Effect of Chronic Typical and Atypical Neuroleptic Treatment on Proenkephalin mRNA Levels in the Striatum and Nucleus Accumbens of the Rat

Abstract

We measured proenkephalin (PEK) mRNA levels in the anterior and medial aspects of the caudate-putamen (CPU) and in the nucleus accumbens (NAc) of the rat by in situ hybridization histochemistry after chronic treatment for 21 days with typical (haloperidol and prolixin) and atypical (molindone, thioridazine, and clozapine) neuroleptics. Chronic administration with these drugs resulted in PEK mRNA levels that were 60-80% higher than controls in the anterior and medial aspects of the CPU but only 25-30% over controls in the NAc. All three atypical neuroleptics studied increased PEK mRNA in the following order: anterior-CPU, thioridazine greater than clozapine and molindone; medial-CPU, thioridazine and molindone greater than clozapine; and NAc, thioridazine much greater than molindone and clozapine. Chronic treatment with the specific dopamine D2 antagonist sulpiride also caused elevation in PEK mRNA levels in all three brain regions studied whereas the specific serotonin S2 receptor blocker, cinanserin, had no significant effects on PEK mRNA levels. These results are consistent with the hypothesis that elevated levels of the enkephalins in the mesolimbic system may be necessary for antipsychotic activity. They also support the idea that the undesirable motoric signs and symptoms observed after chronic treatment with typical neuroleptics may not be the result of increased levels of enkephalins in the basal ganglia because atypical neuroleptics which are almost totally devoid of these side effects caused similar increases in PEK mRNA in the CPU.

Effects of risperidone and haloperidol on tachykinin and opioid precursor peptide mRNA levels in the caudate-putamen and nucleus accumbens of the rat

“…Our finding that both antipsychotic drugs affect striatal preproenkephalin-A mRNA is in line with previous studies demonstrating that haloperidol and a wide range of other antipsychotics induce increases of ppEnk-A mRNA and peptide levels of varying magnitudes (Hong et al, 1980;Tang et al, 1983;Angulo et al, 1990b;Houdi and Van Loon, 1990;Herman et al, 1991). 1 Animals received drug treatment for 14 days and were decapitated 16 h after the last treatment.…”

Differential induction of neurotensin and c-fos gene expression by typical versus atypical antipsychotics.

“…Inter- estingly, NT immunoreactivity in the dorsal striatum also increases selectively following chronic treatment (21 days) with haloperidol but not clozapine (31). Although other peptidergic systems such as cholecystokinin, enkephalins, or tachykinins are affected by antipsychotics, they do not show this pattern of region-specific drug selectivity (32)(33)(34). The data presented here support the hypothesis that differential sensitivity of NT neurons to typical versus atypical antipsychotics may have a functional significance.…”

σ receptors

“…These effects were thought to be mediated through dopamine-D2-receptor blockade. However, BMY-14802 had similar effects (Angulo et al, 1990). Since BMY-14802 has only minimal affinity for the dopamine D2receptor, the effects were attributed to the drug's high affinity at the o receptor (Angulo et al, 1990).…”

“…However, BMY-14802 had similar effects (Angulo et al, 1990). Since BMY-14802 has only minimal affinity for the dopamine D2receptor, the effects were attributed to the drug's high affinity at the o receptor (Angulo et al, 1990). Since haloperidol is a potent o-receptor ligand (Su, 1982), the effects of both haloperidol and BMY-14802 on the mRNA of proenkephalin and protachykinin may be due to their interaction with the o receptor.…”