No effects of l-dopa and bromocriptine on psychophysiological parameters of human selective attention

Patients with schizophrenia exhibit diverse cognitive deficits, one of which is a loss of the ability to focus attention. According to the revised dopamine hypothesis of schizophrenia both an increased mesolimbic and a decreased prefrontal dopaminergic activity is suggested to be involved in schizophrenia. The current study was designed to explore the relationship between dopamine and two psychophysiological parameters of selective attention, i.e. P300 amplitude and processing negativity (PN) in healthy volunteers. In two separate experiments, with a double-blind, balanced and placebo-controlled crossover design, 18 healthy male volunteers were orally administered either 300 mg l-dopa (precursor of dopamine) or placebo (experiment I), or 1.25mg bromocriptine (D2 agonist) or placebo (experiment II). Following this treatment they were tested in an auditory, dichotic selective attention paradigm. An increase in P300 amplitude was found following deviant stimuli when compared to standard stimuli and following attended stimuli when compared to unattended stimuli, regardless of treatment. Similarly, PN was found regardless of treatment. Neither l-dopa nor bromocriptine affected task performance or the amplitudes of PN or P300. In the present study neither l-dopa nor bromocriptine affected PN, P300 amplitude or task performance in healthy controls, phenomena which are usually found to be disrupted in schizophrenia. This indicates that P300 amplitude and PN are neither affected by a global (l-dopa) increased dopaminergic activity, nor by a more selectively towards striatal areas targeted (bromocriptine) increase in dopaminergic activity.     

A role for dopamine in the processing of drug cues in heroin dependent patients

Drug and alcohol dependence are associated with enhanced attention for drug-related stimuli. This cognitive processing bias has been suggested to be related to craving and to represent one of the core mechanisms of addition. The present study tests the hypothesis that enhanced attention for heroin cues is mediated by the dopaminergic system using haloperidol as dopamine antagonist. In a double blind, randomized crossover design, 17 detoxified heroin dependent patients received a single oral dose of haloperidol 2 mg and placebo. Patients performed an Emotional Stroop Task to assess the cognitive processing of drug cues under both conditions. In addition, self-reported craving was assessed. In the haloperidol condition, patients performed better on the Emotional Stroop Task than in the placebo condition. However, no effect of haloperidol on subjective craving was found. These findings provide preliminary indications that attentional bias in heroin dependent humans is mediated by dopaminergic mechanisms.     

Effects of dopaminergic drugs on the mast cell degranulation and nitric oxide generation in RAW 264.7 cells

Effects of dopaminergic drugs on the degranulation of mast cells (RBL-2H3 cells) and the nitric oxide production from macrophage cells (RAW 264.7) were studied. Among the dopaminergic agonists and antagonists tested, bromocriptine, 7-OH-DPAT, haloperidol, and clozapine showed potent inhibitions of mast cell degranualtion (IC50 value, 5 microM). However, these dopaminergic agents did not affect the tyrosine phosphorylations of the signaling components of the high affinity IgE receptor (FcepsilonRI), such as Syk, PLCgamma1, and PLCgamma2.; This suggested that these signaling components were not involved in the inhibition of the mast cell degranulation by these compounds. On the other hand, dopamine, bromocriptine, 7-OH-DAPT, and haloperidol markedly inhibited the nitric oxide production from RAW 264.7 cells (IC50 values, 10-20 microM). Bromocriptine, a dopamine agonist that is routinely used for the treatment of Parkinsons disease, inhibited the expression of the inducible nitric oxide synthase at an early stage of the LPS-induced protein expression in a dose-dependent manner. The results suggested that these dopaminergic agents, when used for the treatment of dopamine receptors-related diseases, such as Schizophrenia or Parkinsons disease, might have additional beneficial effects.     

Central bromocriptine-induced tachycardia is reversed to bradycardia in conscious, deoxycorticosterone acetate-salt hypertensive rats

A central dopaminergic origin has been demonstrated for the bromocriptine-induced tachycardia in conscious, normotensive rats. The present study investigated the effect of bromocriptine on heart rate and the principal site of action of this agonist in conscious, deoxycorticosterone acetate-salt hypertensive rats, in which altered central dopaminergic activity has been previously reported. Intravenous administration of bromocriptine (150 microg/kg) increased heart rate (49+/-5 beats/min.) in uninephrectomized control rats, while it induced a significant bradycardia (50+/-6 beats/min.) in deoxycorticosterone acetate-salt hypertensive rats. In the latter animals, intravenous (500 microg/kg) or intrathecal (40 microg/rat at T9-T10) pretreatment with domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier, reduced partially, but significantly, the bradycardiac responses to bromocriptine (reduction of about 44% and 48% of the maximal effect, respectively). In contrast, the bromocriptine-induced bradycardia was fully abolished by intravenous pretreatment with metoclopramide (300 microg/kg), a dopamine D2 receptor antagonist that crosses the blood-brain barrier, or by combined pretreatment with intravenous and intrathecal domperidone. These results indicate that, in deoxycorticosterone acetate-salt hypertensive rats, bromocriptine decreases rather than increases heart rate, an effect that is mediated partly through a peripheral D2 dopaminergic mechanism and partly through stimulation of spinal dopamine D2 receptors. They further support the concept that, in normotensive, conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at both peripheral and spinal dopamine D2 receptors.     

Effects of bromocriptine and haloperidol on prepulse inhibition: comparison of the acoustic startle eyeblink response and the N1/P2 auditory-evoked response in man

Experiments with animals have shown that D2 dopamine receptors are involved in regulating prepulse inhibition (PPI) of the acoustic startle reflex (suppression of the reflex response evoked by a loud sound by prior presentation of a low-intensity stimulus). Recently we found that PPI of the human eyeblink startle response could be suppressed by a D2 receptor agonist, bromocriptine, and that this suppression could be reversed by a D2 receptor-blocking neuroleptic, haloperidol. The present work attempted to replicate this finding and to extend it to PPI of the N1/P2 component of the auditory-evoked potential. Eleven healthy males (18-30 years) participated in four sessions in which they received oral doses of placebo, bromocriptine 1.25 mg, haloperidol 3mg and combined treatment with bromocriptine 1.25 mg + haloperidol 3 mg, according to a balanced double-blind protocol. Thirty-minute simultaneous recordings of the electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and the vertex auditory-evoked potentials took place 120 min after ingestion of haloperidol and/or 90 min after ingestion of bromocriptine. Sound stimuli (1-kHz) were presented in 60 trials separated by variable intervals (mean 25 sec): (i) 40 msec 115 dB ('pulse alone': 20 trials); (ii) 40 msec 85 dB (20 trials); (iii) 40 msec 85 dB, followed after 120 msec by 40 msec 115 dB ('prepulse/ pulse': 20 trials). The amplitudes of the EMG and N1/P2 responses were not altered significantly by any of the treatments. Bromocriptine attenuated PPI of the EMG response significantly, this attenuation being absent following combined haloperidol/bromocriptine treatment. Neither bromocriptine nor haloperidol significantly altered PPI of the N1/P2 complex. Bromocriptine suppressed and haloperidol elevated serum prolactin levels, these changes being absent when the two drugs were given in combination. The results suggest that different mechanisms may be involved in regulating PPI of the eyeblink and the N1/P2 component of the auditory-evoked potential, and that D2 receptors may be involved in the former case, but not the latter.     

Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?

RATIONALE: Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. OBJECTIVES: The present study determined whether the antidepressant-like effects of selective serotonin reuptake inhibitors measured in the mouse forced swimming test are mediated via dopamine receptors. METHODS: Male Swiss mice were randomly assigned to groups of 24 animals and injected IP with citalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine alone or in combination with the dopamine D(1)agonist SKF 38393, the D(1) antagonist SCH 23390, the D(2) agonist bromocriptine, the D(2) antagonist sulpiride, the D(3) agonist PD 128 907, or the D(3) antagonist nafadotride. RESULTS: The anti-immobility effects of paroxetine, fluvoxamine and citalopram were increased by co-administration of SKF 38393 (0.5 and 2 mg/kg), SCH 23390 (0.06 mg/kg), bromocriptine (0.5 and 2 mg/kg) or PD 128 907 (1 and 2 mg/kg), and were attenuated by SCH 23390 (0.5 mg/kg). The anti-immobility effects of paroxetine and fluvoxamine were also increased with sulpiride (0.5 and 2 mg/kg). The anti-immobility effect of fluoxetine was increased by SKF 38393 (2 mg/kg) and PD 128 907(1 and 2 mg/kg) co-administration. The anti-immobility effect of sertraline (16 mg/kg) was increased by SKF 38393 (0.5 mg/kg), bromocriptine (2 mg/kg) and PD 128 907 (2 mg/kg) and the effect of sertraline (2 mg/kg) was increased by bromocriptine (2 mg/kg). The anti-immobility effect of paroxetine (4 mg/kg) was increased by nafadotride (2 mg/kg). CONCLUSIONS: These data indicate that the antidepressant activity of various SSRIs involves different dopamine receptor subtypes and that the serotoninergic and dopaminergic systems interact with each other.     

Modification of the function of D1 and D2 dopamine receptors in striatum and nucleus accumbens of rats chronically treated with haloperidol

With the aim of evaluating the possible functional modifications of both D1 and D2 dopamine receptor subpopulations after repeated administration of neuroleptics, the ability of selective D1 and D2 dopamine agonists to stimulate or inhibit, respectively, the activity of adenylate cyclase in the striatum and nucleus accumbens of rats treated with either saline or haloperidol for 21 days, was studied. It was found that stimulation of the activity of adenylate cyclase elicited by the selective D1 receptor agonist SKF 38393 was significantly greater in homogenates of striatum in rats treated with haloperidol, than in those of saline-treated rats. Similarly, the inhibitory effect on the activity of the enzyme elicited by the selective D2 agonist bromocriptine was much more evident in homogenates of the striatum from rats treated with neuroleptic than in those from saline-treated rats. When dopamine, sodium fluoride (NaF), or 5-guanylyl imidodiphosphate (Gpp(NH)p), were used as agonists to stimulate the activity of adenylate cyclase, the amount of cyclic AMP formed appeared the same in rats treated with haloperidol or saline. Dopamine receptors in nucleus accumbens behaved like those in the striatum in the pattern of modifications after repeated administration of haloperidol. Indeed, the inhibitory effect elicited by bromocriptine, as well as the stimulatory effect elicited by SKF 38393, was much more evident in nucleus accumbens from rats treated with haloperidol than in that from controls, whereas activation of adenylate cyclase induced by dopamine and sodium fluoride was similar in both experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inverse agonist properties of dopaminergic antagonists at the D(1A) dopamine receptor: uncoupling of the D(1A) dopamine receptor from G(s) protein.

The interaction of dopaminergic antagonists with the D(1A) dopamine receptor was assessed in PC2 cells that transiently express this receptor. The maximal binding and dissociation constants for the D(1A) dopamine receptor, using the ligand [(125)I]SCH23982 were 0.38 +/- 0.09 nM and 1 to 4 pmol/mg, respectively, when assessed 48 h after transfection with cDNA encoding the rat D(1A) receptor. Basal adenylyl cyclase activity increased 50 to 60% in membranes of transfected PC2 cells compared with control membranes. The dopaminergic antagonists clozapine, cis-flupenthixol, (+)-butaclamol, haloperidol, chlorpromazine, and fluphenazine inhibited constitutive adenylyl cyclase activity in membranes of cells expressing the D(1A) receptor. SCH23390, a selective D(1) dopamine receptor antagonist, and (-)-butaclamol did not alter basal cyclase activity, whereas dopamine increased enzyme activity in membranes expressing the D(1A) dopamine receptor. The coupling of D(1A) receptors with G(s) proteins was examined by immunoprecipitation of membrane G(salpha) followed by immunoblotting with a D(1A) dopamine receptor monoclonal antibody. Clozapine, cis-flupenthixol, (+)-butaclamol, haloperidol, and fluphenazine but not SCH23390 or (-)-butaclamol decreased D(1A) receptor-G(salpha) coupling by 70 to 80%, and SCH23390 was able to prevent the receptor-G(salpha) uncoupling induced by haloperidol or clozapine. These results indicate that some dopaminergic antagonists suppress basal signal transduction and behave as inverse agonists at the D(1A) dopamine receptor. This action of the dopamine receptor antagonists may contribute to their antidopaminergic properties that seem to underlie their clinical actions as antipsychotic drugs.     

Age-related changes in dopamine D2 receptors in rat heart and coronary vessels

1. The distribution of dopamine D2 receptors in rat heart and coronary vessels and the possible age-related changes in D2 receptor density were studied. The pharmacological characteristics and the anatomical location of dopamine D2-like receptor sites in rat heart and coronary vessels were investigated using combined binding techniques and light microscopy autoradiography. 2. Samples of heart and coronary vessels were harvested from young and old rats. On frozen slices, dopaminergic D2 receptors were labelled by means of a selective D2 ligand, namely [3H]-spiroperidol (spiperone). Inhibition studies were performed using unlabelled agonists and/or labelled and unlabelled antagonists to define pharmacological specificity of the binding. Physiological experiments were performed to demonstrate the selective antagonism between D2 receptors and many dopaminergic drugs. 3. [3H]-Spiroperidol was bound to sections of rat heart and coronary artery (in a manner consistent with the labelling of dopamine D2-like receptors) with an equilibrium dissociation constant of approximately 2.4 +/- 0.7 nmol/L and a maximum capacity of binding sites of 65.8 +/- 4.5 fmol/mg protein. Experiments performed on sections of coronary veins did not allow the evaluation of specific binding. Autoradiography, observed with light microscopy, showed the development of specific silver grains within the whole wall of rat heart and coronary artery. The greater sensitivity to displacement by amisulpride, bromocriptine, domperidone, haloperidol, raclopride and L-sulpiride than to displacement by N-propyl-norapomorphine, quinpirole and clozapine suggests that the binding sites observed in these experiments are likely to belong to the dopamine D2 receptor subtype. 4. Comparing results in young and old rats, we observed numerous significant age-related changes, including a decrease in D2 receptors localized in rat heart and coronary artery wall. These D2 receptors show a specific location, in close relationship with dopaminergic nerve fibres. They decrease with age and their role remains unknown.     

Differential behavioral and biochemical effects of four dopaminergic agonists

Some behavioral and biochemical effects of four dopaminergic agonists (apomorphine, piribedil, lergotrile, and bromocriptine) were determined in the mouse. As expected, all four drugs dose-dependently reversed the -methyltyrosine-induced decline of fore-brain dopamine. All four compounds reduced locomotor activity at low doses, but only apomorphine and bromocriptine increased motor activity at higher doses. All four drugs caused some reversal of the baclofen-induced elevation in forebrain dopamine concentrations, but only apomorphine and bromocriptine completely reversed the effects of baclofen. After chronic treatment with haloperidol, the behavioral effects of lergotrile and bromocriptine were altered. Doses of those drugs reducing motor activity in normal animals were ineffective after chronic haloperidol. The latent stimulation induced by bromocriptine was enhanced, while a stimulatory effect of lergotrile emerged in these animals. These effects were noted in conjunction with an enhanced sensitivity to the drug-induced decrease in dopamine turnover. These results demonstrate that dopamine agonists may be differentiated on the basis of certain behavioral and biochemical tests and suggest an interaction of these drugs with two different populations of dopamine receptors.     

Enhanced striatal dopamine D(2) receptor-induced [35S]GTPgammaS binding after haloperidol treatment.

Dopamine receptor-G protein coupling and dopamine D(2) receptor density were assessed in rats treated for 3 weeks with either haloperidol (2 mg/kg; i.p.) or vehicle. After 3 days of withdrawal, agonist-induced guanosine 5'-O-(gamma-[35S]thio)triphosphate ([35S]GTPgammaS) and [3H]spiperone binding were determined in striatal homogenates. Maximal [3H]spiperone binding was increased (24.8%, P<0.01) following haloperidol treatment. The efficacy of dopamine and the dopamine D(2) receptor agonist R(-)-10, 11-dihydroxy-N-n-propylnorapomorphine (NPA) to induce [35S]GTPgammaS binding were found to be increased by 24.1% (P<0.01) and 44.6% (P<0. 001), respectively. When measured in the presence of a saturating concentration of a dopamine D(2) receptor antagonist, the response to dopamine was not significantly affected by haloperidol treatment. In addition, the measurement of haloperidol-induced catalepsy confirmed that the efficient dopamine receptor blockade was followed by a progressive development of dopaminergic supersensitivity. Taken together, these results indicate that a functional pool of dopamine D(2) receptors is increased after prolonged haloperidol administration.     

Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity

Parkinson disease is characterized by selective degeneration of mesencephalic dopaminergic neurons, and endogenous dopamine may play a pivotal role in the degenerative processes. Using primary cultured mesencephalic neurons, we found that glutamate, an excitotoxin, caused selective dopaminergic neuronal death depending on endogenous dopamine content. Pramipexole, a dopamine D2/D3 receptor agonist used clinically in the treatment of Parkinson disease, did not affect glutamate-induced calcium influx but blocked dopaminergic neuronal death induced by glutamate. Pramipexole reduced dopamine content but did not change the levels of total or phosphorylated tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis. The neuroprotective effect of pramipexole was independent of dopamine receptor stimulation because it was not abrogated by domperidone, a dopamine D2-type receptor antagonist. Moreover, both active S(-)- and inactive R(+)-enantiomers of pramipexole as a dopamine D2-like receptor agonist equally suppressed dopaminergic neuronal death. These results suggest that pramipexole protects dopaminergic neurons from glutamate neurotoxicity by the reduction of intracellular dopamine content, independently of dopamine D2-like receptor activation.     

Central Bromocriptine‐Induced Tachycardia is Reversed to Bradycardia in Conscious,Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: A central dopaminergic origin has been demonstrated for the bromocriptine‐induced tachycardia in conscious, normotensive rats. The present study investigated the effect of bromocriptine on heart rate and the principal site of action of this agonist in conscious, deoxycorticosterone acetate‐salt hypertensive rats, in which altered central dopaminergic activity has been previously reported. Intravenous administration of bromocriptine (150 μg/kg) increased heart rate (49±5 beats/min.) in uninephrectomized control rats, while it induced a significant bradycardia (50±6 beats/min.) in deoxycorticosterone acetate‐salt hypertensive rats. In the latter animals, intravenous (500 μg/kg) or intrathecal (40 μg/rat at T₉–T₁₀) pretreatment with domperidone, a selective dopamine D₂ receptor antagonist that does not cross the blood‐brain barrier, reduced partially, but significantly, the bradycardiac responses to bromocriptine (reduction of about 44% and 48% of the maximal effect, respectively). In contrast, the bromocriptine‐induced bradycardia was fully abolished by intravenous pretreatment with metoclopramide (300 μg/kg), a dopamine D₂ receptor antagonist that crosses the blood‐brain barrier, or by combined pretreatment with intravenous and intrathecal domperidone. These results indicate that, in deoxycorticosterone acetate‐salt hypertensive rats, bromocriptine decreases rather than increases heart rate, an effect that is mediated partly through a peripheral D₂ dopaminergic mechanism and partly through stimulation of spinal dopamine D₂ receptors. They further support the concept that, in normotensive, conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at both peripheral and spinal dopamine D₂ receptors.     

Dopamine D2 receptors involved in Peony-Glycyrrhiza Decoction,an herbal preparation against antipsychotic-associated hyperprolactinemia

Clinical studies have demonstrated the effectiveness of an herbal preparation called Peony-Glycyrrhiza Decoction(PGD) in alleviating antipsychotic-induced hyperprolactinemia(hyperPRL).In the present study,we further examined the pharmacological action of PGD on hyperPRL in in vitro and in vivo models,and associations with dopamine D2 receptors.Treatment with PGD at 1-5 g·L-1 significantly suppressed prolactin(PRL) secretion and synthesis in MMQ cells,a model of hyperPRL derived from pituitary adenoma cells.The suppressive effects were completely abolished by pretreatment with 10 μmol·L-1 haloperidol,a dopamine D2 receptor antagonist.Consistent with a D2-action,PGD did not affect PRL in rat pituitary somatolactotropic tumor-derived GH3 cells that lack the D2 receptor expression.In a rat model of hyper PRL,produced by repeated injection of metoclopramide(MCP),another dopamine D2 receptor antagonist,chronic PGD(2.5-10 g·kg-1 daily) significantly reduced elevated serum PRL.The reduction in magnitude was similar to that elicited by bromocriptine(BMT),a potent dopamine D2 receptor agonist currently used for treatment of hyperPRL.Neither PGD nor BMT altered serum estradiol,but PGD reversed decreased serum progesterone to control level,whereas BMT did not.These results indicate that the anti-hyperPRL effects of PGD are associated with the modulation of D2 receptors.The present study provides experimental evidence in support of clinical use of PGD as an effective treatment of antipsychotic-induced hyperPRL.     

The effects of kainic acid lesions on dopaminergic responses to haloperidol and clozapine

The antipsychotic drugs haloperidol and clozapine have the common action of increasing dopamine metabolism in the striatum (nucleus accumbens, caudate-putamen) of the rat. Intracerebroventricular administration of kainic acid (KA) produces neuronal loss in limbic-cortical brain regions which project directly or indirectly to the striatum. In the present study, dopamine metabolism in subregions of the striatum was examined in rats with KA lesions after acute and chronic haloperidol or clozapine administration. The main findings was that the elevating effect of acute haloperidol treatment on the dopamine metabolite, DOPAC, was blocked in the nucleus accumbens shell and diminished in medial and laterodorsal caudate-putamen of the KA-lesioned rats. In addition, the elevating effects of both acute and chronic haloperidol treatment on dopamine turnover were attenuated in the laterodorsal caudate-putamen of KA-lesioned rats. The levels of dopamine, DOPAC, and HVA after chronic clozapine treatment were greater in KA-lesioned than control rats. These results indicate that dopaminergic responses to haloperidol may be diminished by limbic-cortical neuropathology, while such pathology does not significantly alter dopaminergic responses to clozapine. Received: 30 September 1996 / Final version: 6 March 1997     

The effects of dopaminergic D2 stimulation and blockade on smoking behavior

Researchers have hypothesized that dopamine mediates the reinforcing effects of stimulant drugs, including nicotine. Three experiments tested whether manipulating dopamine would alter human smoking behavior. Experiments used double-blind, repeated measures designs. In Experiment 1, 4 participants were given haloperidol (a dopamine antagonist; placebo, 0.5, and 1.0 mg) on 3 occasions. The smoking rate was faster in the 1.0 mg versus the placebo condition. In Experiment 2, 12 participants were given haloperidol (2.0 mg) and placebo on 2 occasions. The intercigarette interval was shorter at the expected time of peak drug concentration. In Experiment 3, 5 participants were given bromocriptine (a dopamine agonist, 2.5 mg) and placebo on 2 occasions. The smoking rate was significantly slower with bromocriptine. These results suggest that blockade of D2 receptors increases smoking whereas their stimulation decreases smoking.     

5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine.

The highly selective 5-HT2 receptor antagonist, MDL 100,907, was used to explore the role of serotonin in the stimulation of dopaminergic function produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). MDL 100,907 blocked MDMA-stimulated dopamine synthesis in vivo without affecting basal synthesis. The long-term deficits in 5-HT concentrations believed to be a consequence of MDMA-induced dopamine release were also blocked by MDL 100,907 over the same dose range. In vivo microdialysis confirmed that 5-HT2 receptor blockade with MDL 100,907 attenuated MDMA-induced increases in extracellular concentrations of striatal dopamine. In contrast to its effect on MDMA-induced synthesis, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine. In vivo dopamine release produced by haloperidol was also unaffected by MDL 100,907. The results suggest a permissive role for 5-HT2 receptors in the activation of the dopamine system which occurs during states of high serotonergic activity or during conditions of elevated dopamine efflux with high D2 receptor occupancy.     

A D2 antagonist enhances the rewarding and priming effects of a gambling episode in pathological gamblers.

Previous research indicated shared neurochemical substrates for gambling and psychostimulant reward. This suggests that dopamine substrates may directly govern the reinforcement process in pathological gambling. To investigate this issue, the present study assessed the effects of the relatively selective dopamine D2 antagonist, haloperidol (3 mg, oral) on responses to actual gambling (15 min on a slot machine) in 20 non-comorbid pathological gamblers and 18 non-gambler controls in a placebo-controlled, double-blind, counterbalanced design. In gamblers, haloperidol significantly increased self-reported rewarding effects of gambling, post-game priming of desire to gamble, facilitation of reading speed to Gambling words, and gambling-induced elevation in blood pressure. In controls, haloperidol augmented gambling-induced elevation in blood pressure, but had no effect on other indices. The findings provide direct experimental evidence that the D2 substrate modulates gambling reinforcement in pathological gamblers.     

Dopamine Modulates Reward System Activity During Subconscious Processing of Sexual Stimuli

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive–compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the ‘reward system''. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate ‘wanting'' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.