Central DA Research Articles

Parent-offspring cohabitation after weaning inhibits partner preference and alters central oxytocin and dopamine systems in adult mandarin vole.

In some mammals, offspring may live with their parents for a very long time after weaning, but little is known about the effect of post-weaning parent-offspring cohabitation on the behavioral and neurobiological development of offspring. Here, we explored the effect of this experience on partner preference in adult mandarin vole (Microtus mandarinus). Levels of central oxytocin (OT), tyrosine hydroxylase (TH), as well as OT receptor (OTR), dopamine D1-type and D2-type receptors (D1R and D2R) mRNA expression in the nucleus accumbens (NAcc) and medial amygdala (MeA) were also measured. Our data showed that post-weaning living with parents inhibited the preference to partner over an unfamiliar opposite-sex conspecific. Voles with this experience possessed more OT-but less TH-immunoreactive neurons as compared to the control. Additionally, males with this experience had less D2R and OTR mRNA expression in the NAcc than the control while females had less D2R mRNA expression in the NAcc, but more OTR mRNA expression in the MeA. These findings demonstrate that post-weaning parent-offspring cohabitation inhibits the partner preference formation at adulthood, and these changes may be associated with alterations in the levels of central OT and DA, and their receptor mRNA expression in specific brain regions.

Dopamine and executive function: Increased spontaneous eye blink rates correlate with better set-shifting and inhibition, but poorer updating

The central dopamine system (DA) has a significant role in the executive function (EF). The spontaneous eye blink rate (EBR) is an effective clinical and non-invasive measure, which is strongly related to the activity of the central dopaminergic system. Previous studies show significant relationships between the two main dimensions of EF (i.e., shifting and inhibition) and the central DA system as measured by EBR. However, most of these studies involve only one EF task for shifting or inhibition; whether or not these relationships are replicated by other EF tasks remains unclear. Besides, the relationship between EBR and another important EF dimension—updating—also remains unknown. The present study examined the correlation between EBR and several EF tasks that captured all the three EF dimensions: shifting, inhibition, and updating. A total of 61 healthy participants were subjected to EBR testing and EF tasks. Results showed that EBR had a different relationship with each of the three tested EF dimensions. An increase in EBR levels was related to an increase in accuracy in shifting and inhibition tasks, a decrease in shifting and inhibition cost, and a decrease in accuracy in updating tasks. These results imply that the role of the central DA system in shifting and inhibition differs from its role in updating.

Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression

Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed in acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and rotenone rat models of degeneration. It is not known if the resistance of TIDA neurons is a constitutive or induced cell-autonomous phenotype for this unique subset of DA neurons. In the present study, treatment with a single injection of MPTP (20mg/kg; s.c.) was employed to examine the response of TIDA versus NSDA neurons to acute injury. An acute single dose of MPTP caused an initial loss of DA from axon terminals of both TIDA and NSDA neurons, with recovery occurring solely in TIDA neurons by 16h post-treatment. Initial loss of DA from axon terminals was dependent on a functional dopamine transporter (DAT) in NSDA neurons but DAT-independent in TIDA neurons. The active metabolite of MPTP, 1-methyl, 4-phenylpyradinium (MPP+), reached higher concentration and was eliminated slower in TIDA compared to NSDA neurons, which indicates that impaired toxicant bioactivation or distribution is an unlikely explanation for the observed resistance of TIDA neurons to MPTP exposure. Inhibition of protein synthesis prevented TIDA neuron recovery, suggesting that the ability to recover from injury was dependent on an induced, rather than a constitutive cellular mechanism. Further, there were no changes in total tyrosine hydroxylase (TH) expression following MPTP, indicating that up-regulation of the rate-limiting enzyme in DA synthesis does not account for TIDA neuronal recovery. Differential candidate gene expression analysis revealed a time-dependent increase in parkin and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) expression (mRNA and protein) in TIDA neurons during recovery from injury. Parkin expression was also found to increase with incremental doses of MPTP. The increase in parkin expression occurred specifically within TIDA neurons, suggesting that these neurons have an intrinsic ability to up-regulate parkin in response to MPTP-induced injury. These data suggest that TIDA neurons have a compensatory mechanism to deal with toxicant exposure and increased oxidative stress, and this unique TIDA neuron phenotype provides a platform for dissecting the mechanisms involved in the natural resistance of central DA neurons following toxic insult.

Evidence that a novel dopamine receptor agonist, RDS-127 [2-di-n-propylamino-4,7-dimethoxyindane] has some centrally mediated cardiovascular actions.

The cardiovascular effects of RDS-127 [2-di-n-propylamino-4,7-dimethoxyindane] were examined in normotensive, anaesthetized rats. RDS-127 given i.v. (12.5-125 micrograms kg-1) produced dose-dependent bradycardia. The bradycardic effect was 20.5 times more potent when the drug was administered intracerebroventricularly (i.c.v.) than when given i.v. RDS-127 produced a slight, but significant hypotension. Haloperidol given i.c.v. or i.v. reversed these bradycardic and hypotensive actions, whereas phentolamine was ineffective. Methylatropine partially reduced the bradycardic effect. These results suggest that RDS-127 activates central DA receptors to produce hypotension and bradycardia in rats.

Effects of dietary fat and enterostatin on dopamine and 5-hydroxytrytamine release from rat striatal slices

Studies have demonstrated defects of DA and 5 HT neurotransmission in dietary fat induced obese animals. In the present study, we used a perfusion system to assay the release of DA and 5 HT from striatal slices preloaded with [ 3H]-DA or [ 3H]-5 HT. The release of both DA and 5 HT from striatal slices of rats fed a high fat diet for 10 days, but not 3 days, was reduced when compared to striatal slices taken from rats fed a low fat diet. Enterostatin, an endogenous pentapeptide inhibits dietary fat intake when administered peripherally and centrally in animals. The central mechanism for the action of enterostatin is not yet determined even though several mechanisms have been suggested. We have shown that enterostatin enhanced [ 3H]-DA release, but not [ 3H]-5HT release from striatal slices of rats that had been adapted to high fat diet for 10 days. The enterostatin-induced increase in [ 3H]-DA release was blocked by nomifensine. Enterostatin did not alter [ 3H]-DA or [ 3H]-5HT release from striatal slices of rats adapted to high fat or low fat diet feeding for 3 days. These findings suggest that enterostatin may inhibit dietary fat intake by blocking dopamine reuptake transport to increase central striatal DA release from rats that have acquired diminished dopamine signal after an adaptive period of fat consumption.

Increased left striatal dopamine transmission in unaffected siblings of schizophrenia patients in response to acute metabolic stress

A genetic alteration in sensitivity to stress, mediated by mesolimbic hyperdopaminergia, is thought to play a role in the onset, exacerbation and relapse of schizophrenia. Dopamine sensitivity to stress was tested in individuals at higher than average genetic risk for schizophrenia (siblings of patients). Using a PET paradigm of [ 11C]raclopride in a bolus plus constant infusion tracer injection, the central DA response to acute metabolic stress (bolus of 2-Deoxy- d-Glucose, 40 mg/kg) in unaffected siblings of patients with schizophrenia ( n = 8) and healthy controls ( n = 10) was measured by BP ND of [ 11C]raclopride before and after the 2DG challenge. After metabolic stress, controls but not siblings displayed a significant decrease in BP ND of [ 11C]raclopride in the striatum; no such differences were apparent in the ventral striatum. Siblings but not controls displayed significant asymmetry (L > R) in the stress-induced DA release, especially in ventral striatum, which correlated strongly with psychometric measures of psychosis liability. The results suggest that asymmetry in the mesolimbic DA response to stress is associated with genetic risk for schizophrenia, possibly reflecting the functional consequences of structural disconnectivity underlying psychotic symptoms.

Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals

We investigated the effects of salvinorin A on the basal and the 12 mM K +-evoked release of preloaded [ 3H]noradenaline ([ 3H]NA) and [ 3H]serotonin ([ 3H]5-HT) from mouse hippocampal nerve terminals (synaptosomes), as well as on the basal and 12 mM K +-evoked release of preloaded [ 3H]dopamine ([ 3H]DA) from mouse striatal and prefrontal cortex (PFc) synaptosomes. Salvinorin A (0.1–1000 nM) failed to affect the basal release of amines, but inhibited the 12 mM K +-evoked, Ca 2+-dependent, exocytotic-like release of [ 3H]5-HT and [ 3H]DA. At the same concentration, salvinorin A facilitated the 12 mM K +-evoked, Ca 2+-dependent, exocytotic-like release of [ 3H]NA. These effects could not be observed in pertussis toxin (PTx) entrapped synaptosomes. The broad spectrum κ-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 1–100 nM) antagonized the inhibition of [ 3H]5-HT and [ 3H]DA exocytosis as well as the facilitation of [ 3H]NA overflow induced by 100 nM salvinorin A. The KOR agonist U69593 (1–100 nM) mimicked salvinorin A in inhibiting [ 3H]5-HT and of [ 3H]DA exocytosis, its effect being prevented by norBNI, but leaving unchanged the K +-evoked release of [ 3H]NA. The effects of Salvinorin A on neurotransmitter exocytosis were not prevented by the selective μ opioid (MOR) receptor antagonist CTAP (10–100 nM), whereas facilitation of [ 3H]NA exocytosis, but not inhibition of [ 3H]5-HT and [ 3H]DA K +-evoked release, was counteracted by the δ opioid receptor (DOR) antagonist naltrindole (1–100 nM). We conclude that salvinorin A presynaptically modulates central NA, 5-HT, and DA exocytosis evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptors having different pharmacological profiles.

Effect of Apomorphine on the Conflict-Induced Jumping Stereotypy in Bank Voles

In conventional laboratory cages, bank voles ( Clethrionomys glareolus) develop a jumping up-and-down stereotypy already before the age of one month. Central DA systems are thought to be involved in the expression of these conflict-induced stereotypies (CIS). Stereotypies can also be elicited pharmacologically, most commonly by amphetamine and apomorphine. Hence, administration of apomorphine to jumping bank voles provides the opportunity to compare pharmacologically-induced stereotypies (PHIS) and CIS in that species. A pilot study showed that apomorphine induced stereotyped licking that is qualitatively different from the CIS elicited by captivity. The present study investigated whether apomorphine has an effect on CIS-levels. The lowest dose (0.625 mg/kg) did not elicit licking but neither influenced jumping levels. Higher doses (0.938 and 1.094 mg/kg) lead to the occurence of licking but also suppressed CIS-levels. However, the discordance in time profiles of licking and jumping argues against a shift from jumping to licking due to further stimulation of already activated DA systems. Therefore, expression of jumping seems to depend on stimulation of other DA receptor subtypes or jumping may even be DA independent.

Gamma hydroxybutyrate is not a GABA agonist

Gamma hydroxybutyrate (GHB) is primarily known and used as a relatively specific inhibitor of central DA release. However, it is also widely assumed to be an agonist or prodrug of gamma-aminobutyric acid (GABA) and its central activity has been attributed to an action exerted at GABA receptors. Nevertheless, there is compelling evidence that: (1) GHB formation may occur independently of GABA; (2) GHB is behaviorally, biochemically and physiologically distinct from GABA in many ways, and does not consistently effect GABAAor GABAB agonist induced responses; (3) GHB has little effect on either GABAA or GABAB receptors at less than millimolar concentrations. Consequently, GHB does not appear to be either a GABA prodrug or a GABA agonist. However, the GHB metabolite gamma butyrolactone (GBL) may possess some limited GABA agonist activity.

Brain neuromediator systems in the immune response control: pharmacological analysis of pre- and postsynaptic mechanisms

The involvement of the dopaminergic (DAergic), GABAergic and serotoninergic (5-HTergic) synaptic mechanisms in neuroimmunomodulation are considered. It is shown that the central DA- and GABAergic systems exert a stimulatory influence on the immune reactivity. Activation of postsynaptic DA receptors with apomorphine and (+)(3-hydroxyphenyl)- N-n-propylpiperidine [(+)-3-PPP] at high doses, D2 receptor activation with quinpirole, as well as DA reuptake blockade with amantadine and bupropion, resulted in an increase in the immune response. The intensity of the immune response was also increased during activation of the GABAergic system with the GABA agonist muscimol or the benzodiazepine agonists diazepam and tazepam. On the other hand, decreases in the activity of either system by different drugs inhibiting DAergic and GABAergic neurotransmission (antagonists of DA postsynaptic receptors haloperidol at 1.0 mg/kg and (-)-3-PPP at 6.8 mg/kg, agonists of DA autoreceptors apomorphine at 0.02 mg/kg, (-)- and (+)-3-PPP at 1.7 and 3.4 mg/kg, antagonist of GABA receptors bicuculline, blocker of chloride channels picrotoxin, blockers of benzodiazepine receptors Ro 15-1788 and Ro 15-3505) produce suppression of the immune response. The 5-HTergic system is involved in the inhibitory mechanism of neuroimmunomodulation. 5-HT reuptake blockade with 4-(5,6-dimethyl- R-benzophuranil)-piperidine (CGP-6085A) and sertraline led to immunosuppression.

Synthesis of (+)-(R)- and (-)-(S)-5-hydroxy-2-methyl-2-dipropylaminotetralin: effects on rat hippocampal output of 5-HT, 5-HIAA, and DOPAC as determined by in vivo microdialysis.

Racemic 5-methoxy-2-methyl-2-dipropylaminotetralin (3) has been prepared by a short synthetic route, in which the N,N-dipropyliminium perchlorate of 5-methoxy-2-tetralone (4) is a key intermediate. Racemic 3 was resolved by crystallization of the corresponding diastereomeric di-p-toluoyltartrates. The enantiomeric excess (%ee) of the phenolic derivatives of (+)-(R)- and (-)-(S)-3 [(+)-(R)- and (-)-(S)-2] was determined by 1H NMR spectroscopic analysis of the corresponding diastereomeric (-)-(R)-1,1'-binaphthyl-2,2'-diylphosphoric acid salts utilizing 13C satellites. X-ray crystallography established the absolute configuration of (-)-(S)-2.HCl. The enantiomers of 2 were tested for hippocampal output of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, and dihydroxyphenylacetic acid in rats by use of in vivo microdialysis. The (-)-(S)-enantiomer appeared to affect 5-HT-turnover, whereas (+)-(R)-2 was inactive. Results obtained provide support for the previously reported hypothesis that the inactivity of (-)-(S)-2 at central DA receptors is caused by the steric bulk of the C(2)-methyl group. This makes it possible to define a "DA D2 receptor essential volume."

Antagonism of limbic and extrapyramidal actions of intracerebrally injected dopamine by ergolines with partial D 2 agonist activity in the rat

Bromocriptine and a series of experimental ergoline D 2 partial agonists (SDZ-208-911, SDZ-212-327, SDZ-208-912) were evaluated for their interactions with exogenous dopamine (DA, at ED 50 = 16 μg) stereotaxically injected unilaterally into a limbic (superior-medial nucleus accumbens septi) or extrapyramidal (central corpus striatum) target site in rat brain. Behavioral measures to quantify responses were locomotor arousal induced by DA in, accumbens and contralateral head turning with striatum. All agents, given systematically (i.p.), induced dose-dependent inhibition of behavioral responses to DA from both brain sites. In both accumbens and striatum, SDZ-212-327 was most potent and bromocriptine, least; however, bromocriptine was relatively much more potent in accumbens striatum, SDZ-208-912 somewhat more potent in striatum. These results add to the growing impression that agents with partial agonist actions at central DA receptors can show behaviorally inhibitory effects that may reflect paradoxical antidopaminergic actions against the full, natural agonist of DA receptors and that such effects can be regionally selective.

Increased apomorphine-induced hypothermia precedes development of hypertension in SHRs

Apomorphine produced a greater hypothermic response in spontaneously hypertensive rats (SHRs) than in normotensive Wistar-Kyoto rats (WKYs). Experiments were conducted in SHRs and WKYs of three age groups to determine whether the increased hypothermie responsiveness to apomorphine occurs prior to the development of hypertension. The mean systolic blood pressures (SBPs) of SHRs and WKYs were comparable at 4–6 weeks of age. The mean SBP of SHRs were significantly greater than that of WKYs at both 8–10 and 12–15 weeks of age. Yet SHRs responded to apomorphine with significantly greater hypothermia than WKYs at all three ages. These findings indicate that the hyperresponsiveness of SHRs to apomorphine-induced hypothermia precedes the development of hypertension. This sequence of events is consistent with the hypothesis that central DA systems play a role in development of hypertension in SHRs.

Stressor-induced alterations of natural killer cell activity and central catecholamines in mice

Natural killer (NK) cell cytotoxicity was determined at various intervals (0.5, 24 or 48 h) following exposure to uncontrollable footshock in 3 strains of mice. Stressor application provoked reductions of NK activity, but the time course of the NK changes varied across strains. Whereas NK cytotoxicity was markedly reduced in C57BL/6J mice 0.5–48 h following stressor exposure, this effect was delayed in C3H/HeJ mice, being evident 24–48 h following stressor application. In BALB/cByJ mice, NK activity was significantly reduced 24 h after footshock, but in contrast to the other strains returned to control levels within 48 h of stressor exposure. Central NE and DA concentrations and activity were influenced by the stressor treatment in a strain-dependent fashion. However, the relationship between the central amine variations and the alterations of NK cytotoxicity associated with the stressor was limited.

Role of central dopaminergic pathways in the neural control of growth hormone secretion in normal men: studies with metoclopramide.

The aim of this study was to gain further insight into the role that central dopaminergic pathways play in GH neuroregulation in man. Our experimental hypothesis was based on the possibility that most of the controversies on DA role could be due to the fact that the hypothalamic somatotroph rhythm (HSR) was not taken into account when interpreting the GH responses after pharmacological manipulations on dopaminergic pathways. In 10 normal subjects we monitored the effect of central dopaminergic blockade, achieved with metoclopramide (MCP; 10 mg, i.v. bolus), on the pattern of spontaneous GH secretion and the GH responses to a GHRH challenge (GRF1-29, 1 microgram/kg, i.v. bolus) administered together with MCP or 60 min after this drug was given. The study of HSR was made according to our previous postulate. Our results indicate that MCP administration, either prior to or together with the GHRH bolus, significantly increased GHRH-induced GH release during a refractory HSR phase; but not when the GHRH challenge took place during a spontaneous secretory phase. The strong relationship between pre-GHRH plasma GH values and GHRH-elicited GH peaks was lost when MCP was given. These data indicate that MCP was able to disrupt the intrinsic HSR by inhibiting the hypothalamic release of somatostatin (SS). While a main conclusion would be that central DA is a secretagogue for SS secretion, our results also suggest that this role could be dependent on its effects on the adrenergic inputs to SS neurons.

Neurotensin attenuates dopamine D2 agonist quinpirole-induced inhibition of midbrain dopamine neurons

The effects of intracerebroventricular (i.c.v.) administration of NT on the activity of midbrain DA neurons were studied in rats using single unit recording techniques. NT (i.c.v., 50 μg) was found to have no significant effect on the spontaneous activity of DA cells. On the other hand, NT treatment significantly attenuated the inhibitory effect of quinpirole (i.v.), a specific D2 agonist, on a subpopulation of DA cells. This result is consistent with previous behavioral and biochemical studies suggesting that NT may produce some of its effects through modulation of central DA systems.

The effects of intracranial administration of the dopamine agonist apomorphine on penile reflexes and seminal emission in the rat

Previous studies employing systemic administration of the dopamine agonist apomorphine have shown that the dose response curves for apomorphine's effects on penile reflexes and seminal emission differ, suggesting that experimentally separable populations of dopamine receptors regulate these two responses. The present experiments examined the locations of central nervous system DA receptors mediating genital responses in the restrained, supine rat by injecing apomorphine into the medial preoptic area and the paraventricular nucleus through chronic, indwelling cannulae. Medial preoptic area injections facilitated penile reflexes, but not seminal emission, while paraventricular injections facilitated seminal emission. These results suggest that systemically administered apomorphine may facilitate penile reflexes by acting on the medial preoptic area and may enhance seminal emission by acting on the paraventricular nucleus.

Relationships between mesolimbic dopamine function and eating behavior.

These experiments are the first to correlate a specific stimulus of eating--the orosensory stimulation by sucrose--to mesolimbic dopaminergic activity. The pharmacological results and the increase in hypothalamic DOPAC/DA are convergent evidence for this relationship. The meaning of the relationship is not clear. The possibility that the decreased intake after dopaminergic receptor antagonist treatment and the increase in hypothalamic DOPAC/DA is related to the ingestive movements necessary for sham feeding seems unlikely for the following reasons: first, at least one dose of the antagonist had a preferential inhibition on sucrose intake compared to water intake; second, the D1 and D2 selective receptor antagonists decreased the initial rate of sucrose intake, but did not affect the rate of decay of sucrose intake over a 30-min test; third, in the second neurochemical experiment (Table 1), the volume ingested during 9 min of sham feeding 10% sucrose was not significantly different from the volume ingested from sham feeding 40% sucrose, but there was a significantly larger increase in the hypothalamic DOPAC/DA after 40% sucrose. Of course, a finer measurement of movements, such as lick rate, may reveal a significant difference that would correlate with the metabolic change. Fourth, striatal DOPAC/DA did not change during sham feeding of sucrose. Fifth, Bailey et al. demonstrated that a response-frequency summation analysis of the inhibitory effect of pimozide on sucrose intake did not reveal a motoric deficit. Thus, we interpret the increase of hypothalamic DOPAC/DA during the sham feeding of sucrose as evidence that activation of mesolimbic dopaminergic terminals in the hypothalamus is necessary for the normal processing of the central sensory and/or positive-reinforcing information produced by oral sucrose stimulation. Experiments are in progress to test this hypothesis and to attempt to distinguish between the sensory and positive-reinforcing effects of sucrose during sham feeding. In addition to generating this specific hypothesis concerning sucrose and hypothalamic DA activity, the results of these experiments suggest that the sham feeding preparation will be useful for the analysis of the important problem of the natural reinforcing properties of sweet taste. And finally, since sham feeding of sucrose is a form of oral self-stimulation, it provides a new experimental tool for comparing the role of central DA mechanisms in the positive-reinforcing effects of food, psychostimulant self-administration, and intracranial electrical self-stimulation.

Imidazole and yohimbine antagonize hypomotility, penile erection, stretching and yawning induced in rats by BHT 920, a selective dopamine autoreceptor agonist

When the azepine derivative BHT 920, a putative agonist at dopamine autoreceptors, was injected i.p. into adult male rats at 100 μg/kg, it induced numerous penile erections, stretching and yawning and sedation, all considered typical signs of central DA autoreceptor stimulation, but did not elicit stereotyped behaviour. Imidazole (37.5–150 mg/kg i.p.) and the α2 antagonist yohimbine (0.5–1 mg/kg i.p.) both antagonized the behavioural effects of BHT 920. In the light of the proposed selective action of the drugs used, the possible involvement of specific receptors for the modulation of these forms of behaviour, as well the possible relevance of the data presented, are briefly discussed.

Central dopamine-peptide interactions: Electrophysiological studies

A variety of peptides have been shown to have physiological activity, either pre- or post-synaptically in DA systems. Significantly, this has not been true of all the peptides tested and physiological activity has for the most part, correlated with anatomical evidence for the presence of that peptide in the same area as DA and with the presence of specific receptors for the active peptide. In the main, biochemical and behavioral studies of the effects of peptides on the function of DA systems also correlate well with the effects of the various peptides on the activity of DA neurons. However, despite this growing body of knowledge we still know very little about the physiological relevance of most peptides to animal behavior or the interaction between these peptides and DA systems. This is due, in part, to the fact that the functioning of peptide systems is still relatively difficult to study in terms of synthesis, release, metabolism and turnover. The fact that there are very few selective non-peptide antagonists for many of these substances has also hampered the study of their function in the brain. Nevertheless, their proven interaction with midbrain DA systems, regardless of whatever else they may do in the brain, makes them of great potential clinical interest. Given the number of neurological and mental disorders in which malfunction of the DA system is presumed to be involved, any endogenous substance that can modulate activity of the DA cells and thus provide a new mechanism for controlling the functioning of central DA systems may have potential therapeutic value. Furthermore, in many of the CNS disorders in which DA systems are thought to be involved a change in the concentration (in dopamine-containing areas) of one or more of the peptides reviewed here has been found. Such findings provide further support for the idea that these substances and their interaction with dopamine systems may turn out to be clinically relevant.