Frank I. Tarazi

Comparative postnatal development of dopamine D1, D2 and D4 receptors in rat forebrain

Postnatal development of dopamine D1, D2 and D4 receptors in the caudate–putamen, nucleus accumbens, frontal cortex and hippocampus was assessed in rat brain between postnatal days 7 and 60. In the caudate–putamen and nucleus accumbens, density of all three receptor subtypes increased to a peak at postnatal day 28, then declined significantly in both regions (postnatal days 35–60) to adult levels. In the frontal cortex and hippocampus, these receptors rose steadily and continuously to stable, maximal adult levels by postnatal day 60. Evidently, D1, D2 and D4 receptors follow a similar course of development in several cortical, limbic and extrapyramidal regions of rat forebrain, with selective elimination of excess dopamine receptors at the time of puberty in the caudate–putamen and accumbens but not other brain regions.

Animal models of attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) involves clinically heterogeneous dysfunctions of sustained attention, with behavioral overactivity and impulsivity, of juvenile onset. Experimental models, in addition to mimicking syndromal features, should resemble the clinical condition in pathophysiology, and predict potential new treatments. One of the most extensively evaluated animal models of ADHD is the spontaneously hypertensive rat. Other models include additional genetic variants (dopamine transporter gene knock-out mouse, coloboma mouse, Naples hyperexcitable rat, acallosal mouse, hyposexual rat, and population-extreme rodents), neonatal lesioning of dopamine neurons with 6-hydroxydopamine, and exposure to other neurotoxins or hippocampal irradiation. None is fully comparable to clinical ADHD. The pathophysiology involved varies, including both deficient and excessive dopaminergic functioning, and probable involvement of other monoamine neurotransmitters. Improved models as well as further testing of their ability to predict treatment responses are required.

3,4-Dihydroxyphenylalanine Reverses the Motor Deficits in Pitx3-Deficient Aphakia Mice: Behavioral Characterization of a Novel Genetic Model of Parkinson's Disease

Parkinsons disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra. There is a need for genetic animal models of PD for screening and in vivo testing of novel restorative therapeutic agents. Although current genetic models of PD produce behavioral impairment and nigrostriatal dysfunction, they do not reproduce the loss of midbrain dopaminergic neurons and 3,4-dihydroxyphenylalanine (l-DOPA) reversible behavioral deficits. Here, we demonstrate that Pitx3-deficient aphakia (ak) mice, which have been shown previously to exhibit a major loss of substantia nigra dopaminergic neurons, display motor deficits that are reversed by l-DOPA and evidence of “dopaminergic supersensitivity” in the striatum. Thus, ak mice represent a novel genetic model exhibiting useful characteristics to test the efficacy of symptomatic therapies for PD and to study the functional changes in the striatum after dopamine depletion and l-DOPA treatment.

Postnatal development of dopamine and serotonin transporters in rat caudate-putamen and nucleus accumbens septi.

Density of dopamine transporter (DAT) and serotonin transporter (5-HTT) membrane proteins in the caudate-putamen (CPu) and nucleus accumbens (NAc) of rat brain was assessed at seven ages at postnatal days (PD) 7-60, by in vitro quantitative autoradiography. Binding of [3H]GBR-12935 (to DAT) and [3H]paroxetine (to 5-HTT) increased steadily and very similarly, from low levels at PD-7 to maximal levels, to 6-7-fold higher density at PD-60 in both regions. These findings indicate that DAT and 5-HTT follow a synchronized course of development in rat CPu and NAc. In contrast to reported elimination of excessive receptors in CPu and NAc during maturation, there was no evidence of pruning of DAT or 5-HTT in these regions of rat forebrain.

Postnatal Development of Dopamine D1-Like Receptors in Rat Cortical and Striatolimbic Brain Regions: An Autoradiographic Study

Postnatal development of dopamine D₁-like (D₁/D₅) receptors in rat caudate-putamen (CPu), nucleus accumbens (NAc), hippocampus, frontal and entorhinal cerebral cortex was assessed between postnatal days (PD) 7–60 by in vitro receptor autoradiography. Density of [³H]SCH-23390 binding to D₁-like receptors increased from PD-7 to a peak at PD-28 in CPu (11-fold) and NAc (23-fold), then declined by 20–40% in both regions over PD-35–60, to adult levels. In hippocampus, frontal and entorhinal cortex, D₁-like receptors increased by lesser amounts (3- to 4-fold) from PD-7 to stable, maximal adult levels at PD-60. Evidently, excess D₁-like receptors were eliminated during maturation of CPu and NAc, but not in the other forebrain regions. Postnatal D₁-like receptor development in rat forebrain paralleled that of D₂- and D₄-like receptors in the same regions.

Long-term effects of prenatal stress on dopamine and glutamate receptors in adult rat brain.

Prenatal stress greatly influences the ability of an individual to manage stressful events in adulthood. Such vulnerability may result from abnormalities in the development and integration of forebrain dopaminergic and glutamatergic projections during the prenatal period. In this study, we assessed the effects of prenatal stress on the expression of selective dopamine and glutamate receptor subtypes in the adult offsprings of rats subjected to repeated restraint stress during the last week of pregnancy. Dopamine D2-like receptors increased in dorsal frontal cortex (DFC), medial prefrontal cortex (MPC), hippocampal CA1 region and core region of nucleus accumbens (NAc) of prenatally stressed rats compared to control subjects. Glutamate NMDA receptors increased in MPC, DFC, hippocampal CA1, medial caudate-putamen, as well as in shell and core regions of NAc. Group III metabotropic glutamate receptors increased in MPC and DFC of prenatally stressed rats, but remained unchanged in all other regions examined. These results indicate that stress suffered during the gestational period has long lasting effects that extend into the adulthood of prenatally stressed offsprings. Changes in dopamine and glutamate receptor subtype levels in different forebrain regions of adult rats suggest that the development and formation of the corticostriatal and corticolimbic pathways may be permanently altered as a result of stress suffered prenatally. Maldevelopment of these pathways may provide a neurobiological substrate for the development of schizophrenia and other idiopathic psychotic disorders.

Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitors

Alzheimers disease (AD) is the most common cause of memory impairment and dementia in the elderly. AD is pathologically characterized by extracellular deposits of beta-amyloid (Aβ) peptide, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, neuronal loss, and neurotransmitter dysfunction. Clinically, AD is characterized by progressive cognitive decline that usually starts with memory impairment and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms. These symptoms collectively lead to a progressive and relentless decline in the ability to perform functions of daily living, eventually leading to total incapacitation. The incidence and prevalence of AD are expected to exponentially increase with the aging of the population. Currently approved treatments, including the acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine and rivastigmine, and the N-methyl-D-aspartate (NMDA) antagonist memantine, do not halt the progression of the disease, and have provided marginal therapeutic benefits. Accordingly, there is an urgent need to develop novel and effective medications for AD that go beyond AChEIs and NMDA antagonists. Modern research has focused on discovering effective disease-modifying therapies, which specifically target the pathophysiologic cascade, hoping to delay the onset of the disease and slow its progression. In this review, different pharmacological drugs and therapeutic approaches will be discussed, with an emphasis on novel therapies that are currently being investigated in clinical trials.

Localization of dopamine receptor subtypes in corpus striatum and nucleus accumbens septi of rat brain: comparison of D1-, D2- and D4-like receptors

Changes in D1-, D2- and D4-like dopamine receptor binding in rat brain were examined by quantitative autoradiography following: (i) unilateral surgical ablation of frontal cerebral cortex to remove descending projections to corpus striatum and nucleus accumbens, (ii) unilateral injections of kainic acid into corpus striatum or nucleus accumbens to degenerate local intrinsic neurons, (iii) unilateral injections of 6-hydroxydopamine into substantia nigra to degenerate ascending dopamine projections. Rats were killed one week after lesioning, with contralateral tissue controls. Radioligands were: [3H]SCH-23390 for D1-like (D1/D5) receptors, [3H]nemonapride alone for D2-like (D2/D3/D4) receptors, and [3H]nemonapride with 300 nM S[-]-raclopride and other masking agents for D4-like receptors (identified by blockade with D4 selective L-745,870). Frontal cerebral cortex ablation did not alter D1- or D2-like receptor density, but D4-like binding decreased significantly in both corpus striatum (18%) and nucleus accumbens (23%). Kainic acid markedly reduced D1-like (75% and 84%) and D2-like binding (44% and 52%), with smaller D4-like losses (28% and 27%) in corpus striatum and nucleus accumbens, respectively. Nigral 6-hydroxydopamine lesions (verified by autoradiographic loss of dopamine transporters labelled with [3H]GBR-12935) did not significantly change D1-, D2-, or D4-like binding in the corpus striatum. These results suggest that the majority of D1-, and D2-like, and a smaller portion of D4-like receptors in corpus striatum and nucleus accumbens arise on intrinsic postsynaptic neurons, and that some D4-like, but neither D1- nor D2-like, receptors are found on presynaptic corticostriatal afferents.

Postnatal development of dopamine D4-like receptors in rat forebrain regions: comparison with D2-like receptors

Development of dopamine D4-like receptors in rat caudate-putamen (CPu), nucleus accumbens (NAc), frontal cortex, hippocampus, and entorhinal cortex was assessed at seven points between postnatal days 7 and 60 by computed in vitro receptor autoradiography, and compared with dopamine (DA) D2-like receptors. Density of radioligand binding to both receptor types increased from day 7 to a peak at day 28 in caudate-putamen (D4, 3.3-fold; D2, 4.3-fold) and nucleus accumbens (2.9- and 3.6-fold), then declined by 28%-33% over days 35-60 to adult levels in both brain regions. In hippocampus, frontal and entorhinal cortex, both receptor types increased by 3.8- to 5.8-fold from day 7 to maximal levels at day 35 that remained unchanged to day 60. These findings suggest: (1) D4- and D2-like receptors follow a similar course of development in several cortical, extrapyramidal, and limbic regions of rat forebrain; (2) elimination of excessive receptors of both types occurred in caudate-putamen and nucleus accumbens but not in the other brain regions.

Differential regulation of dopamine receptors after chronic typical and atypical antipsychotic drug treatment

Changes in dopamine receptor subtype binding in different brain regions were examined after 28 days treatment of rats with haloperidol, raclopride, clozapine or SCH23390 using in vitro receptor autoradiography. [3H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin binding to dopamine D3 receptors was not changed in any brain region by any of the drug treatments. [3H]SCH23390 was only increased by chronic SCH23390 treatment. Haloperidol significantly increased [3H]nemonapride and [3H]spiperone binding to dopamine D2-like receptors in the caudate putamen. In contrast, haloperidol caused a small, significant increase in [3H]raclopride binding in the lateral caudate putamen only. Raclopride also elevated, but to a lesser extent [3H]nemonapride and [3H]spiperone binding in caudate putamen, whereas it did not affect [3H]raclopride binding. Clozapine did not significantly change D2-like striatal binding of [3H]nemonaipride, [3H]spiperone or [3H]raclopride. The differences in radioligand binding suggest that [3H]nemonapride and [3H]spiperone may be binding to additional subsets of dopamine D2-like receptors (including D4-like receptors) that are not recognized by [3H]raclopride, which has high affinity for D2 and D3 receptors only. Quantification of [3H]nemonapride or [3H]spiperone binding in the presence of 300 nM raclopride (to block D2 and D3 receptors) revealed that haloperidol, raclopride and clozapine up-regulated D4-like receptors in the caudate putamen using either radioligand. These results suggest that D4-like receptors may be a common site of action of both typical and atypical antipsychotics.