The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.

https://science.sciencemag.org/content/sci/250/4986/1429.full.pdf

D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons

Drug addiction, dysregulation of reward, and allostasis.

A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions It seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease, that were previously thought to interact only with D2 receptors

Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics.

Understanding the neurobiological mechanisms of addiction requires an integration of basic neuroscience with social psychology, experimental psychology, and psychiatry. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug-taking. Sensitization and counteradaptation are hypothesized to contribute to this hedonic homeostatic dysregulation, and the neurobiological mechanisms involved, such as the mesolimbic dopamine system, opioid peptidergic systems, and brain and hormonal stress systems, are beginning to be characterized. This framework provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and to relapse in individuals with a history of addiction.

https://science.sciencemag.org/content/sci/278/5335/52.full.pdf

Drug Abuse: Hedonic Homeostatic Dysregulation

Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis

[3H]Prazosin and [3H]WB4101 [2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4 benzodioxane] have both been proposed to label alpha 1-adrenergic receptors in the rat central nervous system. As many discrepancies between the binding of these two ligands have arisen, we conducted these studies in order to reevaluate their binding characteristics and resolve the similarities and differences in the pharmacological characteristics of their respective binding sites. [3H]Prazosin binding is characterized by a monophasic saturation isotherm. Prazosin, indoramine, and dihydroergocryptine competitions with [3H]prazosin are steep and monophasic, and model best to a single binding site. In contrast, phentolamine and WB4101 competition curves are shallow in rat cortex, exhibiting Hill coefficients significantly less than 1.0, and model to two binding sites of approximately equal proportions. The higher and lower affinity components are defined as alpha 1A and alpha 1B, respectively. [3H]WB4101 also labels two binding sites in rat cortex and hippocampus with picomolar and nanomolar affinity, respectively. However, the nanomolar binding site is serotonergic and not adrenergic. The picomolar site (KD = 150 pm) has characteristics of an alpha 1-receptor binding site: prazosin, WB4101, and phentolamine affinities for this [3H]WB4101 binding site correlate with their affinities for the highest affinity component (alpha 1A) of [3H]prazosin binding. In addition, the Bmax of this [3H] WB4101-labeled site is equal to one-half of the total [3H]prazosin Bmax. Agonist competitions with [3H]prazosin binding are multiphasic with pseudo-Hill slopes less than 1.0 and with a rank order of affinity of epinephrine greater than norepinephrine greater than phenylephrine. When binding to the alpha 1A component is blocked by a 30 nM phentolamine mask, the same rank order of agonist affinities is preserved. Although the affinities of epinephrine and norepinephrine at the two subtypes are identical, phenylephrine is weaker at the alpha 1B site. The ratio of the potency of phentolamine versus prazosin is about 4 at the alpha 1A component but about 80 at the alpha 1B binding site. We discuss these data in relation to the reported potencies of these antagonists in blocking alpha 1-receptor-mediated responses which may correlate with our designation of alpha 1A or alpha 1B binding sites.

Characterization of alpha 1-adrenergic receptor subtypes in rat brain: a reevaluation of [3H]WB4104 and [3H]prazosin binding.

The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat

Behavioral and radioligand binding evidence for irreversible dopamine receptor blockade by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline

Dopamine receptor subtype imbalance in schizophrenia.

BEHAVIOURAL1 and neurophysiological2 data suggest the existence of more than one dopamine receptor in the brain3. Differences in drug specificity of the dopamine-sensitive adenylate cyclase and dopamine receptors labelled by the butyrophenones, 3H-haloperidol or 3H-spiroperidol, indicate that the cyclase and the binding sites may, in part, involve distinct receptors4,5. Lesion studies directly demonstrate the existence of physically distinct dopamine receptors in the corpus striatum6. Kainic acid microinjections, which selectively destroy intrinsic neurones in the corpus striatum, almost totally deplete the dopamine-sensitive adenylate cyclase while producing only a 40–50% decline in 3H-haloperidol or 3H-spiroperidol binding. Most of the remaining 3H-haloperidol or 3H-spiroperidol binding is lost following cerebral cortex ablation, which removes a major neuronal input to the corpus striatum, indicating that these binding sites are localised to axons and terminals of the cortico-striate projection6. As the dopamine-sensitive adenylate cyclase is not reduced by cerebral cortex ablation, the cortico-striate dopamine receptors do not seem to be linked to adenylate cyclase. Whether or not the 3H-butyrophenone binding sites destroyed by kainic acid represent the same dopamine receptors as those linked to adenylate cyclase has not been clear. Guanine nucleotides regulate binding at several hormone and neurotransmitter receptors, especially those associated with adenylate cyclase7–13. Previously, we14–16 and others17 showed that dopamine receptor binding of 3H-agonists and 3H-antagonists can be regulated by guanine nucleotides. We now report that kainic acid lesions abolish the sensitivity of dopamine receptor binding to guanine nucleotides. Thus, 3H-spiroperidol and 3H-apomorphine binding sites involve two dopamine receptors, only one of which is regulated by guanine nucleotides.

Ian Creese

Papers

Characterization of alpha 1-adrenergic receptor subtypes in rat brain: a reevaluation of [3H]WB4104 and [3H]prazosin binding.

The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat

Behavioral and radioligand binding evidence for irreversible dopamine receptor blockade by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline

Dopamine receptor subtype imbalance in schizophrenia.

Guanine nucleotides distinguish between two dopamine receptors