Differential effects of dopamine agonists on acoustically and electrically elicited startle response: Comparison to effects of strychnine

This study sought to determine where drugs that are known to alter sensorimotor reactivity measured with the acoustic startle reflex ultimately act within the acoustic startle pathway. To do this, startle was elicited either acoustically or electrically within various nuclei believed to comprise the acoustic startle pathway. Direct infusion of serotonin into the subarachnoid space of the lumbar spinal cord increased acoustic startle and startle elicited electrically through the ventral cochlear nucleus (VCN) to a comparable degree. Subconvulsant doses of strychnine increased startle elicited acoustically or electrically through either the VCN or the nucleus reticularis pontis caudalis (RPC), pointing to spinal locus of action of strychnine after systemic administration. In marked contrast, the dopamine agonists d-amphetamine and apomorphine consistently increased acoustic startle but actually depressed startle elicited electrically through the VCN or the RPC. These later results suggest that dopamine agonists increase sensorimotor reactivity measured with acoustic startle by acting on sensory rather than motor parts of the reflex arc.     

Differential effects of three dopamine receptor agonists in MPTP-treated monkeys

Summary The behavioral effects of cabergoline, pergolide and bromocriptine were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity, as evidenced by irritability, excitability and aggressiveness. All three drugs improved the parkinsonism in a dose-dependent fashion following a single injection. Among the three dopamine (DA) receptor agonists used, the antiparkinsonian effect of pergolide was the strongest and had an immediate effect, while cabergoline showed the longest duration of the antiparkinsonian effect and was least potent in inducing hyperactivity.     

Differential effects of dopamine agonists on evoked dopamine release from slices of striatum and nucleus accumbens in rats

The effects of dopamine receptor agonists on electrically evoked dopamine release from slices of nucleus accumbens were compared with the effects on release from striatal slices in rats. Apomorphine, which has equal potency at the dopamine D₂ and D₃ receptors, reduced the evoked dopamine release from both regions to the same extent (ED₅₀, 0.42 μM for nucleus accumbens; ED₅₀, 0.46 μM for striatum). Quinpirole of 7-[³H]hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT), which are much more potent at the D₃ receptor than at the D₂ receptor, reduced the evoked dopamine release from the nucleus accumbens (ED₅₀, 0.12 μM for quinpirole; 0.02 μM for 7-OHDPAT) much more than the release from the striatum (ED₅₀, 1.6 μM for quinpirole; 0.55 μM for 7-OHDPAT). These results suggest that the contribution of D₃ receptors in nucleus accumbens to regulate dopamine release from dopamine nerve terminals is much greater than that in striatum.     

Differential effects of intrafrontocortical microinjections of dopamine agonists and antagonists on circling behavior of rats

Asymmetric posturing and circling behavior resulting from acute unilateral manipulation of central dopamine have been used to assess this neurotransmitter's contribution to motor control. Although providing extensive evidence for the involvement of mesolimbic and nigrostriatal dopamine in motor activity, this approach has not been used to study the mesocortical system. We now report circling behaviour following acute manipulation of frontal cortical dopamine. Unilateral microinjections of the agonists, (+)-amphetamine (12 and 25 micrograms in 1.0 microliter) and LY 141865 (12 micrograms in 1.0 microliter) resulted in contraversive circling. Conversely, unilateral intrafrontocortical microinjections of the antagonist, metoclopramide (25 and 100 micrograms in 1.0 microliter) resulted in ipsiversive circling in amphetamine (1.5 mg/kg, i.p.) pretreated rats. Lower central doses of each drug and vehicle injections had no significant effect. These results provide evidence for an excitatory influence of mesocortical dopamine on motor control. This finding may implicate frontal cortical dopamine in the extrapyramidal motoric side effects of chronic neuroleptic treatment which previously have been attributed to dopamine function in subcortical areas.     

Differential effects of D1 and D2 dopamine agonists on stereotyped locomotion in rats.

The study examines the effect of selective D1 dopamine stimulation with SKF38393 (1.25-10 mg/kg), on stereotyped locomotion induced by the D2 agonist, quinpirole (0.5 mg/kg). Quinpirole induces repeated travel along a few routes in a limited portion of the environment. Co-administration of low doses of SKF38393 (1.25-2.5 mg/kg) produces the following results: the rate of route perseveration is not affected; the area explored expands to encompass the entire periphery of the open field; and, spatial distribution of locomotion is transformed from routes that cross the center under quinpirole to travel only along the edge. Under higher doses of SKF38393, locomotion ceases. These findings suggest that D1 and D2 stimulation may control the spatial organization of locomotion in oppositional rather than synergistic manner.     

The electrically elicited startle blink reflex in patients with schizophrenia: A threshold study of different reflex components

The electrically elicited blink reflex consists of three components (R1, R2, R3). In humans the excitability of these components is influenced by attentional states. In particular, distraction from the stimulus leads to facilitation of the bilateral R2 and R3. The present study was performed in order to investigate the excitability of the different components of the electrically evoked blink reflex in 13 patients with schizophrenia and 13 normal controls under standard conditions. Therefore, the thresholds of the distinct components were determined without any inhibitory or facilitatory procedure. There was no significant difference in R1 and R2 thresholds between patients and controls. In contrast, the R3 threshold was significantly reduced in schizophrenic patients (R3 threshold = 17.5 mA in normal subjects, 10.5 mA in patients, p = 0. 0001). In recent studies the R3 magnitude was found to be highly susceptible to changes in the attentional state of normal subjects. The lower threshold of R3 in patients with schizophrenia might therefore be a neurophysiological marker of attentional dysfunctions in schizophrenia.     

Differential effects of D1 and D2 dopamine receptor agonists on substantia nigra pars reticulata neurons

Dopamine was shown in previous studies to exert a dual effect on non-dopaminergic neurons of the substantia nigra pars reticulata: it increases the firing rates of about 50% of cells, and consistently lessens the ability of iontophoretically applied or endogenously released GABA to inhibit their firing. These studies were undertaken to determine (1) whether the two effects could occur independently and, (2) whether different dopamine receptor subtypes might mediate the two responses. Extracellular, single unit activities of pars reticulata neurons were monitored in male rats anesthetized with chloral hydrate. Repeated 30-s iontophoretic pulses of GABA were delivered at an ejection current sufficient to inhibit cell firing by at least 50%, but not totally. After establishing a consistent response to GABA, co-iontophoresis of a test compound was initiated to determine its effects on basal firing rates and responsiveness to GABA. When acetylcholine and glutamate were evaluated in the test paradigm using ejection currents which excited cells by 54.0 +/- 4.9%, neither compound consistently altered the inhibition elicited by GABA. This confirmed that increases in cell firing could occur without concurrent GABA-attenuating effects, and supported the contention that the dual effects of dopamine could be dissociated and perhaps independently mediated. To examine whether the effects of dopamine involve actions at different dopamine receptor subtypes within the nigra, the D1 agonist SKF 38393 and the D2 agonist LY 171555 were substituted in the procedure. Applications of R,S(+/-)-SKF 38393 caused current-dependent increases in firing with a maximal increase at 8 nA of 55 +/- 18% above baseline (n = 14). The excitatory effect appeared to be D1-mediated since R(+)-SKF 38393, but not the inactive S(+)-enantiomer, could elicit the response. Conversely, graded applications of LY 171555 caused only occasional and more modest increases in basal activities, but consistently and markedly attenuated responses to GABA, decreasing GABA's inhibitory potency by 60.9 +/- 4.3% at 10 nA (n = 17). These results provide support for discrete roles of D1 and D2 receptors in substantia nigra pars reticulata, and suggest mechanistically distinct ways by which dendritically released dopamine could act to modify basal ganglia output from this region.     

Dystonia-Parkinson syndrome: differential effects of levodopa and dopamine agonists

Eleven patients who presented with predystonic syndrome later developed pure dystonic syndromes and later developed parkinsonism. This suggests that dystonic syndromes can be the precursor to a mixed syndrome including both dystonia and parkinsonism. While the parkinsonian features in such patients respond to either levodopa or direct-acting agonists, levodopa often exacerbates the underlying dystonia. Direct acting agonists appear to be less liable to do this.     

Differential responses of rat cerebral somatostatinergic and cholinergic cells to glutamate agonists

Reductions in cortical somatostatin (SRIH) and choline acetyltransferase (ChAT) are major biochemical deficits in Alzheimer disease (AD). SRIH and ChAT were measured in fetal rat cerebral neurons after exposure to the glutamate agonistsN-methyl-d-aspartate (NMDA), kainate (KA), and quisqualate (Q). NMDA (96 h incubation) stimulated SRIH release and content in a dose-dependent manner with aB _max of 10^?5 M and EC₅₀ of 2?3×10^?6 M. KA showed a small stimulation in SRIH levels at 10^?5 M, but produced marked inhibition at 10^?4 M. Q decreased both intracellular and secreted SRIH. KA (51–76% of basal) and Q (27–56% of basal) but not NMDA (91–114% of basal) also inhibited the incorporation of [³⁵S]methionine into proteins. In similar experiments 10^?4 M Q (23±9% of basal) and KA (20±3% of basal) but not NMDA (80±16% of basal) reduced ChAT levels in hypothalamic/septal cultures. These inhibitory actions on ChAT activity by KA and Q were reversed by γ-glutamyltaurine (GT) but not by 2-amino-5-phosphonopentanoic acid (AP5). Chronic NMDA exposure partially inhibited muscarinic acetylcholine receptor (mAChR) mediated inositol phospholipid (PI) turnover, whereas it was abolished after KA and Q pretreatment. These findings suggest that in cerebral cell cultures, NMDA has a stimulatory action on somatostatinergic neurons and non-NMDA receptor agonism could play an important role in EAA-mediated neural damage.     

An in vivo voltammetric comparison of the effects of three psychomotor stimulants on electrically evoked neostriatal dopamine release

The effects of three psychomotor stimulants (mazindol, beta-phenylethylamine and D-phenmetrazine) on electrically evoked neostriatal dopamine release were studied by in vivo voltammetry. Mazindol (10 mg/kg) enhanced release and this effect persisted after dopamine synthesis inhibition by alpha-methyl-p-tyrosine. beta-Phenylethylamine (100 mg/kg) caused a large decrease in stimulated dopamine release and exerted no effect after dopamine synthesis inhibition. D-Phenmetrazine (45 mg/kg) enhanced dopamine release on the first post-drug stimulation and also restored release after dopamine synthesis inhibition. Disruption of vesicular dopamine storage by Ro 4-1284 abolished electrically stimulated dopamine release. Only D-phenmetrazine was able to cause dopamine release following Ro 4-1284. These results imply different biochemical modes of action of these three stimulants.     

Effects of dopamine depletion on rotational behavior to dopamine agonists

The contralateral rotation to various dopamine agonists was determined in rats with unilateral lesions of the left nigrostriatal pathway both with and without dopamine depletion caused by dopamine synthesis inhibition. The rotation to drugs possessing D-2 dopamine agonist activity alone was greatly diminished by dopamine depletion. In contrast, the rotation induced by drug possessing D-1 dopamine agonist activity (either D-1 alone or D-1 plus D-2) was affected to a much lesser extent by dopamine depletion.     

Contribution of the amygdala and nucleus accumbens to ventral pallidal responses to dopamine agonists.

Neurons recorded from ventral pallidum/substantia innominata (VP) of the basal forebrain respond to dopaminergic agonists that activate either the D1 or D2 the receptor subtype. Major afferent systems to the VP originate within amygdaloid nuclei (AMN) and the nucleus accumbens (NA). Since both the AMN and the NA are dopaminoceptive, the present study sought to analyze the contribution of these afferent systems to VP responses to dopaminergic agonists. Single VP neurons were electrophysiologically recorded in vivo from chloral hydrate-anesthetized rats, and the following determinations were made. 1) Effects of pharmacologic inactivation of an afferent system were assessed by monitoring VP neurons during intracerebral microinjections of the local anesthetic procaine, administered directly into either the AMN or the NA. 2) With procaine-induced VP rate changes used to indicate an afferent influence on the recorded neuron, VP responses to apomorphine (an agonist that acts at D1 and D2 receptor subtypes), SKF38393 (a D1 agonist), or quinpirole (a D2 agonist) were determined and compared with responses in rats not receiving the procaine pretreatment. Following pharmacologic inactivation of either the AMN or the NA, approximately 80% of the VP neurons monitored demonstrated rate changes, illustrating that spontaneous neuronal firing in the Vp is dependent on tonically input systems. Following afferent cessation, responses to apomorphine and quinpirole remained intact, suggesting that the AMN or NA is not necessary for VP responding to the systemic administration of dopaminergic agonists that act at D2 receptors. In contrast, the number of neurons that responded to SKF38393 was diminished follow intra-AMN (but not intra-NA) procaine. This suggests that D1-induced VP responses are mediated, at least in part, via the AMN.     

Effects of ageing on the behavioural responses to dopamine agonists: decreased yawning and locomotion, but increased stereotypy

Sensorimotor function and the behavioural responses to a range of doses of subcutaneous apomorphine were assessed in mature (6-8 months) and old (23-26 months) Sprague-Dawley rats of comparable weight. In addition, the locomotor activity response of 12-month-old and 24-month-old rats to continuous infusions (14 days by osmotic minipump) of a selective dopamine D2 agonist. (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 10 micrograms/h) was investigated. Measures of spontaneous locomotor activity and motor coordination revealed impairments in the aged animals. Low doses of apomorphine (10-50 micrograms/kg), which preferentially activate dopamine autoreceptors, induced yawning, chewing mouth movements and penile grooming. The frequency of yawning and duration of penile grooming were significantly decreased in the old animals. In contrast, 200 micrograms/kg of apomorphine induced stereotyped sniffing and licking or gnawing, and these responses were significantly increased in the aged animals. There was a 25% decrease in striatal dopamine levels in the aged animals in this experiment. PHNO increased the amplitude of the circadian rhythms in locomotor activity exhibited by mature rats, and daytime tolerance to the stimulant effects of PHNO was reversed by stress in these animals. Both of these effects were attenuated in the aged rats. These findings suggest that (1) the dopamine receptors mediating yawning and stereotypy have different anatomical locations (2) ageing is associated with decreased responsiveness to stimulation of dopamine autoreceptors, consequent upon the loss of dopaminergic nerve terminals, and (3) while the functional response to selective stimulation of postsynaptic D2 receptors decreases with age, the postsynaptic response to a mixed D1/D2 agonist increases.     

Dihydroergocriptine in Parkinson's disease: clinical efficacy and comparison with other dopamine agonists

The present paper reviews clinical studies on the use of dihydroergocriptine (DHEC), an ergot derivative with dopamine agonist activity, for the treatment of Parkinson's disease. This compound is a hydrogenated ergot derivative structurally quite similar to bromocriptine, from which it differs because of the hydrogenation in C9 C10 and the lack of bromine in C2. DHEC has a potent D2-like receptor agonist and a partial D1-like receptor agonist activity; because of this biochemical profile, it has been suggested that DHEC may produce fewer side-effects and have clinical efficacy equal to that of a classical dopamine agonist. Several open-label and double-blind studies indicate that DHEC is an efficacious remedy for parkinsonian signs and symptoms. Further studies are necessary to compare DHEC to new dopamine agonists (pergolide, cabergoline, ropinirole, and pramipexole) which have been more recently marketed.     

A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson's disease

To compare the efficacy and tolerability of three dopamine agonists--pergolide (PRG), pramipexole (PRX), and ropinirole (ROP)-and two catechol-O-methyltranferase (COMT) inhibitors-tolcapone (TOL) and entacapone (ENT)-as add-on therapies to levodopa (L-Dopa) in Parkinson's disease, we analyzed randomized, double-blind, placebo-controlled, multicenter studies. To our knowledge, they had not yet been evaluated in comparison with each other. Statistical analyses used odds ratios, numbers needed to harm, and Fisher's inverse chi2 method. Seven studies meeting the inclusion criteria included treatment of 1,756 patients. The common efficacy measures were the reduction of L-Dopa dose and "off' duration. The reported reduction in L-Dopa dose was significant for all drugs in relation to placebo, but was most significant for PRX and ENT (p < 0.0001). The most significant reduction in "off' duration was with PRG, PRX, and ENT (p < 0.001). The common tolerability measures were the percentage of patients withdrawn because of side effects, because of any reason, and because of the development of dyskinesias. Ropinirole, PRX, and ENT caused fewer withdrawals related to side effects. Pergolide was better than other analyzed drugs concerning withdrawals for any reason. All drugs caused more dyskinesias than placebo (p < 0.0001), with overlapping confidence intervals, except for TOL 600 mg, which caused more dyskinesias than dopamine agonists and ENT. Pramipexole and ENT had the best efficacy and tolerability profile in this analysis.     

Effects of various direct or indirect dopamine agonists on the latency of the acoustic startle response in rats

Summary The effects of dopamine agonists were investigated on the latency of the acoustic startle response in male Wistar rats. Four indirect dopamine agonits were tested: GBR 12783 (5–20mg/kg), BTCP (5–20mg/kg), dexamphetamine (3–6mg/kg) and L-DOPA 100 mg/kg associated with benserazide 25 mg/kg; they induced an increase in startle latency. Apomorphine at a dose (50 g/kg) known to decrease dopaminergic transmissions, was ineffective on the startle response. On the contrary, at 0.6 or 2 mg/kg, apomorphine induced an increase in the startle latency. A similar effect was observed with bromocriptine at 10 mg/kg from the 10th min up to at least the 9th hour after treatment. The specific agonist of D2 receptors Ru 24926 (0.45 mg/kg) enhanced the startle latency as well as the specific agonist of D1 receptors SKF 38393 (10 mg/kg). The association of these drugs resulted in an apparent additivity of their individual effects. The effect of apomorphine (0.6 mg/kg) was only partially reduced by a high dose of the specific D2 antagonist amisulpride (80 mg/kg) and more clearly antagonized by the specific D1 antagonist SCH 23390 (50 g/kg). It is concluded that D2 and D1 receptors contribute to the increase in startle latency elicited by direct or indirect dopamine agonists.     

Behavioral effects of fetal substantia nigra tissue grafted into the dopamine-denervated striatum: responses to selective D1 and D2 dopamine receptor agonists

Grafts of fetal ventral mesencephalon/substantia nigra cell suspensions into the dopamine-denervated striatum have been shown to reduce many of the behavioral alterations associated with striatal dopamine depletion. In this report, the behavioral response to amphetamine, apomorphine, the D1 receptor agonist SKF82958, and the D2 receptor agonist LY171555 were tested before and after intrastriatal grafts of fetal substantia nigra, of fetal striatum or no implantation procedure in animals with unilateral dopamine denervation. Grafts of fetal substantia nigra tissue were associated with significant behavioral recovery, as indicated by decreased turning induced by amphetamine (P ≤ 0.005), SKF82958 (P < 0.005), and LY171555 (P < 0.002). These effects were significantly different from the response in animals that did not receive grafts (P < 0.05) and occurred in the absence of decreased apomorphine-induced turning. These data suggest that the response to selective D1 or D2 dopamine receptor agonists is diminished following grafts of fetal dopaminergic tissue and that this behavioral effect is dissociable from the phenomena of behavioral supersensitivity to apomorphine. In a subset of substantia nigra grafted animals, it was found that D1 or D2 dopamine receptor antagonists administered 30 min prior to apomorphine could significantly reduce apomorphine-induced turning.     

Differential blockade of bicuculline and strychnine on GABA- and glycine-induced responses in dissociated rat hippocampal pyramidal cells

The inhibitory effects of bicuculline (BIC) and strychnine (STR) on GABA- and glycine-induced responses were studied in the rat dissociated hippocampal CA1 pyramidal neurons in whole-cell mode by using the conventional patch-clamp technique. Both GABA and glycine elicited inward Cl- currents in a dose-dependent manner and had almost the same maximal responses. The half-maximum dose (Ka) and Hill coefficient were 6.4 microM and 1.1 for the GABA response, and 74 microM and 1.5 for the glycine response. BIC and STR antagonized both GABA and glycine responses in a competitive manner. The blocking potency of BIC and STR on the GABA response was comparable. The half inhibition dose (IC50) was 2.7 microM for BIC and 6.7 microM for STR. STR blocked the glycine response about 3,000 x more effectively than BIC. The IC50 was 28 nM for STR and 100 microM for BIC. The BIC and STR did not have voltage-dependent blocking effects on either GABA or glycine responses. Neither GABA nor glycine showed outward rectification in their current-voltage relationships. The functional role of glycine in the rat hippocampal CA1 region is discussed.