Striatal DOPA Accumulation Research Articles

Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats

Administering manganese chloride (Mn) to rats on postnatal day (PD) 1–21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1–21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., “autoreceptor” doses) of apomorphine (0.06 and 0.12mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired.

Effects of aripiprazole and terguride on dopamine synthesis in the dorsal striatum and medial prefrontal cortex of preweanling rats

The purpose of this study was to determine whether aripiprazole, a D2-like partial agonist increasingly prescribed to children, alters DA synthesis via actions at autoreceptors in the dorsal striatum and medial prefrontal cortex (mPFC) of preweanling rats. The ability of dopaminergic agents to alter DOPA accumulation in the striatum and mPFC was measured after NSD-1015 on postnatal day (PD) 20. Dopaminergic tone was manipulated by administering reserpine, gamma-butyrolactone (GBL), or through amphetamine withdrawal. Results showed that the partial agonists aripiprazole and terguride increased striatal DOPA accumulation under normosensitive conditions, but decreased DOPA accumulation in states of low dopaminergic tone. A different pattern of results was observed in the mPFC, because terguride and haloperidol, but not aripiprazole, increased DOPA accumulation under normosensitive conditions. In conclusion, the present data show that aripiprazole affects striatal synthesis modulating autoreceptors in an adult-typical manner during the late preweanling period. Unlike in adult rats, however, the mPFC of preweanling rats appears to contain transitory synthesis modulating autoreceptors that are sensitive to drug manipulation.

Pre- and postsynaptic actions of a partial D2 receptor agonist in reserpinized young rats: Longevity of agonistic effects

Partial D2 receptor agonists (e.g., terguride, preclamol, and aripiprazole) have antagonist-like effects at normosensitive D2 postsynaptic receptors and synthesis modulating autoreceptors. In reserpine-pretreated adult and young rats, however, partial D2 agonists function like high efficacy agonists at D2 postsynaptic receptors and autoreceptors (i.e., terguride increases locomotor activity and decreases dopamine synthesis). The purpose of the present study was to examine the time-course of these pharmacological effects. In all experiments, preweanling rats were given daily injections of reserpine (1 mg/kg, i.p.) or vehicle on postnatal day (PD) 16–PD 20. In the dopamine synthesis experiments, the ability of terguride (0.8 mg/kg) to reduce striatal DOPA accumulation (in NSD-1015 treated rats) was assessed either 5 h or 1, 2, 4, or 8 days (Experiment 1) or 4, 8, 12, 16, 20, or 24 days (Experiment 2) after reserpine pretreatment. In the behavioral experiments, locomotor activity of vehicle or terguride (0.8 mg/kg, i.p.) treated rats was assessed 5 h or 1, 2, 4, or 8 days after the 5-day reserpine regimen. Results from the dopamine synthesis experiments showed that terguride caused agonist-like effects (i.e., decreased DOPA accumulation) at only the 5 h and 1 day time points, although terguride did not induce its normal antagonist-like effects even 20 days after reserpine pretreatment. In the behavioral experiments, terguride stimulated locomotor activity for only the initial 2 days after reserpine pretreatment. The results of the present study show that the agonistic effects of terguride at pre- and postsynaptic receptors are short-lived, but terguride may not exhibit normal antagonistic effects, at least at synthesis modulating autoreceptors, until long after conclusion of reserpine pretreatment.

Increased striatal dopamine synthesis is associated with decreased tissue levels of tyrosine

Tyrosine levels do not generally affect indices of dopamine (DA) synthesis or efflux under basal conditions, but can do so when DA synthesis is increased. One possibility is that a high rate of DA synthesis depletes the normally adequate pool of endogenous tyrosine. To study this, we administered drugs known to preferentially increase striatal DA synthesis and examined DOPA levels in striatal microdialysate during perfusion with NSD-1015. In additional groups, we also measured DA, tyrosine and large neutral amino acids in striatal microdialysate, as well as in tissue from striatum and medial prefrontal cortex (MPFC). γ-butyrolactone (GBL) (750 mg/kg i.p.) increased DOPA levels in striatal microdialysate, increased tissue DA levels in the MPFC and striatum, but lowered tissue tyrosine levels only in striatum. In striatal microdialysate, GBL markedly lowered DA levels; tyrosine levels were only marginally lower. Haloperidol (HAL) (1.0 mg/kg s.c.) ± amfonelic acid (AFA) (5 mg/kg i.p.) increased striatal DOPA accumulation, increased striatal DA efflux, lowered striatal tissue tyrosine levels, but did not affect microdialysate tyrosine levels. There were no consistent changes in levels of other large neutral amino acids. We conclude that increased tyrosine hydroxylation can significantly deplete the endogenous pool of tyrosine. Under such conditions, near normal extracellular tyrosine levels are maintained despite lower tissue levels. The data are consistent with a net transfer of tyrosine from non-DAergic cells to DA terminals in support of DA synthesis.

Effects of a partial D 2-like receptor agonist on striatal dopamine autoreceptor functioning in preweanling rats

There is evidence that partial D 2-like dopamine agonists (e.g., terguride) may not affect D 2-like postsynaptic receptors in an adult-typical manner during the preweanling period. To determine whether synthesis modulating dopamine autoreceptors are also affected in an adult atypical manner by partial D 2-like agonists, preweanling rats were treated either acutely or repeatedly with reserpine (low dopaminergic tone) or vehicle (high dopaminergic tone). The ability of terguride, quinpirole (a full D 2-like agonist), or haloperidol (a D 2-like antagonist) to alter striatal DOPA accumulation was assessed after NSD-1015 treatment on postnatal day (PD) 21. In a separate set of experiments, terguride's ability to modulate dopamine synthesis was assessed in rats treated with the nerve impulse flow inhibitor γ-butyrolactone (GBL). Results showed that both terguride and quinpirole reduced striatal DOPA accumulation during a state of low dopaminergic tone (i.e., after reserpine pretreatment). During a state of high dopaminergic tone (i.e., after vehicle pretreatment), terguride had similar effects as haloperidol and increased DOPA accumulation. Terguride, like quinpirole, partially inhibited the GBL-induced increase in striatal DOPA accumulation. When considered together, these results indicate that synthesis modulating D 2-like autoreceptors are functional during the late preweanling period, and they respond in an adult-typical manner to a partial D 2-like agonist.

Increased site-specific phosphorylation of tyrosine hydroxylase accompanies stimulation of enzymatic activity induced by cessation of dopamine neuronal activity.

Activation of striatal dopamine (DA) neurons by neuroleptic treatment or by electrical stimulation of the nigrostriatal pathway increases the activity of tyrosine hydroxylase (TH). The increase is mediated by phosphorylation of the enzyme. However, abolition of DA neuronal activity [by gamma-butyrolactone (GBL) treatment or transection of the nigrostriatal pathway] also increases TH activity. Quantitative blot immunolabeling experiments using site- and phosphorylation state-specific antibodies to TH demonstrated that GBL treatment (750 mg/kg, 35 min) significantly increased phosphorylation at Ser19 (+40%) and Ser40 (+217%) without altering Ser31 phosphorylation. Concomitantly, GBL treatment [along with the 3,4-dihydroxyphenylalanine (dopa) decarboxylase inhibitor NSD-1015, 100 mg/kg, 30 min] increased in vivo striatal dopa accumulation and in vitro TH activity 3-fold. Likewise, cerebral hemitransection of the nigrostriatal pathway significantly increased phosphorylation of TH at Ser19 (+89%) and Ser40 (+158%) but not at Ser31; dopa levels were increased accordingly (+191%). Kinetic analysis of TH activity established that GBL treatment and hemitransection primarily decreased the Km for the cofactor tetrahydrobiopterin (3-fold). The effects of GBL and hemitransection were abolished or attenuated by pretreatment with the DA agonist R-(-)-N-n-propylnorapomorphine (NPA; 30 microgram/kg, 40 min), presumably via stimulation of inhibitory presynaptic DA autoreceptors. NPA dose-response curves for reversal of GBL-induced dopa accumulation and Ser40 phosphorylation were identical; however, only the highest dose of NPA reversed the small and variable increase in Ser19 phosphorylation. Thus, TH activity seems to be regulated by phosphorylation in both hyper- and hypoactive striatal DA neurons; in the latter case, activation seems to be caused by selective phosphorylation of Ser40.

Partial dopamine receptor agonists reverse behavioral, biochemical and neuroendocrine effects of neuroleptics in the rat: Potential treatment of extrapyramidal side effects

The partial DA receptor agonist preclamol, (−)-3-PPP (50–200 c, s.c.) partially reversed the catalepsy induced by the dopamine (DA) receptor antagonists haloperidol (5.3 μmol/kg, i.p.) and raclopride (20.1 μmol/kg, i.p.) in rats. Terguride (transdihydrolisuride), a partial DA receptor agonist with an efficacy lower than that of preclamol, blocked haloperidol (10.6 μmol/kg, i.p.) induced catalepsy at 5 μmol/kg, s.c., but not at 20 μmol/kg, s.c. The effects of terguride in this assay are possibly related to the compound's mixed partial DA agonist/5-HT 1A receptor agonist properties. The high efficacy agonist, pramipexole (SND 919) also blocked haloperidol induced catalepsy at 50 μmol/kg, s.c. Haloperidol (0.33–1.3 μmol/kg, i.p.) reduced the locomotor activity down to 5% of saline controls and elevated limbic and striatal DOPA accumulation. When combined with haloperidol, preclamol (100–200 μmol/kg, s.c.) antagonized both the strong hypomotility and increase in DOPA accumulation. Finally, the elevation of serum prolactin in rats induced by haloperidol (0.25 μmol/kg, i.p.) was significantly antagonized by co-administration of preclamol (39 μmol/kg, s.c.). These results show that partial DA agonists can reverse both behavioral, biochemical and neuroendocrine effects of neuroleptics. It also suggests the utility of partial DA receptor agonists in combination with classical neuroleptics in order to minimize the appearance of extrapyramidal side-effects and hyperprolactinemia.

Stimulation of brain dopamine autoreceptors by remoxipride administration in reserpine-treated male rats.

Male Sprague-Dawley rats were treated subcutaneously with reserpine (5 mg kg-1, -18 h) and with the aromatic amino acid decarboxylase inhibitor, NSD-1015 (3-hydroxybenzylhydrazine) (100 mg kg-1 -30 min). Remoxipride 0.8, 3.2 or 12.8 mg kg-1 was administered subcutaneously at -50 min. Immediately following decapitation (0 h), the ventral striatum and the anterior neocortex were dissected. Dopa and 5-hydroxytryptophan accumulation in these brain areas were analysed by HPLC with electrochemical detection. Reserpine produced a marked increase in striatal and neocortical dopa accumulation, in comparison with glucose vehicle + NSD-1015-treated controls, and this increase was dose-dependently antagonized by remoxipride treatment. Thus, together with demonstrated dopamine receptor antagonist actions in intact animals, remoxipride behaves as a mixed dopamine receptor agonist-antagonist. Such properties could contribute to the favourable endocrine and extrapyramidal side effect profile of remoxipride as an antipsychotic agent.

Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Blockade of dopamine receptors explains the lack of 5-HT stereotypy on treatment with the putative 5-HT1A agonist LY165163.

The putative serotonin (5-HT)1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.

Time course of adaptations in dopamine biosynthesis, metabolism, and release following nigrostriatal lesions: implications for behavioral recovery from brain injury.

Alterations in neostriatal dopamine metabolism, release, and biosynthesis were determined 3, 5, or 18 days following partial, unilateral destruction of the rat nigrostriatal dopamine projection. Concentrations of dopamine and each of its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT) were markedly decreased in the lesioned striata at 3, 5, or 18 days postoperation. The decline in striatal high-affinity [3H]dopamine uptake closely matched the depletion of dopamine at 3 and 18 days postoperation. However, neither DOPAC, HVA, nor 3-MT concentrations were decreased to as great an extent as dopamine at any time following lesions that depleted the dopamine innervation of the striatum by greater than 80%. In these more severely lesioned animals, dopamine metabolism, estimated from the ratio of DOPAC or HVA to dopamine, was increased two- to four-fold in the injured hemisphere compared with the intact hemisphere. Dopamine release, estimated by the ratio of 3-MT to dopamine, was more increased, by five- to sixfold. Importantly, the HVA/dopamine, DOPAC/dopamine, and 3-MT/dopamine ratios did not differ between 3 and 18 days postlesioning. The rate of in vivo dopamine biosynthesis, as estimated by striatal DOPA accumulation following 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibition with NSD 1015, was increased by 2.6- to 2.7-fold in the surviving dopamine terminals but again equally at 3 and 18 days postoperation. Thus, maximal increases in dopamine metabolism, release, and biosynthesis occur rapidly within neostriatal terminals that survive a lesion. This mobilization of dopaminergic function could contribute to the recovery from the behavioral deficits of partial denervation by increasing the availability of dopamine to neostriatal dopamine receptors. However, these presynaptic compensations are not sufficient to account for the protracted (at least 3-week) time course of sensorimotor recovery that has been observed following partial nigrostriatal lesion.

Effect of Subchronic Treatment with Methamphetamine on Apomorphine-lnduced 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 γ-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.

Dopamine receptor blockade by imidoline and its proposed active conformation

Imidoline, 1-[2-(N,N-dimethylamino)ethyl]-3-m-chlorophenyl-2-imidazolidinone, has been found to be as potent as chlorpromazine in increasing striatal DOPA accumulation and prolactin secretion in vivo. In contrast, imidoline exhibited only weak inhibitory activity towards dopamine-sensitive adenylate cyclase and 3H-spiroperidol binding to striatal membranes in vitro. These neuroleptic effects in vivo are probably caused by blockade of dopamine receptors, since imidoline did not deplete the striatum of dopamine. Imidoline is of interest because its structure is distinct from those of other neuroleptics. A proposed active conformation involves intramolecular hydrogen bonding between the protonated dimethylamino group and the oxygen of the imidazolidinone ring. The spatial relationship between the amine nitrogen and phenyl ring in this conformation allows proper fit of imidoline with key dimensions described for the dopamine receptor.

The effect of phencyclidine on dopamine synthesis and metabolism in rat striatum

Previous behavioral and neurochemical studies indicate that phenyclidine (PCP), a potent psychotomimetic agent, interacts with central dopaminergic systems. We have examined the effects of PCP on the rate of accumulation of 3,4-dihydroxyphenylalanine (DOPA) after the inhibition of L-aromatic amino acid decarboxylase and on the levels of dopamine (DA) metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum. PCP, in doses from 2.5 to 50 mg/kg, decreased the rate of striatal DOPA accumulation. PCP did not antagonize the increase in the rate of striatal DOPA formation caused by haloperidol, reserpine or γ-butyrolactone (GBL). When given alone, PCP decreased striatal levels of DOPAC and HVA, while it greatly potentiated the haloperidol-induced rise in striatal levels of these two metabolites. PCP is considerably less effective than d-amphetamine in promoting the release of 3H-DA from preloaded striatal slices in vitro. Our results are consistent with the interpretation that PCP potentiates the synaptic effects of endogenous DA. Its mechanism of action appears to be closely related to that of a category of drugs known as non-amphetamine stimulants, which, among others, includes methylphenidate, amfonelic acid and cocaine.

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 alter 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 γ-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 (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.

D-Amphetamine-induced increase in catecholamine synthesis in the corpus striatum of the rat: Persistence of the effect after tolerance

The effect of d-amphetamine on in vivo catecholamine synthesis in four regions of rat brain was determined by measuring the accumulation of dopa after inhibiton of dopa decarboxylase. In doses up to 2.5 mg/kg, d-amphetamine caused dose-dependent increases in striatal dopa accumulation to a maximum of 280% of control; further increases in dose resulted in smaller effects until 10 mg/kg d-amphetamine was not significantly different from control. d-Amphetamine did not alter dopa accumulation in telencephalon, in diencephalon-mesencephalon, or in pons-medulla oblongata. d-Amphetamine did not affect either dopamine levels in striatum or NE levels in pons-medulla oblongata; at high doses, d-amphetamine did reduce norepinephrine levels in telencephalon and in diencephalon-mesencephalon. Daily administration of pre-session but not of post-session d-amphetamine produced tolerance to the effects of d-amphetamine on milk consumption in rats. The ability of d-amphetamine to increase striatal catecholamine synthesis was not altered by the development of tolerance to d-amphetamine. These results suggest that tolerance to d-amphetamine is not related to its effect on catecholamine synthesis but instead occurs via changes in aspects of catecholamine metabolism other than synthesis via change in catecholamine release, reuptake, or receptor sensitivity, or via changes in non-catecholaminergic mechanisms.

The effect of lysergic acid diethylamide (LSD) and 2-bromo-lysergic acid diethylamide (BOL) on the striatal dopa accumulation: Influence of central 5-hydroxy-tryptaminergic pathways

Selective chronic lesions of the dorsal raphe nucleus or combined lesions of the dorsal and median raphe nuclei did not significantly change the in vivo tyrosine hydroxylation in the striatum as measured by the DOPA accumulation after decar☐ylase inhibition. Neither did acute combined lesions of the raphe nuclei, nor did electrical stimulation of the dorsal raphe nucleus have any significant effect. p-Chloroamphetamine (PCA, 20 mg/kg, i.p.) and p-chlorophenylalanine (PCPA, 400 mg/kg, i.p.), known inhibitors of the 5-hydroxytryptamine (5-HT) synthesis, significantly decreased the DOPA accumulation. The increase in DOPA accumulation observed after LSD (0.5 mg/kg, i.p.) or BOL (0.5 mg/kg, i.p.) was seemingly unaffected by pretreatment with PCA or PCPA and also after lesion of the dorsal raphe nucleus. The results suggest that the effect of LSD or BOL on the DOPA accumulation in the striatum is not mediated via a 5-hydroxytryptaminergic control mechanism originating in the dorsal raphe nucleus. A control mediated via the median raphe nucleus cannot be excluded, since LSD did not increase the DOPA accumulation after combined chronic raphe lesions. Such a control would also be in agreement with our previous results suggesting that the DOPA generation after LSD is controlled by 5-HT receptors.

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 γ-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 autoreceptors. It is proposed in addition that LSD activates and BOL blocks 5-HT receptors that control DOPA formation.

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.