D2. The dopamine D2 receptors are linked to inhibitory G-proteins and initiate their action by inhibiting the enzyme adenylate cyclase. The D2 receptors are localized both presynaptically and postsynaptically. Researchers have identified two molecular forms of the D2 receptor, referred to as D2-long and D2-short because of their differing size. The two isomers of D2 are pharmacologically identical except for minor differences in their affinity for specific G-proteins. These receptors exhibit high affinity for a number of drugs, such as apomorphine, bromocriptine (Parlodel) and dopamine (Intropin), that act as agonists. Their anatomical distribution includes the striatum, substantia nigra and the pituitary gland. Antipsychotic action and extrapyramidal side effects of classical neuroleptics are a function of dopamine D2-like receptor blockade. The potency of a neuroleptic is defined by its ability to block D2 receptors.
This ability to block the D2 receptor is not uniform throughout the dopaminergic system. For example, clozapine has a moderate affinity for the D2 receptor in the striatum but a much higher affinity for the D2 receptor in the olfactory tubercle, a structure closely tied to the limbic system.
D3. The dopamine D3 receptor appears to be pharmacologically very similar but distinct from the D2 receptor. The D3 receptor may have a two- to five-times lower affinity for classical neuroleptics, making it unlikely to be the main site of neuroleptic action. The D3 receptor has not been found to affect adenylate cyclase and appears to be a presynaptic receptor. Its anatomical distribution includes the olfactory tubercle, nucleus accumbens, striatum, substantia nigra and hypothalamus. The presynaptic location and high affinity for dopamine exhibited by these receptors suggests that they may play an autoreceptor role, monitoring the amount of synaptic dopamine.
D4. The dopamine D4 receptor appears pharmacologically similar to D2 and D3 receptors but has a 10-times-greater affinity for the atypical antipsychotic clozapine, suggesting that D4 receptors may be the main site of clozapine's antipsychotic action. The anatomical distribution of this receptor includes the frontal cortex, medulla, hypothalamus and lower levels located in the basal ganglia.
Clinicians are beginning to realize the possible benefits from gaining a more complete understanding of the dopaminergic system. Advances in molecular genetics, combined with positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning capable of performing receptor-ligand imaging, have provided a new, more direct access into brain functioning.
Schizophrenia. There has been considerable debate over what role the dopamine receptors play in the pathophysiology of schizophrenia. In 1986, Wong and coworkers reported a significant increase in D2 receptors in the caudate of drug-naive schizophrenic patients compared with controls. Subsequently, Farde and associates, using a different ligand, found no difference in the D2 receptor density. In 1993, Seeman and colleagues reported that the discrepancy in the findings noted above was not secondary to an increase in D2 receptors, as initially reported by Wong, but actually may be secondary to a six-fold increase in the density of D4 receptors in schizophrenic patients versus controls.
Recently, a modified dopamine hypothesis of schizophrenia has been introduced. It suggests some schizophrenic patients have a hypodopaminergic state in the prefrontal cortex, resulting in negative symptoms, which could lead to hyperdopaminergia in the mesolimbic system and striatum, resulting in positive symptoms.
High-level dopamine receptor blockade occurs within 24 hours after initiation of neuroleptic treatment, yet the antipsychotic effects take days to achieve. This delay suggests that the initial blockade of dopamine receptors eventually leads to a secondary change that ameliorates the symptoms. Current theories on these secondary changes include electrophysiological adaptations, such as a depolarization of dopamine neurons and changes in gene expression of dopaminergic and dopaminoceptive neurons.
Clinically, a lag exists between the discontinuation of a neuroleptic and the resolution of extrapyramidal symptoms. Using PET, Baron and colleagues found that normal receptor availability may take five to 15 days to resume after discontinuation of neuroleptic treatment and lags significantly behind plasma levels of the neuroleptic, as illustrated in Figure 4.
Farde has proposed that striatal D2 receptors have to be blocked more than 75 to 80 percent before extrapyramidal symptoms appear. PET and SPECT studies have revealed a D2 occupancy rate of 65 percent to 85 percent with the classic neuroleptics but a lower occupancy rate of 40 percent to 60 percent for the atypical neuroleptic clozapine. Atypical neuroleptics have been shown to cause fewer extrapyramidal symptoms, which, in the case of clozapine, may be secondary to decreased blockade of D2 receptors in the striatum compared with classical neuroleptics (See Figure 5).
Much attention has focused recently on the interaction between dopamine and serotonin neurons in mediating psychosis, negative symptoms and the extrapyramidal side effects of neuroleptics.
Serotonin can inhibit the firing of dopaminergic neurons that project to the striatum. Serotonin reuptake inhibitors used to treat depression occasionally can produce extrapyramidal side effects, and the lesioning of serotonergic neurons in the dorsal raphe can diminish haloperidol-induced catalepsy. Serotonin also can inhibit the firing of dopaminergic neurons in limbic structures such as the nucleus accumbens. Serotonin's effects on dopamine can be mediated by 5-HT2, 5-HT1A and 5-HT3-receptor systems. Ondansetron (Zofran), the only clinically approved 5-HT3 receptor antagonist (for chemotherapy-induced nausea), is being tested for its antipsychotic properties.
Meltzer has suggested that a high 5-HT2/D2 affinity ratio may be critical for producing antipsychotic effects without extrapyramidal symptoms. Clozapine has been found to be effective in nearly half of treatment-resistant schizophrenic patients. Its efficacy in this population may, in part, be due to its increased affinity for D4 or other limbic dopaminergic receptors and/or its serotonin-5-HT2 antagonist properties. The new antipsychotic medication risperidone (Risperdal) also has been found to improve negative symptoms and cause fewer acute and chronic motor side effects compared with classical neuroleptics. This superior profile is believed to be secondary to its serotonin 5-HT2 antagonist properties, which may ameliorate the negative symptoms and affect the dopamine receptors in such a way as to reduce the incidence of extrapyramidal symptoms.
Cocaine. Many researchers are investigating the role that dopamine receptors may play in substance abuse. Acute cocaine use results in an increase in synaptic dopamine as the cocaine blocks presynaptic dopamine reuptake. Chronic cocaine use appears to down-regulate the D2 receptors in response to overstimulation.
Abrupt discontinuation of cocaine leads to a state of dopamine depletion, which can cause the intense depression and agitation experienced during the crash phase as well as the subsequent anhedonia, dysphoria, lethargy, somnolence and apathy that can be present for six to 18 weeks after discontinuation of cocaine (See Figure 6).
Dopamine agonists, such as amantadine (Symmetrel), bromocriptine and other amines currently are being investigated as potential relapse-prevention treatments.
Scientists are embarking on an exciting period in understanding the dopaminergic system. The next challenges will be: to determine the function of each receptor; to better understand the regulatory interaction between the dopamine receptors and other neuromodulators; and to use this knowledge to develop psychopharmacological treatments that target specific symptoms and cause minimal side effects.
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