Modulation Of Dopaminergic Neurotransmission Research Articles

The trace amine-associated receptor 1 agonists - non-dopaminergic antipsychotics or covert modulators of D2 receptors?

A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments.

Are CB2 Receptors a New Target for Schizophrenia Treatment?

Schizophrenia is a complex disorder that involves several neurotransmitters such as dopamine, glutamate, and GABA. More recently, the endocannabinoid system has also been associated with this disorder. Although initially described as present mostly in the periphery, cannabinoid type-2 (CB2) receptors are now proposed to play a role in several brain processes related to schizophrenia, such as modulation of dopaminergic neurotransmission, microglial activation, and neuroplastic changes induced by stress. Here, we reviewed studies describing the involvement of the CB2 receptor in these processes and their association with the pathophysiology of schizophrenia. Taken together, these pieces of evidence indicate that CB2 receptor may emerge as a new target for the development of antipsychotic drugs.

Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase.

The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating “Go” responses upon exposure to reward-related stimuli and “NoGo” responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson’s disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.

Inflammation-induced aversion is elicited by prostaglandin-dependent modulation of dopaminergic neurotransmission

Inflammation-induced aversion is elicited by prostaglandin-dependent modulation of dopaminergic neurotransmission

Experimental treatment of antipsychotic-induced movement disorders.

Antipsychotic drugs are extensively prescribed for the treatment of schizophrenia and other related psychiatric disorders. These drugs produced their action by blocking dopamine (DA) receptors, and these receptors are widely present throughout the brain. Therefore, extended antipsychotic use also leads to severe extrapyramidal side effects. The short-term effects include parkinsonism and the later appearing tardive dyskinesia. Currently available treatments for these disorders are mostly symptomatic and insufficient, and are often linked with a number of detrimental side effects. Antipsychotic-drug-induced tardive dyskinesia prompted researchers to explore novel drugs with fewer undesirable extrapyramidal side effects. Preclinical studies suggest a role of 5-hydroxytryptamine (serotonin)-1A and 2A/2C receptors in the modulation of dopaminergic neurotransmission and motivating a search for better therapeutic strategies for schizophrenia and related disorders. In addition, adjunctive treatment with antioxidants such as vitamin E, red rice bran oil, and curcumin in the early phases of illness may prevent additional oxidative injury, and thus improve and prevent further possible worsening of related neurological and behavioral deficits in schizophrenia. This review explains the role of serotonergic receptors and oxidative stress, with the aim of providing principles for prospect development of compounds to improve therapeutic effects of antischizophrenic drugs.

The behavioural neurology of basal ganglia disorders.

Basal ganglia disorders are common clinical conditions characterised by specific motor dysfunction and associated behavioral problems. The underlying pathophysiology primarily consists in alterations of the cortico-striato-thalamo-cortical pathways, which can be related to both neurodegenerative pathology (e.g. Parkinson disease, Huntington disease) and neurodevelopmental processes (e.g. Tourette syndrome, dystonia). Modulation of dopaminergic neurotransmission within the basal ganglia circuitries represents the mainstay of pharmacological treatment for these conditions. This thematic issue on “The behavioural neurology of basal ganglia disorders” explores the pathophysiological mechanisms underlying the most common basal ganglia disorders, with special focus on the neurochemical targets for pharmacotherapy. The introductory article (Ward et al.) presents the functional neuroanatomy and behavioral correlates of basal ganglia as demonstrated by case studies of patients with selective lesions affecting the cortico-basal pathways. Lesions involving the caudate nucleus, putamen and globus pallidus have been found to be associated with a spectrum of behavioral and cognitive symptoms, including abulia, poor working memory and

Modulation of dopaminergic neurotransmission in rat striatum upon in vitro and in vivo diclofenac treatment1

Diclofenac (DCF) is a widely used non-steroidal anti-inflammatory drug, which also act as a mitochondrial toxin. As it is known that selective mitochondrial complex I inhibition combined with mild oxidative stress causes striatal dopaminergic dysfunction, we tested whether DCF also compromise dopaminergic function in the striatum. [3H]Dopamine ([3H]DA) release was measured from rat striatal slices after in vitro (2 h, 10–25 μmol/L) or in vivo (3 mg/kg i.v. for 28 days) DCF treatment. In vitro treatment significantly decreased [3H]DA uptake and dopamine (DA) content of the slices. H2O2 (0.1 mmol/L)-evoked DA release was enhanced. Intracellular reactive oxygen species production was not significantly changed in the presence of DCF. After in vivo DCF treatment no apparent decrease in striatal DA content was observed and the uptake of [3H]DA into slices was increased. The intensity of tyrosine hydroxylase immunoreactivity in the striatum was highly variable, and both decrease and increase were observed in individual rats. The H2O2-evoked [3H]DA release was significantly decreased and the effluent contained a significant amount of [3H]octopamine, [3H]tyramine, and [3H]β-phenylethylamine. The ATP content and adenylate energy charge were decreased. In conclusion, whereas in vitro DCF pre-treatment resembles the effect of the mitochondrial toxin rotenone, in vivo it rather counteracts than aggravates dopaminergic dysfunction.J. Neurochem. (2008) 105, 360–368.

The pharmacology and mechanisms of action of atypical antipsychotic drugs: dopamine and beyond

The essential defining feature of atypical antipsychotic drugs is that they are efficacious against the symptoms of schizophrenia but produce fewer motor side effects (EPS) than classical drugs. In addition, there is evidence that atypical agents may be more effective than classical neuroleptics in treatment resistant patients and patients with predominantly negative symptoms. All currently used antipsychotics, both typical and atypical, have affinity for the D2 family of dopamine receptors, at which they act as antagonists. Nevertheless, because some atypical agents, including clozapine, also bind to receptors for other neurotransmitters, particularly serotonin, it has been proposed that such additional mechanisms may be of particular importance in producing an atypical pharmacological profile. However, there is evidence that selective action at dopaminergic mechanisms in certain brain regions can also give rise to antipsychotic efficacy with a very low risk of EPS. Although most atypical drugs have affinities for a variety of neurotransmitter receptors, two drugs, amisulpride and aripiprazole, have been proposed as selective dopaminergic agents. Amisulpride is a selective antagonist at dopamine D2 and D3 receptors whereas aripiprazole may act through partial agonism at D2 receptors. The good efficacy and safety of these drugs raise questions about the roles of neurotransmitters other than dopamine. Nevertheless, a number of ongoing research programmes are currently underway in the search for the next generation of antipsychotics. While many of these programmes target sites other than dopamine receptors (including receptors for glutamate and neuropeptides), it seems likely that indirect modulation of dopaminergic neurotransmission will play a major role in their mechanisms of action. from International Society on Brain and Behaviour: 2nd International Congress on Brain and Behaviour Thessaloniki, Greece. 17–20 November 2005

??-Synuclein Protein Levels Are Increased in Alcoholic Patients and Are Linked to Craving

Alpha synuclein has been found to be increased in dopamine neurones of cocaine abusers and in rats whose alcohol preference is inbred. Furthermore, increased alpha-synuclein messenger RNA expression has been linked to craving in patients with alcoholism. The aim of the current study was to investigate whether protein levels of alpha synuclein in alcoholics are changed and possibly influence alcohol craving. The alpha-synuclein protein expression level was measured by enzyme-linked immunosorbent assay in the serum of 49 male alcoholics and 50 nondrinking healthy controls. Alcohol craving was assessed by the Obsessive-Compulsive Drinking Scale total score, including subscales for obsessive and compulsive craving. Alpha-synuclein protein expression in patients with alcoholism (14.33 ng/ml; SD, 13.01 ng/ml) was significantly higher (t test, T = 3.66, p < 0.0001) when compared with that of healthy controls (5.92 ng/ml; SD, 9.72 ng/ml). Using a multivariate analysis, all craving scores (Obsessive-Compulsive Drinking Scale total score and obsessive and compulsive subscale scores) in alcoholics were significantly associated with their alpha-synuclein protein levels (multiple linear regression, p < 0.014). To our knowledge, this is the first study evaluating alpha-synuclein protein expression in alcoholics. The current study provides further evidence of altered alpha-synuclein levels in patients with alcoholism and their linkage to alcohol craving. Because alpha synuclein is involved in the modulation of dopaminergic neurotransmission, these results deliver further pathophysiological explanations of craving mechanisms.

Serotonin transporters upregulate with chronic cocaine use

Cocaine potently inhibits serotonin (5-HT) reuptake in cell bodies and at nerve terminals and 5-HT has been implicated as a modulator of dopaminergic neurotransmission. Chronic use of cocaine may lead to a ‘serotonin-deficit’ form of 5-HT dysregulation. We have examined the status of the 5-HT transporter (SERT) using ligand binding and autoradiographic methods in subgroups of cocaine overdose deaths. Quantitative autoradiography of [ 125I]RTI-55 was used to map and measure the effect of chronic cocaine use on SERT densities in the striatum, substantia nigra, amygdala, and adjacent paralimbic cortical areas of cocaine overdose (CO) victims with and without preterminal evidence of excited delirium (ED). SERT densities were elevated in the nucleus accumbens and throughout the anterior and posterior sectors of striatum in CO victims compared with age-matched and drug-free control subjects. In contrast, SERT densities were increased significantly in the anterior striatum, but not the posterior sectors in ED victims. Significant elevations in SERT were measured in the orbitofrontal gyrus (Brodmann area 11), the anterior portion of the insular cortex and the cingulate gyrus (Brodmann area 24) in CO and ED victims. Saturation binding site analysis demonstrated an increase in the density of RTI-55 binding sites with no change in the affinity of the radioligand for the SERT. Chronic cocaine exposure upregulated SERT densities in the substantia nigra of the CO, but not ED victims. The lack of SERT upregulation in the substania nigra and posterior striatum suggests the possibility of a distinct phenotype for fatal ED victims that exhibited an acute onset of bizarre and violent behavior prior to death. Adaptive changes in the SERT densities may contribute to depressed mood and drug craving associated with acute cocaine abstinence.

Regulated Trafficking of the Human Dopamine Transporter: CLATHRIN-MEDIATED INTERNALIZATION AND LYSOSOMAL DEGRADATION IN RESPONSE TO PHORBOL ESTERS

The dopamine transporter plays an essential role in the modulation of dopaminergic neurotransmission by mediating the reuptake of dopamine into presynaptic neurons. In cells expressing the dopamine transporter, activation of protein kinase C by phorbol esters results in a significant reduction in dopamine uptake. This phorbol ester-mediated inhibition of dopamine transport is associated with a decrease in V(max), although the apparent affinity of the transporter for dopamine remains unchanged. Using a green fluorescent protein-tagged dopamine transporter stably expressed in Madin-Darby canine kidney cells, we show in live cells that the decrease in transporter activity is caused by the rapid internalization of carriers from the plasma membrane. This redistribution of the transporter is specific to phorbol ester activation and is unaffected by the presence of either substrates or inhibitors of the carrier. Upon the addition of phorbol esters, transporters at the cell surface are rapidly endocytosed through a clathrin-mediated and dynamin-dependent mechanism into early endosomes, where they colocalize with transferrin. The internalized carrier is targeted to the endosomal/lysosomal pathway and is completely degraded within 2 h of protein kinase C activation. Phorbol ester-mediated alterations in the trafficking of the dopamine transporter may serve as a mechanism for controlling extracellular dopamine levels in the central nervous system.

Injections of N-methyl-D-aspartate into the ventral hippocampus increase extracellular dopamine in the ventral tegmental area and nucleus accumbens.

The nucleus accumbens septi receives inputs from dopaminergic neurons of the ventral tegmental area (VTA) and glutamatergic neurons of the ventral subiculum (VS). The convergence of these inputs in the NAS is important for the normal expression of exploratory locomotion; stimulation of the VS by injection of the glutamate receptor agonist N-methyl-D-aspartate (NMDA) causes dopamine-dependent increases in locomotion. In the present study, in vivo microdialysis in conjunction with high-performance liquid chromatography and electrochemical detection (HPLC-EC) was used to estimate changes in extracellular dopamine in the VTA and NAS in response to intra-VS injections of NMDA (0.074, 0.28, 0.74 microg). NMDA injections caused dose-dependent elevations in extracellular dopamine in each region. Each dose of NMDA clearly increased extracellular dopamine in the NAS, whereas only the two higher doses increased dopamine significantly in the VTA. The highest dose of NMDA elevated extracellular dopamine to approximately 180% of baseline in each region. Whereas elevations in NAS dopamine might be induced by impulse-independent local mechanisms, elevations of dopamine in the VTA are presumed to reflect increased somatodendritic release associated with increased impulse flow through dopamine neurons. Thus, the present study suggests that the modulation of dopaminergic neurotransmission by the ventral subiculum results from a trans-synaptic activation of dopamine cell bodies in the VTA.

μ-, δ- and κ-opioid receptor agonists do not alter the discriminative stimulus effects of cocaine or d-amphetamine in rats

Opioid receptor agonists can modulate the activity of dopamine neurons and could therefore, modify the behavioral effects of drugs that act through the dopamine systems, such as d-amphetamine and cocaine. We tested the ability of agonists selective for the μ- (morphine, methadone, buprenorphine, nalbuphine and heroin), δ- (DPDPE and SCH32615), and κ- (U69593 and bremazocine) opioid receptors to alter the discriminative stimulus effects of d-amphetamine and cocaine in rats. Separate groups of male Sprague-Dawley rats were trained to discriminate between 1.0 mg/kg d-amphetamine or 10 mg/kg cocaine from saline. Rats were pretreated with vehicle or an agonist, then dose-response curves for d-amphetamine or cocaine were generated. None of the opioid agonists changed significantly the ED 50 values of cocaine and d-amphetamine. As a positive control, we tested for antagonism of these effects by the D1 and D2 dopamine receptor antagonists, SCH23390 and eticlopride, respectively. Both antagonists at least partially attenuated the stimulus effects of both training drugs. Our results suggest that any modulation of dopaminergic neurotransmission by the agonists tested in the present study is not sufficient to affect the stimulus effects of d-amphetamine and cocaine in rats.

Dopamine and migraine

This review summarizes a growing body of biological, pharmacologic, and genetic data that support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine. Recent genetic data suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.

Modulation of dopaminergic neurotransmission in the 6-hydroxydopamine lesioned rotational model by peptidomimetic analogues of l-prolyl- l-leucyl-glycinamide

Melanocyte stimulating hormone release inhibiting factor (MIF-1), also known as l-prolyl- l-leucyl-glycinamide (PLG), has previously been found to have the ability to modulate dopamine D 2-receptor agonist binding both in the striatum and limbic regions. In the present study the 6-hydroxydopamine unilateral lesion model of apomorphine-induced rotational behaviour, in Wistar rats, was used to assess the dopaminergic modulatory activity of PLG and two novel analogues, l-prolyl- l-prolyl- l-prolinamide (analogue A) and (2S,5R,7R)-1-Aza-7[3′(S)-1-(2′,5′-dioxo-pyrrolidino[2,1-c]piperazino)]-8-oxo-4-thiabicyclo[3.3.0] octane-2-carboxamide (analogue B). PLG and the two novel analogues showed a bell-shaped dose-response relationship, suggesting that analogue A, B and PLG all manifest their effect through a similar mechanism and exhibit a window of therapeutic efficacy. Analogue A was a 100 times, while analogue B was 10 times, more potent than PLG in increasing the contralateral rotational response when given in combination with apomorphine. Analogue A was also more efficacious than PLG or analogue B at increasing apomorphine-induced contralateral rotations. Intrastriatal administration of either analogue A or B resulted in a greater increase in apomorphine-induced rotations than the most efficacious intraperitoneally delivered dose. The results of the present study suggest that PLG and its two novel analogues are able to modulate dopamine receptor activity and may be possible therapeutic agents for the treatment of Parkinsonian symptoms as well as tardive dyskinesia.

Chronic continuous or intermittent infusion of cocaine differentially alter the concentration of neurotensin-like immunoreactivity in specific rat brain regions.

Neurotensin (NT) is an endogenous brain tridecapeptide that exhibits selective anatomic and neurochemical interactions with rat brain dopaminergic systems. Because modulation of dopaminergic neurotransmission may underlie many of the behavioral properties of cocaine, the effects of both acute and chronic administration of cocaine on the concentration of NT-like immunoreactivity (NT-LI) in specific brain regions was determined. Adult male rats were treated with cocaine for 14 days at a dose of 40 mg/kg/day (0.118 mmoles/kg/day) administered as either 1 subcutaneous injection per day, or infused continuously using subcutaneously implanted minipumps. Neurotensin-like immunoreactivity in specific brain regions was then measured 24 hours or 8 days following drug administration. After 24 hours of withdrawal from daily subcutaneous injection, the concentration of NT-LI was significantly increased in the substantia nigra (SN) and frontal cortex. After 24 hours of withdrawal from continuous infusion with cocaine, NT-LI was increased only in the SN. After 8 days of withdrawal, NT-LI was increased in the SN of rats treated with daily subcutaneous infections of cocaine, but not in the group treated with continuous infusion. Twenty-four hours following a single acute injection of 40 mg/kg of cocaine, NT-LI was increased in the SN and nucleus accumbens. These results provide evidence consistent with a neuroanatomically selective involvement of NT systems in the behavioral and/or addictive properties of cocaine.

Facilitation of amphetamine-induced hypothermia in mice by GABA agonists and CCK-8

1. Amphetamine-induced hypothermia in mice is facilitated by dopaminergic stimulation and 5-hydroxytryptaminergic inhibition. The present study was designed to investigate: (a) the involvement of other neuronal systems, such as the gamma-aminobutyric acid (GABA), the opioid and the cholecystokinin (CCK-8) systems; (b) the possible contribution of hydroxylated metabolites of amphetamine to the hypothermia; (c) the capacity of dopamine itself to induce hypothermia and its mechanisms, in order to clarify the resistance of amphetamine-induced hypothermia to certain neuroleptics. 2. Pretreatment with the GABA antagonists, bicuculline and picrotoxin, did not inhibit amphetamine-induced hypothermia. The GABAB agonist, baclofen (2.5 mg kg-1, i.p.) potentiated this hypothermia, whereas the GABAA agonist, muscimol, did not. gamma-Butyrolactone (GBL) (40 mg kg-1, i.p.) and the neuropeptide CCK-8 (0.04 mg kg-1, i.p.) also induced potentiation. The opioid antagonist, naloxone, was without effect. 3. Dopamine itself (3, 9, 16 and 27 micrograms, i.c.v.) induced less hypothermia than the same doses of amphetamine. Sulpiride did not block dopamine-induced hypothermia, but pimozide (4 mg kg-1, i.p.), cis(z)flupentixol (0.25 mg kg-1, i.p.) and haloperidol (5 micrograms, i.c.v.) did. The direct dopamine receptor agonist, apomorphine, did not alter the hypothermia. Neither the 5-hydroxytryptamine (5-HT) receptor blocker, cyproheptadine, nor the inhibitor of 5-HT synthesis, p-chlorophenylalanine (PCPA), modified dopamine-induced hypothermia. Fluoxetine, an inhibitor of 5-HT reuptake, had no effect, whereas quipazine (6 mg kg-1, i.p.), a 5-HT agonist, totally prevented the hypothermia. Hypothermia was unaffected by pretreatment with CCK-8. 4. These data indicate that the hypothermia induced by amphetamine involves not only dopaminergic and 5-hydroxytryptaminergic systems which are functionally antagonistic, but is also facilitated by direct or indirect GABA and CCK-8 receptor stimulation. This facilitation could result, in part, from modulation of dopaminergic neurotransmission. This may explain the apparent resistance of amphetamineinduced hypothermia to some neuroleptics, while dopamine-induced hypothermia is not resistant. The possible action of hydroxylated metabolites of amphetamine may also help to explain these differences.

An Improved Radioimmunoassay for &lt;i&gt;α&lt;/i&gt;-Melanocyte-Stimulating Hormone (&lt;i&gt;α&lt;/i&gt;-MSH) in the Rat: Serum and Pituitary &lt;i&gt;α&lt;/i&gt;-MSH Levels after Drugs Which Modify Catecholaminergic Neurotransmission

A modification of our previous radioimmunoassay (RIA) for alpha-melanocyte-stimulating hormone (alpha-MSH) is described that permits the measurement of circulating levels in the rat without the need for an extraction procedure. Using this method, serum and neurointermediate lobe (NIL) immunoreactive alpha-MSH levels were measured in rats after administration of haloperidol, 2-bromo alpha-ergocryptine (CB 154), and alpha-methyl-p-tyrosine (alpha-MPT). Haloperidol caused a rapid increase, alpha-MPT a slow increase, and CB 154 a rapid decrease in serum alpha-MSH. At the time intervals studied none of the drugs had any significant effect on NIL alpha-MSH content. It was concluded from the results of the above drug treatments that modulation of dopaminergic neurotransmission both pre- and postsynaptically produces changes in serum immunoreactive alpha-MSH levels. This supports the suggestion that circulating alpha-MSH in the rat is under an inhibitory control by a catecholaminergic system.