Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis

Abstract

Dopamine supersensitivity occurs in schizophrenia and other psychoses, and after hippocampal lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts of Dbh (dopamine beta-hydroxylase), Drd4 receptors, Gprk6 (G protein-coupled receptor kinase 6), Comt (catechol-O-methyltransferase), or Th-/-, DbhTh/+ (tyrosine hydroxylase), and in rats born by Cesarean-section. The functional state of D2, or the high-affinity state for dopamine (D2High), was measured in these supersensitive animal brain striata. Increased levels and higher proportions (40-900%) for D2High were found in all these tissues. If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2High states, it suggests that there are many pathways to psychosis, any one of which can be disrupted.

Fig. 1.

Detection of D2^High states. (A) Dopamine recognizes high-affinity states for dopamine D2 receptors when competing with 2 nM [³H]raclopride in the presence of 10 mM NaCl, but not in the presence of 120 mM NaCl. Rat homogenized striatum is shown. Average values ± SE (n = 3) are given. Nonspecific binding in the presence of 10 μM S-sulpiride is shown. (B)[³H]Raclopride saturation method for measuring D2^High states after 9 days of olanzapine treatment. Using 120 mM NaCl, saturation of striatal dopamine D2 receptors with [³H]raclopride in the presence and absence of 200μM GN is shown. The increase in binding with GN reflects the high-affinity states of the dopamine D2 receptor, D2^High.(C) Using 10 mM NaCl, the dopamine/[³H]raclopride competition method also revealed an increase in the proportion of D2^High states after 9 days of olanzapine (Table 1).

Fig. 2.

Increase in D2^High states after 9 days of antipsychotic treatment. (Left) [³H]Raclopride saturation method (additional details in Fig. 1). (Right) Dopamine/[³H]raclopride competition method. Representative experiments are shown (Table 1).

Fig. 3.

Increase in D2^High states in gene knockouts for the Drd4 dopamine receptor, Dbh, and Gprk6.(Left)[³H]Raclopride saturation method (see Fig. 1). (Center) Dopamine/[³H]raclopride competition method. (Right) Dopamine/[³H]domperidone competition method. Representative experiments are shown, bars indicate SE (Table 1).

Fig. 4.

Increased D2^High states in knockouts and lesions. (A) Increase in D2^High states in gene knockouts for Comt, using the dopamine/[³H]domperidone competition method (n = 4 ± SE; Table 1). (B) Increase in D2^High states in striata from adult animals that had been lesioned in the hippocampus at an early age. [³H]Raclopride saturation method; control value was 2 pmol/g (see Table 1). (C) Dopamine/[³H]raclopride competition method. (D) Dopamine/[³H]domperidone competition method. Bars indicate SE (n = 3; Table 1).

Fig. 5.

Increase in D2^High states in adult rats born by cesarean section with or without anoxia. (Left) [³H]Raclopride saturation method. (Center) Dopamine/[³H]raclopride competition method. (Right) Dopamine/[³H]domperidone competition method. Representative experiments are shown; vertical bars indicate SE (Table 1).