the accumulation of DOPA after inhibition of neuronal decarboxylase. However, with 2--4 mg/kg doses, the maximum effect of BOL was larger than that of LSD. LSD and BOL antagonized the apomorphine-induced decrease of DOPA accumulation, without affecting the haloperidol-induced increase. LSD like apomorphine inhibited the increase of DOPA accumulation seen after reserpine, cerebral hemisection and after gamma-butyrolactone (GBL). The effect of apomorphine in rats given GBL was blocked by haloperidol, but not by BOL and promethazine, whereas that of LSD was inhibited by haloperidol, BOL, and promethazine. These findings suggest that LSD and BOL directly affect nigro-neostriatal dopamine neurons. LSD therefore appears to be a partial agonist and BOL a pure antagonist at dopamine autoreceptors. It is proposed in addition that LSD activates and BOL blocks 5-HT receptors that control DOPA formation.