Dopamine Receptor Sensitivity Research Articles

Technetium-99m-ethyl cysteinate dimer brain perfusion loss in pediatric postictal psychosis

A 91/i-YEAR-OLD BOY was admitted to the hospital with status epilepticus and was treated with intravenous diazepam, phenytoin, and midazolam. After the convulsions stopped, he remained agitated and confused. Twenty-four hours later, psychotic ideation was noticed. He developed visual hallucinations, confused speech, auditory illusions, psychomotor restlessness, and disorganized behavior. His medical history was remarkable for a right hemiplegia diagnosed in the first year of life, caused by a polycythemia-related neonatal stroke. A brain computed tomography (CT) scan that was performed a year later showed an enlarged left ventricle and left hemispheric atrophy. At age 9, the patient was hospitalized for prolonged left-sided complex partial seizures, followed by Todd's paralysis on the right side. The neurological examination on the current admission revealed mild right hemiparesis, unchanged from before. Routine serum biochemistry and a complete blood count were normal. A lumbar puncture was normal. Repeated electroencephalograms (EEGs) showed left-sided slowing but no epileptic activity. A brain magnetic resonance imaging (MRI) scan showed severe atrophy of the left hemisphere with a thalamic hypodensity (Fig 1), similar to the previous imaging. The patient was diagnosed with postictal schizophrenia-like psychosis. A perfusion brain single photon emission computed tomography (SPECT) was performed 30 minutes after injecting 12 mCi (444 MBq) of Technetium (Tc)-99m-ethyl cysteinate dimer (ECD) intravenously by using a dualhead gamma camera. The images showed markedly decreased perfusion to the left hemisphere, including the basal ganglia and the thalamus (Fig 2A). The hypoperfusion was most prominent in the left medial temporal lobe. Moderately diminished perfusion was also observed in the frontal lobes. The psychosis lasted for 7 days and resolved gradually without treatment. A repeat SPECT study 3 months later (Fig 2B) showed improved perfusion to the left temporal lobe and to the fight frontal lobe. The patient remained asymptomatic after a 6-month follow-up. Brief psychotic episodes may follow a bout of seizure clusters or a recent exacerbation in seizure frequency. 17 Postictal psychosis may develop in nearly 10% of adult patients, 6 but it is rare in children. The psychosis may be caused by repeated electrical discharges that change local neurotransmitter activity. It is also conceivable that structural brain abnormalities, eg, cortical dysgenesis or diffuse brain lesions, may lead to both the epilepsy and the psychosis. Postictal psychosis usually resolves within a few days. 5 Recurrent seizures may exacerbate the psychosis, and careful monitoring of anticonvulsant therapy is mandatory. EEG abnormalities persist in the majority of patients during the psychosis. 1 Some suggested risk factors are early onset and severe epilepsy, secondary generalization of seizures, certain anticonvulsive drugs, and temporal lobectomy. Most investigators suggest that psychosis in epilepsy is preferentially associated with temporal lobe seizures. 8-a2 MRI studies show that postictal psychosis is most likely to occur in patients with resistant temporal lobe epilepsy stemming from mesial temporal sclerosis, especially on the left side. 6 Changes in postsynaptic dopamine receptor sensitivity have been suggested as the mediating mechanism. SPECT studies have shown low levels of striatal dopamine D2 receptors in patients with peri-ictal psychosis. 13 Possible differential diagnoses for our patient are listed below.

Geriatric Men at Altitude: Hypoxic Ventilatory Sensitivity and Blood Dopamine Changes

Background: Short-term exposure to high-altitude hypoxia increases hypoxic ventilatory sensitivity (HVS) in healthy humans. Dopamine (DA) is the implicated neurotransmitter in carotid body (CB) chemoreceptor response, and the microenvironmental conditions in CB tissue are comparable to blood. Continuous DA infusion affected ventilation in animals and humans. Age-related oscillations in blood DA levels may influence peripheral chemoreflexes. Objective: Hypoxic ventilatory responses (HVR) relative to blood DA concentration and its precursor, dihydroxyphenylalanine (DOPA) was measured in young and elderly men during short-term altitude adaptation. Methods: Nine elderly climbers (group 1: 61 ± 1.4 years) and 7 young healthy subjects (group 2: 23 ± 2 years) were tested at sea level on day 0, on day 3 after passive transport to 2,200 m, and on day 14 after climbing to 4,200 and 5,642 m. Results: Sea level HVR in group 1 was 47% lower than in group 2, accompanied by higher blood DOPA (300%) and DA (37%) content. Initial DA and DOPA concentrations showed a negative correlation with initial HVR but a positive correlation with age. Passive transport to middle altitude (2,200 m) increased HVS, doubling HVR slopes in groups 1 and 2 and producing increased maximum expired minute ventilation during isocapnic rebreathing (29 and 28%, respectively). Day 3 2,200-meter blood DOPA content decreased by 22% in group 1 and increased by 300% in group 2. DA increased in both groups. Conclusion: The relationship between HVR and the reciprocal DA and DOPA values seen in both groups is associated with age, producing decreased DA receptor sensitivity and enhanced DA reuptake during adaptation to high altitude.

Effect of Time-of-Day on the Yawning Response to Apomorphine in Normal Subjects

The yawning response to the dopamine (DA) receptor agonist apomorphine HCl (Apo, 7 μg/kg s.c.) and placebo (physiological saline) were examined in two groups of normal men. One group (n = 11) was investigated in the morning and the other group (n = 16) in the afternoon. The frequency of yawning was polygraphically monitored for 60 min following injection. Apo increased yawning compared with placebo when given in the morning (p < 0.02), but not when given in the afternoon. Yawning frequency was increased after both Apo (p < 0.01) and placebo (p < 0.025) when given in the morning compared with responses in the afternoon. These results suggest that yawning frequency with both Apo and placebo is influenced by time of day, possibly as a result of diurnal variation in DA receptor sensitivity.

Intrarenal Dopamine: A Key Signal in the Interactive Regulation of Sodium Metabolism

The kidney regulates sodium metabolism with extraordinary precision and sensitivity. This is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between anti-natriuretic and natriuretic factors. Dopamine, produced in renal proximal tubule cells, plays a central role in this interactive network. Natriuretic hormones that are released from extrarenal sources, such as atrial natriuretic peptide, mediate some of their effects via renal dopamine receptors. On the level of the tubules, dopamine acts by opposing the effects of anti-natriuretic factors, such as angiotensin II and alpha-adrenergic receptors. Sodium retention leads to an increase in renal dopamine tonus, and the natriuretic effects of dopamine are more prominent under this condition. Inhibition or down-regulation of dopamine receptors significantly attenuates the natriuretic response to salt loading. Renal dopamine is modulated by the supply of filtered L-DOPA and the metabolism of dopamine via catechol-O-methyldopamine. The importance of dopamine as a natriuretic hormone is reflected by its capacity to inhibit the majority of renal tubule sodium transporters. Notably, the activity of Na+, K+ ATPase is inhibited in most tubule segments by dopamine. Recent studies have elucidated many of the signaling pathways for renal dopamine receptors. Novel principles for homologous and heterologous sensitization of dopamine receptors have been detected that may explain some of the interaction between dopamine and other first messengers that modulate renal tubule sodium transport. A broad understanding of the renal dopamine system has become increasingly important, since there is now strong evidence from both clinical and experimental studies that dysregulation of the renal dopamine system plays a role in many forms of multigenetic hypertension.

Neurotoxic regimen of methamphetamine produces evidence of behavioral sensitization in the rat.

A neurotoxic regimen of methamphetamine (MA) produces long-term depletions in neostriatal dopamine and serotonin concentrations. In addition to evidence of dopaminergic and serotonergic neurotoxicity, there is evidence of MA-induced behavioral changes. In this regard, stereotypic behavior elicited by MA is greater in rats treated previously with a neurotoxic regimen of MA than in control animals. The present study was designed to determine whether the enhanced stereotypy observed in MA-treated rats is due to the MA-induced loss of dopamine (neurotoxicity) or to the repeated exposure to MA (sensitization). Rats were treated with MA (10 mg/kg every 2 h for four injections) or vehicle at either a normal (24 degrees C) room temperature or a cold (4 degrees C) room temperature, which has been shown to attenuate the MA-induced loss of dopamine. Stereotypy was assessed 7 days after treatment. Rats that had received a neurotoxic regimen of MA at 24 degrees C exhibited 49% and 45% reductions in neostriatal dopamine and serotonin concentrations, respectively, whereas rats treated with MA at 4 degrees C had no significant neurochemical depletions. Stereotypy elicited by MA (5.0 mg/kg) was significantly greater in rats treated with a neurotoxic regimen of MA regardless of the initial treatment temperature. In addition, an injection of apomorphine (0.5 mg/kg) elicited an enhanced stereotypic response in MA-treated rats. These data suggest that the augmented stereotypic behavior observed in rats treated with a neurotoxic regimen of MA is not due to the loss of dopamine, but rather the manifestation of behavioral sensitization, possibly due to an increase in dopamine receptor sensitivity.

The benzamide tiapride: treatment of extrapyramidal motor and other clinical syndromes.

The benzamide derivative tiapride (Tiapridex, Synthelabo) has a highly selective antagonistic effect on striatal adenylate cyclase-independent dopamine-2 receptors. Its in vitro binding affinity is especially high for dopamine receptors which have been sensitized by pre-incubation with dopamine. The involvement of altered dopamine receptor sensitivity in several extrapyramidal dys- and hyperkinesia has been hypothesized. By its high affinity for these receptors, without any affinity for other neurotransmitter receptors of the brain, tiapride is especially well suited for the treatment of movement disorders related to functional dopamine hyperactivity. Even at higher doses, tiapride does not exceed a D2-receptor occupancy of 80%, which is in accordance with the finding that tiapride rarely causes acute extrapyramidal syndromes and has, up to now, never implicated in inducing tardive dyskinesias. On the contrary, clinical studies demonstrate its excellent efficacy in neuroleptic-induced tardive dyskinesia, L-Dopa-induced dyskinesias, psychomotor agitation in geriatric patients and choreatic movement disorders. Since tiapride is not available in the USA as yet, most of the studies concerning tiapride have been carried out in Europe. In a recent study, based on objective measurements, tiapride effectively controlled choreatic movements in patients suffering from Huntington's disease (HD). Tiapride is well tolerated in daily doses between 300 and 1200 mg. Adverse events are generally rare and mild.

Inhibitory effects of ginseng total saponin on nicotine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity

A single administration of a low dose of nicotine produced hyperactivity in mice. A repeated administration of nicotine developed reverse tolerance to the ambulation-accelerating activity of nicotine and also developed postsynaptic dopamine (DA) receptor supersensitivity. The development of reverse tolerance was evidenced by an increased ambulatory response to nicotine, and the development of postsynaptic DA receptor supersensitivity was evidenced by the enhanced response in ambulatory activity to apomorphine, a DA receptor agonist. Administration of ginseng total saponin (GTS) prior to and during the nicotine treatment in mice inhibited not only nicotine-induced hyperactivity and reverse tolerance, but also postsynaptic DA receptor supersensitivity in nicotine-induced reverse tolerant mice. These results suggest that inhibition by GTS of nicotine-induced hyperactivity and reverse tolerance may be closely related with the inhibition of the dopaminergic activation induced by nicotine and that the development of nicotine-induced reverse tolerance may be associated with enhanced DA receptor sensitivity.

Rat Strain Differences in the Ability to Disrupt Sensorimotor Gating Are Limited to the Dopaminergic System, Specific to Prepulse Inhibition, and Unrelated to Changes in Startle Amplitude or Nucleus Accumbens Dopamine Receptor Sensitivity

Previous studies indicate that a variety of pharmacological agents interfere with the prepulse inhibition of the acoustic startle (PPI) response including phencyclidine (PCP), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), amphetamine, and apomorphine. Strain differences have been observed in the ability of apomorphine to disrupt PPI, although the degree to which these strain differences occur after administration of nondopaminergic drugs or the degree to which differences can be observed in other models of dopamine (DA) receptor activation has not been elucidated. The present study tested the effects of apomorphine, amphetamine, 8-OH-DPAT, and PCP on PPI in the Sprague Dawley and Wistar rat strains. Because apomorphine disrupts PPI via activation of DA receptors in the nucleus accumbens, apomorphine-induced hyperlocomotion, also a behavioral model of nucleus accumbens DA receptor activation, was measured in both rat strains. Administration of PCP or 8-OH-DPAT attenuated PPI in both strains, whereas apomorphine and amphetamine only attenuated PPI in Wistar rats. The ability of apomorphine to increase motor activity in the absence of a startle-eliciting stimulus was similar in the two strains, as was apomorphine-induced hyperlocomotion. A time course analysis of the effects of apomorphine on startle response in Sprague Dawley rats found that changes in the magnitude of PPI followed changes in basic startle amplitude. Similarly, no apomorphine-induced attenuation of PPI was observed in Sprague Dawley rats after 6-OHDA-induced DA receptor supersensitivity in the nucleus accumbens. These data suggest a dissociation between the effects of DA receptor agonists in PPI and other behavioral models of DA receptor activation.

Inhibition by Ginsenosides Rb 1 and Rg 1 of Cocaine-Induced Hyperactivity, Conditioned Place Preference, and Postsynaptic Dopamine Receptor Supersensitivity in Mice

A single or repeated administration of cocaine (15 mg/kg) in mice produced hyperactivity and conditioned place preference (CPP). Ginsenoside Rb 1 (Rb 1) and ginsenoside Rg 1 (Rg 1), prior to and during the cocaine treatment in mice, inhibited cocaine-induced hyperactivity and CPP. The development of enhanced postsynaptic dopamine (DA) receptor sensitivity in mice displaying a cocaine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg). Rb 1 and Rg 1 inhibited the development of postsynaptic DA receptor supersensitivity. However, Rb 1 and Rg 1 did not show any antidopaminergic activity at the postsynaptic DA receptors, because the apomorphine-induced climbing behavior was not inhibited by Rb 1 and Rg 1. Therefore, it is presumed that Rb 1 and Rg 1 modulate DA activity induced by cocaine at the presynaptic DA receptors, and this modulation results in the inhibition of postsynaptic dopaminergic activation. These results suggest that the cocaine-induced CPP may be associated with enhanced DA receptor sensitivity. The inhibition by Rb 1 and Rg 1 of cocaine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by cocaine at the presynaptic DA receptors.

Sensitization of amphetamine-induced stereotyped behaviors during the acute response: role of D 1 and D 2 dopamine receptors

During the response to an injection of amphetamine, rapid changes occur in the ability of the drug to induce stereotyped behaviors. This enhanced responsivity does not involve changes in the caudate–putamen or nucleus accumbens extracellular dopamine response, but appears to require activation of dopamine receptors. In the present studies we examined the role that D 1 and D 2 dopamine receptors might play in the development and expression of the enhanced stereotypy response. In one series of experiments we used the dopamine agonists, SKF 82958 and quinpirole as relatively selective probes at D 1 and D 2 dopamine receptors, respectively, to test for changes in dopamine receptor sensitivity following a pretreatment (`priming') with 4.0 mg/kg amphetamine. Doses of both SKF 82958 and quinpirole which were sub-threshold to induce perseverative behaviors in control animals, promoted stereotyped behaviors in amphetamine-primed animals, suggesting an enhanced sensitivity of both D 1 and D 2 receptors. In a second series of experiments, we sought to determine whether priming with these relatively selective dopamine receptor agonists, as well as the mixed D 1/D 2 agonist, apomorphine, would result in an enhanced stereotypy response to the subsequent administration of non-stereotypy producing doses of amphetamine (0.5–1.5 mg/kg). Priming with the dopamine receptor agonists each resulted in an enhanced amphetamine-induced stereotypy response. These results indicate that both D 1 and D 2 dopamine receptors contribute to both the development and the expression of the altered stereotypy responsivity, though several dose- and time-related observations suggest that other mechanisms likely contribute as well. Because these changes are apparent during the amphetamine response, they may have important implications for the evolving behavioral alterations which result when stimulants are administered in a binge pattern of drug abuse.

Growth hormone response to placebo, apomorphine and growth hormone releasing hormone in abstinent alcoholics and control subjects

Abstinent alcoholics and control subjects were challenged with placebo (saline), growth hormone releasing hormone (GHRH) and apomorphine (APO). While both groups did not differ in their growth hormone response (HGH) to placebo and GHRH, the alcoholics revealed a significant lower HGH response to dopamine receptor stimulation with APO. These findings provide no evidence that in abstinent alcoholics HGH blunting after dopamine receptor stimulation could be related to an alteration at the pituitary level but they give neuroendocrinological support to the hypothesis of a lower dopamine receptor sensitivity in abstinent alcoholics.

Behavioral responsitivity to dopamine receptor agonists after extensive striatal dopamine lesions during development

Dopamine (DA) receptor responsitivity was investigated in adult rats that received intrastriatal (i.s.) injections of 6-OHDA (20 micrograms per striatum) on day of birth or postnatal Day 1 (Day 0/Day 1). Neonatally lesioned rats exhibited self-biting behavior and increases in stereotypic gnawing following treatment with the mixed D1/D2 receptor agonist apomorphine (0.32-3.2 mg/kg) or the D1-like receptor agonist SKF38393 (10 mg/kg). Increases in locomotor activity, rearing, and paw treading were also observed in the lesioned rats after SKF38393 (1-10 mg/kg) treatment. The incidences of the prototypical D1 receptor-mediated behaviors, grooming and abnormal perioral movements (i.e., oral dyskinesias) were not increased in the lesioned rats. However, the low dose (0.32 mg/kg) of apomorphien as well as all doses of the D2-like receptor agonist quinpirole (0.32-3.2 mg/kg) induced grooming in the lesioned rats, which was not observed in nonlesioned control rats. Autoradiographs of [3H]mazindol binding to high affinity DA uptake sites revealed an extensive loss of DA terminals in the striata of the neonatally lesioned rats. These data suggest that near-total (> or = 95%) DA depletions on Day 0/Day 1 result in long-term alterations in the functional sensitivity of DA receptors, as well as possible changes in the interactions between D1 and D2 receptors. Comparisons of these results with those seen following lesions of the early-developing DA system ("patch-selective" lesions) and lesions made at other time points will be discussed.

Behavioral responsitivity to dopamine receptor agonists after extensive striatal dopamine lesions during development

Dopamine (DA) receptor responsitivity was investigated in adult rats that received intrastriatal (i.s.) injections of 6-OHDA (20 μg per striatum) on day of birth or postnatal Day 1 (Day 0/Day 1). Neonatally lesioned rats exhibited self-biting behavior and increases in stereotypic gnawing following treatment with the mixed D1/D2 receptor agonist apomorphine (0.32–3.2 mg/kg) or the D1-like receptor agonist SKF38393 (10 mg/kg). Increases in locomotor activity, rearing, and paw treading were also observed in the lesioned rats after SKF38393 (1–10 mg/kg) treatment. The incidences of the prototypical D1 receptor-mediated behaviors, grooming and abnormal perioral movements (i.e., oral dyskinesias) were not increased in the lesioned rats. However, the low dose (0.32 mg/kg) of apomorphine as well as all doses of the D2-like receptor agonist quinpirole (0.32–3.2 mg/kg) induced grooming in the lesioned rats, which was not observed in nonlesioned control rats. Autoradiographs of [3H]mazindol binding to high affinity DA uptake sites revealed an extensive loss of DA terminals in the striata of the neonatally lesioned rats. These data suggest that near-total (≥95%) DA depletions on Day 0/Day 1 result in long-term alterations in the functional sensitivity of DA receptors, as well as possible changes in the interactions between D1 and D2 receptors. Comparisons of these results with those seen following lesions of the early-developing DA system (“patch-selective” lesions) and lesions made at other time points will be discussed. © 1998 John Wiley & Sons, Inc. Dev Psychobiol 32: 313–326, 1998

Effects of ginseng total saponin on morphine-induced hyperactivity and conditioned place preference in mice

A single or repeated administration of morphine in mice produced hyperactivity, conditioned place preference (CPP) and postsynaptic dopamine (DA) receptor supersensitivity. The hyperactivity induced by morphine was evidenced by measuring the enhanced ambulatory activity using a tilting-type ambulometer. CPP effects were evaluated assessing the increased time spent by the mice to morphine and the inhibition of CPP by the decreased time spent by the mice in the white compartment. Postsynaptic DA receptor supersensitivity in mice displaying a morphine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg, s.c.). The intraperitoneal injection of ginseng total saponin (GTS) from the root of Panax ginseng C.A. Meyer ( Araliaceae), prior to and during the morphine treatment in mice inhibited morphine-induced hyperactivity and CPP. GTS inhibited the development of postsynaptic DA receptor supersensitivity. A single dose administration of GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic action of GTS at the postsynaptic DA receptor. These results suggest that the development of morphine-induced CPP may be associated with the enhanced DA receptor sensitivity and that GTS inhibition of the morphine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by morphine.

Effects of repeated administration of l-DOPA and apomorphine on circling behavior and striatal dopamine formation

We tested the circling response to l-DOPA and apomorphine administration in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Rats demonstrated a progressively diminished circling response when l-DOPA–carbidopa was repeatedly administered at 120 min intervals. This decreasing response was not present when apomorphine was administered under the same conditions. We also perfused l-DOPA directly into the striatum in vivo of rats with an ipsilateral 6-OHDA nigrotomy at 60 min intervals and monitored striatal dopamine levels with the technique of brain microdialysis. Dopamine formation increased from the first to the fifth trial. This may be secondary to the decrease in uptake sites which accompanies the loss of striatal dopamine nerve terminals. We postulate that the continued presence of dopamine at striatal receptor sites conditions a short-term loss of dopamine receptor sensitivity and a consequent decreased circling response. The observation that desensitization (as measured by decreasing circling) was not present following repeated apomorphine administration may be attributable to its shorter duration of action. We also perfused l-DOPA into the striatum of normal rats and noted a progressive decrease in striatal dopamine levels from the first to the fifth trial. Since this occurred following direct administration of l-DOPA into the striatum, the decrease could not be accounted for by peripheral pharmacodynamics or bioavailability of l-DOPA in the striatum. Since this decrease in dopamine formation was seen only in the normal striatum, its relevance to the diminished behavioral response is unclear.

Dopamine D2 receptor upregulation in rat neostriatum following in vivo infusion of forskolin.

Intracerebroventricular (i.c.v.) forskolin infusion for 5 days resulted in a concentration-dependent increase in rat striatal dopamine (DA) D2 receptors measured with [3H]raclopride. In animals given 50 nmol/h forskolin, the highest concentration used, raclopride-mediated suppression of spontaneous locomotor activity was attenuated, and (+/-)-7-hydroxy-dipropyl-aminotetralin HBr (7-OH-DPAT)-mediated inhibition of striatal DA synthesis, as estimated by the accumulation of DOPA following inhibition of cerebral decarboxylase, was enhanced. These data suggest that the DA D2 receptor increase comprises receptors localized both post- and presynaptically. The density of striatal DA D1 receptors was also changed with the forskolin treatment, in a concentration-dependent fashion, but in the opposite direction to DA D2 receptors. These findings suggest that striatal DA receptor sensitivity can be changed by manipulation at the second messenger level (e.g. independent of direct neurotransmitter-receptor interactions) in vivo.

P.1.029 Different mechanisms underlie fluoxetine- and imipramine-induced behavioural sensitization of dopamine receptors

P.1.029 Different mechanisms underlie fluoxetine- and imipramine-induced behavioural sensitization of dopamine receptors

Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol-dependent patients.

To explore 2 facets of dopamine receptor sensitivity in alcoholics: (1) whether reduced sensitivity of central dopamine receptors is correlated with anxiety, depression, or novelty seeking and (2) whether this reduction is associated with poor treatment outcome. Sixty-four alcohol-dependent patients were assessed according to their clinical outcome, sensitivity of central dopamine receptors (apomorphine-induced growth hormone secretion), mood states, and personality traits before and after detoxification. Patients with poor treatment outcome displayed a blunted growth hormone response before, but not after, detoxification. Growth hormone response was not significantly correlated with novelty seeking. Relapsing patients tended to be less depressed than patients who remained abstinent during observation. This study did not support the hypothesis that reduced sensitivity of dopamine receptors is associated with anxiety, depressed mood, or high novelty seeking in alcoholism.

Alcohol withdrawal and dopamine receptor sensitivtty after prolonged abstinence

1. 1. Forty-four male inpatients suffering from moderate to severe alcohol dependence (DSMIII-R and ICD-10) as well as 14 healthy controls entered this study. Individuals were classified according to the severity of their withdrawal symptoms during Detoxification I. e. group 1) no withdrawal, group 2) autonomie hyperactivity, group 3) withdrawal delirium and group 4) controls. 2. 2. During the 6th week of treatment, that is, when all patients were recovered, controlled abstinent, and several weeks away from the end of their withdrawal syndrome, dopamine receptor sensitivity was neuroendocrinologically assessed by stimulating human growth hormone (HGH) with apomorphine (APO). 3. 3. In a repeated measures model ANOVA, the four groups differed significantly in their HGH release. However, when excluding the controls from the analysis and focusing on alcoholics only (group 1 – 3), the significant difference disappeared. Covariates such as age, weight, quantity of drinking and duration of dependence were not related to the dependent variable. 4. 4. In conclusion, the first significant result (with controls) reflects a blunted HGH response in alcoholics. It confirms earlier reports. The second, non significant result with the alcohol dependents only, suggests that the severity of withdrawal is not reflected by the amount of HGH released. Therefore, in alcoholics, a reduced dopamine receptor function after six weeks of abstinence, as neuro-endocrinologicaliy assessed with apomorphine, seems to be related to alcohol dependence rather than to the severity of alcohol withdrawal.

Influence of dopaminergic transmission on severity of withdrawal syndrome in alcoholism.

Dysfunction of dopaminergic transmission has been suggested as influencing withdrawal syndrome in alcohol-dependent patients. Therefore, dopamine levels and sensitivity of dopamine receptors were correlated with the severity of withdrawal syndrome in 40 alcoholics. Dopamine blood plasma levels and apomorphine-induced Growth Hormone (GH) release were measured on the first day of detoxification (Day 1) and after 8 days of abstinence (Day 8). Severity of withdrawal syndrome was assessed daily by the Clinical Institute Withdrawal Assessment (CIWA) score. In the 22 patients (out of the 40) treated by chlormethiazole, severity of withdrawal was measured by the required chlormethiazole dose. A positive correlation was found between dopamine levels on Day 1 and the total CIWA score and necessary chlormethiazole dose, respectively. Correlation with the CIWA score was even stronger when the sensitivity of post-synaptic dopamine receptors was taken into account. No significant correlation between dopamine levels on Day 8 and withdrawal syndrome was found. Our findings indicate an influence of dopaminergic transmission on withdrawal syndrome during early withdrawal.