Dopamine Downregulation Research Articles

Enriched Environment Contributes to the Recovery from Neurotoxin-Induced Parkinson’s Disease Pathology

Parkinson’s disease (PD) is a neurological disorder that affects dopaminergic neurons. The lack of understanding of the underlying molecular mechanisms of PD pathology makes treating it a challenge. Several pieces of evidence support the protective role of enriched environment (EE) and exercise on dopaminergic neurons. The specific aspect(s) of neuroprotection after exposure to EE have not been identified. Therefore, we have investigated the protective role of EE on dopamine dysregulation and subsequent downregulation of DJ1 protein using in vitro and in vivo models of PD. Our study for the first time demonstrated that DJ1 expression has a direct correlation with dopamine downregulation in PD models and exposure to EE has a significant impact on improving the behavioral changes in PD mice. This research provides evidence that exercise in EE has a positive effect on PD without interfering with the current line of therapy.

Dopamine downregulation in novel rodent models useful for the study of postpartum depression.

Postpartum depression (PPD) is the most common psychiatric disorder following childbirth and is characterized by maternal mood disturbances, impaired maternal responses, and disrupted caregiving- all of which negatively impact offspring development. Since PPD has detrimental consequences for both mother and child, clinical and preclinical research has focused on identifying brain changes associated with this disorder. In humans, PPD is linked to dysregulated mesolimbic dopamine (DA) system function and altered neural responses (i.e., decreased reward-related activity) to infant-related cues, which are considered hallmark features of PPD. In accordance, rodent models employing translational risk factors useful for the study of PPD have demonstrated alterations in mesolimbic DA system structure and function, and these changes are reviewed here. We also present two novel rodent models based on postpartum adversity exposure (i.e., pup removal, scarcity-adversity) which result in PPD-relevant behavioral changes (e.g., disrupted mother-infant interactions, deficits in maternal behavior, depressive-like phenotypes) and attenuated ventral tegmental area (VTA) DA neuron activity consistent with a hypodopaminergic state. Furthermore, we highlight open questions and future directions for these rodent models. In sum, human and rodent studies converge in showing blunted mesolimbic DA function (i.e., DA downregulation) in PPD. We propose that reduced activity of VTA DA neurons, resulting in downregulation of the mesolimbic DA system, interferes with reward-related processes necessary for maternal motivation and responsiveness. Thus, the mesolimbic DA system may constitute a therapeutic target for ameliorating reward-related deficits in PPD.

Occlusion of dopamine-dependent synaptic plasticity in the prefrontal cortex mediates the expression of depressive-like behavior and is modulated by ketamine

Unpredictable chronic mild stress (CMS) is among the most popular protocols used to induce depressive-like behaviors such as anhedonia in rats. Differences in CMS protocols often result in variable degree of vulnerability, and the mechanisms behind stress resilience are of great interest in neuroscience due to their involvement in the development of psychiatric disorders, including major depressive disorder. Expression of depressive-like behaviors is likely driven by long-term alterations in the corticolimbic system and by downregulation of dopamine (DA) signaling. Although we have a deep knowledge about the dynamics of tonic and phasic DA release in encoding incentive salience and in response to acute/chronic stress, its modulatory action on cortical synaptic plasticity and the following implications on animal behavior remain elusive. Here, we show that the expression of DA-dependent synaptic plasticity in the medial prefrontal cortex (mPFC) is occluded in rats vulnerable to CMS, likely reflecting differential expression of AMPA receptors. Interestingly, such difference is not observed when rats are acutely treated with sub-anesthetic ketamine, possibly through the recruitment of dopaminergic nuclei such as the ventral tegmental area. In addition, by applying the synaptic activity sensor SynaptoZip in vivo, we found that chronic stress unbalances the synaptic drive from the infralimbic and prelimbic subregions of the mPFC toward the basolateral amygdala, and that this effect is counteracted by ketamine. Our results provide novel insights into the neurophysiological mechanisms behind the expression of vulnerability to stress, as well as behind the antidepressant action of ketamine.

Cohabitation With Atlantic Salmon (Salmo salar) Affects Brain Neuromodulators But Not Welfare Indicators in Lumpfish (Cyclopterus lumpus).

Lumpfish are utilized to combat ectoparasitic epidemics in salmon farming. Research gaps on both cleaning behavior and client preferences in a natural environment, emphasizes the need to investigate the physiological impacts on lumpfish during cohabitation with piscivorous Atlantic salmon. Lumpfish (39.9 g, S.D ± 8.98) were arranged in duplicate tanks (n = 40 per treatment) and exposed to Live Atlantic salmon (245.7 g, S.D ± 25.05), salmon Olfaction or lifelike salmon Models for 6 weeks. Growth and health scores were measured every second week. In addition, the final sampling included measurements of neuromodulators, body color, and plasma cortisol. A stimulation and suppression test of the hypothalamic-pituitary-interrenal (HPI) axis was used for chronic stress assessment. Results showed that growth, health scores, and body color remained unaffected by treatments. Significant reductions in levels of brain dopamine and norepinephrine were observed in Live compared to Control. Plasma cortisol was low in all treatments, while the stimulation and suppression test of the HPI axis revealed no indications of chronic stress. This study presents novel findings on the impact on neuromodulators from Atlantic salmon interaction in the lumpfish brain. We argue that the downregulation of dopamine and norepinephrine indicate plastic adjustments to cohabitation with no negative effect on the species. This is in accordance with no observed deviations in welfare measurements, including growth, health scores, body color, and stress. We conclude that exposure to salmon or salmon cues did not impact the welfare of the species in our laboratory setup, and that neuromodulators are affected by heterospecific interaction.

Central Nervous System Associated With Light Perception and Physiological Responses of Birds.

Environmental light that animal receives (i.e., photoperiod and light intensity) has recently been shown that it affects avian central nervous system for the physiological responses to the environment by up or downregulation of dopamine and serotonin activities, and this, in turn, affects the reproductive function and stress-related behavior of birds. In this study, the author speculated on the intriguing possibility that one of the proposed avian deep-brain photoreceptors (DBPs), i.e., melanopsin (Opn4), may play roles in the dual sensory-neurosecretory cells in the hypothalamus, midbrain, and brain stem for the behavior and physiological responses of birds by light. Specifically, the author has shown that the direct light perception of premammillary nucleus dopamine-melatonin (PMM DA-Mel) neurons is associated with the reproductive activation in birds. Although further research is required to establish the functional role of Opn4 in the ventral tegmental area (VTA), dorsal raphe nucleus, and caudal raphe nucleus in the light perception and physiological responses of birds, it is an exciting prospect because the previous results in birds support this hypothesis that Opn4 in the midbrain DA and serotonin neurons may play significant roles on the light-induced welfare of birds.

Gamma Oryzanol Alleviates High-Fat Diet-Induced Anxiety-Like Behaviors Through Downregulation of Dopamine and Inflammation in the Amygdala of Mice.

BackgroundA high-fat diet (HFD) can induce obesity and metabolic disorders that are closely associated with cognitive impairments, and the progression of several psychiatric disorders such as anxiety. We have previously demonstrated the anxiolytic-like effect of Gamma oryzanol (GORZ) in chronic restraint stressed mice.ObjectiveWe studied the neurochemical and molecular mechanisms that underlie the preventive effect of GORZ in HFD-induced anxiety-like behaviors, monoaminergic dysfunction, and inflammation.MethodsEight-week-old Institute of Cancer (ICR) male mice weighing 33–34 g were divided into the following groups and free-fed for 8 weeks: control (14% casein, AIN 93M); HFD; HFD + GORZ (0.5% GORZ). Body weight gain was checked weekly. The anxiolytic-like effects of GORZ were examined via open-field test (OFT) and elevated plus maze (EPM) test. Brain levels of monoamines [5-hydroxy tryptamine (5-HT), dopamine (DA), and norepinephrine (NE)] and their metabolites [5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], proinflammatory cytokines such as tumor necrosis factor-αα (Tnf-α) mRNA levels, and interleukin 1-β (Il-1β) mRNA levels in the cerebral cortex and amygdala were examined using high-performance liquid chromatography-electrochemical detection (HPLC-ECD), and real-time reverse transcription-polymerase chain reaction (RT-PCR), respectively.ResultsMice fed a HFD for eight weeks showed anxiety-like behaviors in association with HFD-induced body weight gain. GORZ potentially blocked HFD-induced anxiety-like behaviors via significant improvement of the primary behavioral parameters in behavioral tests, with a minor reduction in HFD-induced body weight gain. Furthermore, GORZ treatment significantly downregulated HFD-induced upregulation of dopamine levels in the brain's amygdala. Significant reduction of the relative mRNA expression of Tnf-α and Il-1 β was also observed in the amygdala of HFD + GORZ mice, compared to HFD mice.ConclusionsOur findings strongly suggest that 0.5% GORZ exerts anxiolytic-like effects, possibly through downregulation of dopamine, and via expression of proinflammatory cytokines Tnf-α and Il-1 β in the case of chronic HFD exposure.

The effect of Hordeum vulgare on the monoaminergic system modulating neural-thyroid dysfunction in hypothyroid female rats

Thyroid hormones regulate the development and maturation of the brain by maintaining levels of neurotransmitters and their related metabolites. The present work emphasizes the neural dysfunction in the brain caused by hypothyroidism and the potential role of Hordeum vulgare (water soluble barley, (B)) in ameliorating these effects. The study was conducted on euothyroid and hypothyroid adult female rats. The induction of hypothyroidism was conducted by oral-administration of neo-mercazole (5.0 mg.kg-1) daily for thirty days prior the study and terminated at the end of the study. The groups were assigned as; euthyroid (EU) and hypothyroid (H) groups and other two groups were treated with 100 mg.kg-1 water soluble barley; daily for one month and assigned as (EU+B) and (H+B) groups. Compared with EU and EU+B groups, a reduction in fT4, and ERK1/2 levels and elevation in TSH in brain tissue, Moreover, a significant elevation in 8-OH deoxyguanosine and caspase-3 levels, confirmed with increase percentage DNA-damage in the brain and thyroid tissues in hypothyroid control rats. Furthermore, a significant decrease in all monoamines levels in different brain areas and downregulation of dopamine and 5-hydroxytreptamin receptors transcription, with a significant increase in excitatory amino acids and no significant change in the levels inhibitory amino acids were recorded in control hypothyroid group. Treatment of hypothyroid group with Hordeum vulgare improved the above-mentioned adverse impact by ameliorating the thyroid hormone levels with depleting the DNA-degradation and elaborating the levels of neurotransmitters with related receptors and amino acids in brain areas. Water soluble Hordeum vulgare as a phytonutrient, is safe and efficient agent in ameliorating the neural dysfunction resulting from hypothyroidism status in adult female rats.

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs “rescued” dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of KORs is a promising avenue for developing pharmacotherapies for alcoholism.

Is Sugar a Gateway Drug?

Addiction is a chronic, relapsing disorder with genetic, biochemical and psychosocial antecedents. Chronic use of drugs of abuse results in characteristic biochemical changes in the mesolimbic pathway of the brain including reduced extracellular dopamine levels and down regulation of dopamine 2 receptors. Similar biochemical changes have been identified with consumption of high concentrations of sugar. Cross-sensitization between sugar and drugs of abuse has been demonstrated to occur. This raises the possibility that sugar could act as a gateway drug, increasing the subsequent risk of becoming addicted to drugs of abuse. This article examines the research that indicates sugar can act as a gateway drug.

Abstract 88: Single Nucleotide Polymorphisms of the Dopamine D2 Receptor Increase Inflammation and Fibrosis in Human Renal Proximal Tubule Cells

We have reported that lack or downregulation of dopamine D(2) receptor (D 2 R) function in mice increases the vulnerability to renal inflammation independent of blood pressure and that the D 2 R negatively regulates inflammation and prevents injury in mouse renal proximal tubule cells (RPTCs). Some common single nucleotide polymorphisms (SNPs; rs 6276, 6277 and 1800497) in the human DRD2 gene are associated with decreased D 2 R expression and function, as well as high blood pressure. We tested the hypothesis that human RPTCs expressing these SNPs have increased expression of inflammatory markers and injury. We studied immortalized human RPTCs isolated from normal tissue of nephrectomies which were genotyped for the D 2 R SNPs; 10 cell lines were selected: wild type (WT) n=5; heterozygous for both rs6276 and 6277 n=3; heterozygous for both rs6276 and 1800497 n=2. All 5 cell lines expressing SNPs (hRPTC-SNP) had decreased D 2 R mRNA (0.52±0.03 vs. 1±0.02 (WT) fold; P<0.02 ) and protein (62±4 vs. 100±6%; P<0.04) and were pooled together for analysis. D 2 R function was also decreased as determined by the decreased ability of a D 2 R agonist to increase PMA-induced cAMP accumulation (hRPTC-SNP: 201±16; hRPTC-WT 270 ±5 %; n=4; P<0.05). The expression of the pro-inflammatory cytokines TNFα (2.5 ± 0.3 fold; P<0.04) and CD40L (2.3 ± 0.5 fold; P<0.05), as well as the inflammation marker CRP (1.5 ± 0.2 fold; P<0.04) was increased in hRPTC-SNP. The expression of the pro-fibrotic TGFβ1 (1.8 ± 0.4 fold; P<0.04) and its signaling targets PAI-1 (6.3± 0.5 fold; P<0.01), SMAD3 (2.8± 0.4 fold; P<0.02) and VEGFa (2.3± 0.6 fold; P<0.04) were also increased. Furthermore hRPTC-SNP showed induction of epithelial mesenchymal transition and production of extracellular matrix proteins as shown by increased fibronectin -1 (3.1± 0.7 fold; P<0.03), col 1a (1.6± 0.2 fold; P<0.05), col 3a (2.2± 0.5 fold; P<0.05), MMP3 (5.6± 0.8 fold; P<0.04), and MMP9 (3.5± 0.5 fold; P<0.04). These data support the hypothesis that D 2 R function has protective effects in human RPTCs and suggest that carriers of these SNPs may be prone to chronic renal disease and high blood pressure.

Investigation on the downregulation of dopamine by acetaminophen administration based on their simultaneous determination in urine

A highly sensitive and selective method is developed for the simultaneous detection of dopamine (DA) and acetaminophen (AP) by reactive blue-4 (RB4) dye entrapped poly1,5-diaminonaphthalne (polyDAN) composite film layer. The polyDAN-RB4 composite is electrochemically developed at glassy carbon electrode. The polymeric film, characterized by XPS and SEM is able to catalyze the oxidation of DA and AP. Two well-defined oxidation peaks are observed in the differential pulse voltammogram (DPV). The experimental parameters affecting the analytical performance are optimized in terms of RB4 concentration, temperature, and pH. The dynamic range for DA and AP analysis is between 0.1–150 and 0.2–164μM with a detection limit of 0.061±0.002 and 0.083±0.003μM, respectively. The anionic form of the polyDAN-RB4 composite repels common metabolites present in serum and urine, and hence no interference is observed. The effect of AP on the DA concentrations in urine is also studied after the oral administration of a single as well as multiple doses. The DA concentrations have been found to decrease nearly 50±3% after prolonged AP administration.

How is reward sensitivity related to bodyweight in children?

Previous research assumes that there are two seemingly opposing hypotheses for the relation between reward sensitivity (RS) and bodyweight: hyper-responsiveness model and Reward Deficiency Syndrome (RDS), leading to the proposition of a feed forward process of weight gain. High RS may contribute to overeating and weight-gain among normal weight individuals. Over time the excessive food-intake may evolve in a down-regulation of dopamine (RDS), resulting in overeating as a form of self-medication and the progression to obesity. This process was evidenced in adults showing a curvi-linear relationship between self-reported RS and BMI. The aim of the current study was to investigate the association between self-reported RS and BMI in children (10–15years). The results confirm the non-linear relationship between RS and bodyweight and support the suggestion of the same feed forward process in children. These findings imply that it is crucial to reduce the intake of high palatable foods in high RS children to prevent the decrease in RS and reduce the risk for future weight gain.

The effect of 'two hit' neonatal and young-adult stress on dopaminergic modulation of prepulse inhibition and dopamine receptor density.

A combination of early neurodevelopmental insult(s) and young-adult stress exposure may be involved in the development of schizophrenia. We studied prepulse inhibition (PPI) regulation in rats after an early stress, maternal deprivation, combined with a later stress, simulated by chronic corticosterone treatment, and also determined whether changes in brain dopamine receptor density were involved. Rats were subjected to either 24 h maternal deprivation on postnatal day 9, corticosterone treatment from 8 to 10 weeks of age, or both. At 12 weeks of age, the rats were injected with 0.1, 0.3 or 1.0 mg.kg(-1) of apomorphine or 0.5 or 2.5 mg.kg(-1) of amphetamine and PPI was determined using automated startle boxes. Dopamine D(1) and D(2) receptor levels were assessed in the nucleus accumbens and caudate nucleus using receptor autoradiography. Young-adult treatment with corticosterone resulted in attenuated disruption of PPI by apomorphine and amphetamine. In some rats, maternal deprivation resulted in reduced baseline PPI which added to the effect of corticosterone treatment. There was no down-regulation of dopamine D(1) or D(2) receptors. These results confirm and extend our finding of an inhibitory interaction of developmental stress on dopaminergic regulation of PPI. No corresponding changes in dopamine receptor density were observed in brain regions with a major involvement in PPI regulation, suggesting long-lasting desensitization of dopamine receptor signalling or indirect changes in PPI regulation.

Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease

Huntington disease (HD) is an adult onset neurodegenerative disorder characterized by selective atrophy and cell loss within the striatum. There is currently no treatment that can prevent the striatal neuropathology. Transglutaminase (TG) activity is increased in HD patients, is associated with cell death, and has been suggested to contribute to striatal neuronal loss in HD. This work assesses the therapeutic potential of cystamine, an inhibitor of TG activity with additional potentially beneficial effects. Specifically, we examine the effect of cystamine on striatal neuronal loss in the YAC128 mouse model of HD. We demonstrate here for the first time that YAC128 mice show a forebrain-specific increase in TG activity compared with wild-type (WT) littermates which is decreased by oral delivery of cystamine. Treatment of symptomatic YAC128 mice with cystamine starting at 7 months prevented striatal neuronal loss. Cystamine treatment also ameliorated the striatal volume loss and striatal neuronal atrophy observed in these animals, but was unable to prevent motor dysfunction or the down-regulation of dopamine and cyclic adenosine monophsophate-regulated phosphoprotein (DARPP-32) expression in the striatum. While the exact mechanism responsible for the beneficial effects of cystamine in YAC128 mice is uncertain, our findings suggest that cystamine is neuroprotective and may be beneficial in the treatment of HD.

Role of Dopaminergic Treatment in Dopamine Receptor Down-regulation in Advanced Parkinson Disease

In patients with advanced Parkinson disease (PD) who are undergoing long-term treatment with a dopaminergic medication, a down-regulation of striatal dopamine D2 receptor expression has been demonstrated and interpreted as a consequence of either the disease itself or dopaminergic drug administration. To compare, using positron emission tomography, the striatal binding of raclopride carbon C 11, a dopamine D2 receptor ligand, in PD patients who completely discontinued dopaminergic therapy (off drug) with that in PD patients who continued receiving dopaminergic therapy (on drug) after undergoing subthalamic nucleus stimulation. The positron emission tomographic data were acquired in off-stimulation and, for 12 hours, off-medication conditions. Five off-drug PD patients, 7 on-drug PD patients, and 8 healthy subjects participated. In off-drug PD patients, the putaminal raclopride C 11 binding was 24% higher than in on-drug PD patients. The same tendency was noted for the caudate nucleus, but was not significant (P=.07). Compared with control subjects, the putaminal raclopride C 11 binding was increased by 21% in off-drug and was normal in on-drug PD patients. Compared with controls, the caudate raclopride C 11 binding was reduced by 23% in on-drug and was normal in off-drug PD patients. Further analysis using statistical parametric mapping showed a significant increase of binding bilaterally in the caudate nucleus and putamen in off-drug compared with on-drug PD patients (P=.002 at cluster level). The down-regulation of dopamine D2 receptors probably relates to the long-term and intermittent administration of dopaminergic treatments rather than to disease progression. This phenomenon is reversed by the complete withdrawal of dopaminergic drugs. Furthermore, an up-regulation of putaminal dopamine D2 receptors is demonstrated in late-stage PD after dopaminergic drug withdrawal.

Down-regulation of dopamine D 1 and D 2 receptors in the basal ganglia of PTZ kindling model of epilepsy: effects of angiotensin IV

The present study examined the effect of pentylenetetrazol (PTZ) induced kindling as well as the action of the hexapeptide angiotensin IV (ANG IV) on the dopamine (DA) D 1 and D 2 receptor binding in the basal ganglia of the mouse brain. By using quantitative receptor autoradiography, it was found that PTZ kindling led to a decrease in DA D 2 receptor density (about 20%) in all regions of the neostriatum (NS) as well as in the olfactory tubercle (OT), the nucleus accumbens (NA) and the globus pallidus, which persisted 24 h and 7 days after the kindling procedure. PTZ induced kindling also elicited a decrease in DA D 1 receptor binding sites (about 10%), which however was, restricted to the rostral NS (rNA) and NA. ANG IV (0.2 mg/kg), injected prior to PTZ, not only prevented the development of the kindling process but it also reversed the kindling-induced down-regulation of both DA receptors to the control levels. Furthermore ANG IV induced an area-specific increase of DA D 1 receptor density above control levels in the dorsal part of rNS. These findings suggest that DA D 2 receptors could mainly contribute to epileptogenesis in the PTZ kindling model, whereas the role of DA D 1 receptors is limited to particular regions in the basal ganglia. The anticonvulsant effect of ANG IV pretreatment might be influenced by a DA-related mechanism and particularly by preventing D 2 receptor down-regulation as well as by an adaptive area-specific increase in DA D 1 receptors.

Lack of persistent changes in the dopaminergic system of rats withdrawn from methamphetamine self-administration

A continuing challenge for studies in the neurobiology of drug abuse is to identify and characterize long-lived neuroadaptations that can trigger craving and relapse. We previously reported that rats that had actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D 2 autoreceptor levels in the ventral tegmental area and median and dorsal part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D 1 receptors in the shell of the nucleus accumbens. The purpose of the present study was to determine whether neuroadaptive changes in dopamine receptors or transporters in the brains of rats withdrawn for 24 h from chronic methamphetamine self-administration are persistent changes that can be demonstrated long after withdrawal. A “yoked” procedure was used in which rats were tested simultaneously in groups of three, with only one rat actively self-administering methamphetamine while the other two received yoked injections of either methamphetamine or saline. In vitro quantitative autoradiography was used to determine densities of dopamine uptake sites and dopamine D 1 and D 2 receptors in different brain regions following 7- and 30-day periods of withdrawal from chronic methamphetamine self-administration. No changes in dopamine transporter and dopamine receptor numbers were detected in any brain region examined in rats self-administering methamphetamine compared with littermates receiving yoked infusions of either methamphetamine or saline. Thus, neuroadaptive changes in densities of dopamine receptors or transporters in certain brain areas may contribute to the reinforcing effects of methamphetamine during the acquisition and maintenance phases of self-administration, but do not appear to contribute to the long-lasting neuroadaptive effects of chronic methamphetamine self-administration, which may trigger craving and relapse.

Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine

Methamphetamine is a strong and long-lasting stimulant that can be easily synthesized and is effective when taken either orally, intravenously, or smoked as `ice'. Due to it's escalating abuse, a clear need exists for laboratory procedures to evaluate motivational components of methamphetamine abuse and their underlying neurobiological mechanisms. In the present experiment, we utilized a `yoked' procedure in which rats were run simultaneously in groups of three, with two rats serving as yoked controls which received an injection of either 0.1 mg/kg methamphetamine or saline which was not contingent on responding each time a response-contingent injection of 0.1 mg/kg methamphetamine was self-administered by the third paired rat. Rats that had actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D 2 autoreceptors levels in the ventral tegmental area (34%) and medial (31%) and dorsal (21%) part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D 1 receptors in the shell of the nucleus accumbens (15%), as measured by in vitro quantitative autoradiography. Since the decreases in levels of dopamine D 1 and D 2 receptors which occurred in rats self-administering methamphetamine did not occur in littermates that received either yoked injections of methamphetamine or saline, these changes likely reflect motivational states that were present when methamphetamine injection depended on active drug self-administration behavior.

Long-term imipramine effects are prevented by NMDA receptor blockade

Long-term exposure to different antidepressant treatments induces increased motor response to central stimulants, due to a selective supersensitivity of dopamine D 2 receptors in the limbic areas. Such an effect is accompanied by down-regulation of dopamine D 1 receptor number, and by a decreased response of adenylyl cyclase to dopamine stimulation in the limbic system. Moreover, the number of β-adrenergic receptors and the response of adenylyl cyclase to β-adrenergic stimulation in the cortex result to be reduced. The present data confirms that imipramine (10 mg/kg twice a day for 3 weeks) produces such effects, and shows that the co-administration of imipramine with MK-801 (administered by a subcutaneously implanted minipump delivering 0.05 mg/kg/day of the compound) prevented the occurence of both the behavioral supersensitivity to quinpirole, and the decrease of dopamine D 1 and β-adrenergic receptor function.

Down-regulation of dopamine 1 (D 1) receptors by chronic imipramine is species-specific

Chronic treatment with imipramine (15 mg/kg, twice daily for 14 days) induces a down-regulation of limbic D 1 receptors in rats but not in mice. In this mouse strain, both chronic and acute imipramine treatment have been shown to produce clear behavioral effects in the forced swim test. While the data presented here are consistent with previously reported findings in rats, they demonstrate that the down-regulation of D 1 receptors by chronic antidepressant treatment is species-specific. This phenomenon indicates that D 1 receptor down-regulation is not critical to the therapeutic mechanism of action of antidepressants.