Dopamine D3 receptor agents as potential new medications for drug addiction

2000 ◽  
Vol 15 (2) ◽  
pp. 140-146 ◽  
Author(s):  
B. Le Foll ◽  
J.C. Schwartz ◽  
P. Sokoloff
Keyword(s):  
Drug Addiction ◽  
Dopamine Neurons ◽  
Receptor Subtypes ◽  
Long Term Effects ◽  
Self Administration ◽  
R And D ◽  
Critical Problems ◽  
Dopamine D3 ◽  
Abused Drugs

SummaryAll drugs abused by humans increase dopamine in the shell of nucleus accumbens, which implicate the neurons of this structure in their hedonic and reinforcing properties. Among the various dopamine receptor subtypes, the D1 (D1R) and D3 (D3R) receptors co-localise in accumbal shell neurons. Synergistic D1R/D3R interactions at this level were found on gene expression and during induction and expression of behavioral sensitisation to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitisation to abused drugs is a component of their long-term effects. Converging pharmacologic, human postmortem and genetic studies suggest the involvement of the D3R in reinforcing effects of drugs; D3R agonists reduced cocaine self-administration in rats, without disrupting the maintenance of self-administration. These data suggest the use of D3R agonists as partial substitutes to treat cocaine dependence, by affecting its reward component. However, substitution therapies maintain dependence and may be inefficient on drug craving and relapse, which are the unsolved and critical problems in the treatment of drug addiction. Recently, a highly selective and partial D3R agonist was shown to reduce cocaine-associated cue-controlled behaviour in rats, without having any primary intrinsic effects. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, such D3R agents have potential therapeutic applications.

scholarly journals Long-Term Impacts of Post-weaning Social Isolation on Nucleus Accumbens Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Cari J. Bendersky ◽  
Allison A. Milian ◽  
Mason D. Andrus ◽  
Ubaldo De La Torre ◽  
Deena M. Walker
Keyword(s):  
Nucleus Accumbens ◽  
Social Isolation ◽  
Medium Spiny Neurons ◽  
Long Term Effects ◽  
Self Administration ◽  
Reward Circuitry ◽  
Specific Effects ◽  
Dopamine Receptor 1 ◽  
First Time

Adolescence is a period of incredible change, especially within the brain's reward circuitry. Stress, including social isolation, during this time has profound effects on behaviors associated with reward and other neuropsychiatric disorders. Because the Nucleus Accumbens (NAc), is crucial to the integration of rewarding stimuli, the NAc is especially sensitive to disruptions by adolescent social isolation stress. This review highlights the long-term behavioral consequences of adolescent social isolation rearing on the NAc. It will discuss the cellular and molecular changes within the NAc that might underlie the long-term effects on behavior. When available sex-specific effects are discussed. Finally by mining publicly available data we identify, for the first time, key transcriptional profiles induced by adolescence social isolation in genes associated with dopamine receptor 1 and 2 medium spiny neurons and genes associated with cocaine self-administration. Together, this review provides a comprehensive discussion of the wide-ranging long-term impacts of adolescent social isolation on the dopaminergic system from molecules through behavior.

Long-term effects of cariprazine exposure on dopamine receptor subtypes

CNS Spectrums ◽  
2013 ◽  
Vol 19 (3) ◽  
pp. 268-277 ◽  
Author(s):  
Yong Kee Choi ◽  
Nika Adham ◽  
Béla Kiss ◽  
István Gyertyán ◽  
Frank I. Tarazi
Keyword(s):  
Dopamine Receptor ◽  
Dopaminergic System ◽  
Partial Agonist ◽  
Brain Regions ◽  
Repeated Treatment ◽  
Receptor Subtypes ◽  
Long Term Effects ◽  
Tissue Sections ◽  
Preferential Binding

IntroductionAll clinically effective antipsychotics are known to act on the dopaminergic system, and previous studies have demonstrated that repeated treatment with antipsychotics produced region-specific changes in dopamine receptor levels. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. We examined the effects of chronic cariprazine administration on dopamine receptor levels.MethodsRats were administered either vehicle or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Dopamine receptor levels were quantitated using autoradiographic assays on brain tissue sections from the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIPP), olfactory tubercle (OT), and islands of Calleja (ICj).ResultsChronic treatment with cariprazine did not alter D1 receptor levels in any brain region tested. Cariprazine increased D2 receptor levels in mPFC (27%–43%), NAc (40%–45%), medial (41%–53%) and lateral (52%–63%) CPu, and HIPP (38%). Cariprazine dose-dependently upregulated D3 receptor levels in ICj (32%–57%), OT (27%–67%), and NAc shell (31%–48%). Repeated cariprazine treatment increased D4 receptor in NAc (53%–82%), medial (54%–98%) and lateral (58%–74%) CPu, and HIPP (38%–98%).ConclusionSimilar to other antipsychotics, cariprazine upregulated D2 and D4 receptor levels in various brain regions. Cariprazine was unique among antipsychotics in increasing D3 receptor levels, which may support its unique psychopharmacologic properties.

scholarly journals Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine

CNS Spectrums ◽  
2017 ◽  
Vol 22 (6) ◽  
pp. 484-494 ◽  
Author(s):  
Yong Kee Choi ◽  
Nika Adham ◽  
Béla Kiss ◽  
István Gyertyán ◽  
Frank I. Tarazi
Keyword(s):  
Ampa Receptors ◽  
Brain Regions ◽  
Receptor Subtypes ◽  
Long Term Effects ◽  
Caudate Putamen ◽  
Chronic Effects ◽  
Hippocampal Ca1 ◽  
Term Administration ◽  
Clinical Benefits

ObjectiveThis study examined the chronic effects of aripiprazole and cariprazine on serotonin (5-HT1Aand 5-HT2A) and glutamate (NMDA and AMPA) receptor subtypes. In addition, the effects of aripiprazole on D2and D3receptors were tested and compared with previously reported cariprazine data.MethodsRats received vehicle, aripiprazole (2, 5, or 15 mg/kg), or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Receptor levels were quantified using autoradiographic assays on brain sections from the medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), nucleus accumbens (NAc), caudate-putamen medial (CPu–M), caudate-putamen lateral (CPu–L), hippocampal CA1 (HIPP–CA1) and CA3 (HIPP–CA3) regions, and the entorhinal cortex (EC).ResultsSimilar to previous findings with cariprazine, aripiprazole upregulated D2receptor levels in various regions; D3receptor changes were less than those reported with cariprazine. All aripiprazole doses and higher cariprazine doses increased 5-HT1Areceptors in the MPC and DFC. Higher aripiprazole and all cariprazine doses increased 5-HT1Areceptors in HIPP–CA1 and HIPP–CA3. Aripiprazole decreased 5-HT2Areceptors in the MPC, DFC, HIPP–CA1, and HIPP–CA3 regions. Both compounds decreased NMDA receptors and increased AMPA receptors in select brain regions.ConclusionsLong-term administration of aripiprazole and cariprazine had similar effects on 5-HT1A, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D3receptors while aripiprazole selectively reduced 5-HT2Areceptors. These results suggest that the unique actions of cariprazine on dopamine D3receptors, combined with its effects on serotonin and glutamate receptor subtypes, may confer the clinical benefits, safety, and tolerability of this novel compound in schizophrenia and bipolar mania.

scholarly journals Depression of substantia nigra dopamine transmission is driven by retrograde neurotensin release and is enhanced by methamphetamine self-administration

2019 ◽  
Author(s):  
Christopher W. Tschumi ◽  
Ramaswamy Sharma ◽  
William B. Lynch ◽  
Amanda L. Sharpe ◽  
Michael J. Beckstead
Keyword(s):  
Substantia Nigra ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine Neurons ◽  
Self Administration ◽  
Motivated Behavior ◽  
Neurotensin Receptors ◽  
Midbrain Dopamine ◽  
Postsynaptic Calcium

AbstractMidbrain dopamine neurons play central roles in reward learning and motivated behavior, and inhibition at somatodendritic dopamine D2 receptor (D2R) synapses blunts psychostimulant reinforcement. Release of the neuropeptide neurotensin in the midbrain increases following methamphetamine exposure and induces long-term depression of D2R synaptic currents (LTDDA), however the source of neurotensin that drives LTDDA is not known. Here we show that LTDDA is driven by neurotensin released by dopamine neurons. Optogenetic stimulation of dopamine neurons was sufficient to induce LTDDA in the substantia nigra, but not the ventral tegmental area, and was dependent on neurotensin receptors, postsynaptic calcium, and vacuolar-type H+-ATPase activity in the postsynaptic cell. Further, LTDDA was enhanced in mice that had self-administered methamphetamine. These findings reveal a novel form of signaling between dopamine neurons involving release of the peptide neurotensin, which may act as a feed forward mechanism to increase dopamine neuron excitability and methamphetamine self-administration.

Receptor research for the development of new drug therapies for stimulant addiction

Impact ◽  
2021 ◽  
Vol 2021 (6) ◽  
pp. 43-45
Author(s):  
Kyoji Okita
Keyword(s):  
Side Effects ◽  
Drug Addiction ◽  
Drug Users ◽  
Long Term Effects ◽  
Imaging Center ◽  
Positron Emission ◽  
Negative Side Effects ◽  
Receptor Research ◽  
Methamphetamine Use Disorder

Drug addiction is associated with a range of medical and social problems, not least the negative side effects experienced by those who take drugs. The long-term effects are particularly concerning and can be difficult to treat. Changes in the behaviour of long-term drug users can include impulsivity and irrationality, which can negatively impact on society. Dr Kyoji Okita, Integrative Brain Imaging Center (IBIC), National Center of Neurology and Psychiatry, Japan, is working to shed light on the neurological biochemistry behind drug addiction, as this aspect is little understood. In his work, he is collaborating with experts and he intends to apply the knowledge he and his collaborators uncover to real-world treatments. A particular focus for Okita is the use of positron emission tomography (PET) to explore the dynamics behind psychological and addiction biology. Currently, he is investigating the potential of a drug called Istradefylline as a treatment for methamphetamine use disorder. The drug is currently used as part of the treatment for Parkinson's disease and Okita wants to decipher if administering Istradefylline to people addicted to methamphetamines can help increase their dopamine sensitivity and, in the process, reduce their reliance on the drug, as well as the psychological side effects. If found to be effective, Istradefylline could form a key part of a treatment programme for addiction.

scholarly journals Dopamine and Addiction

2020 ◽  
Vol 71 (1) ◽  
pp. 79-106 ◽  
Author(s):  
Roy A. Wise ◽  
Mykel A. Robble
Keyword(s):  
Dopamine Receptors ◽  
Dopamine Neurons ◽  
Withdrawal Symptoms ◽  
Self Administration ◽  
Conditioned Reflexes ◽  
Appetitive Behavior ◽  
Addictive Drugs ◽  
Habitual Intake ◽  
The Brain

Addiction is commonly identified with habitual nonmedical self-administration of drugs. It is usually defined by characteristics of intoxication or by characteristics of withdrawal symptoms. Such addictions can also be defined in terms of the brain mechanisms they activate; most addictive drugs cause elevations in extracellular levels of the neurotransmitter dopamine. Animals unable to synthesize or use dopamine lack the conditioned reflexes discussed by Pavlov or the appetitive behavior discussed by Craig; they have only unconditioned consummatory reflexes. Burst discharges (phasic firing) of dopamine-containing neurons are necessary to establish long-term memories associating predictive stimuli with rewards and punishers. Independent discharges of dopamine neurons (tonic or pacemaker firing) determine the motivation to respond to such cues. As a result of habitual intake of addictive drugs, dopamine receptors expressed in the brain are decreased, thereby reducing interest in activities not already stamped in by habitual rewards.

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