Increased Central 5‐hydroxtryptamine Receptor Mechanisms in Rats After Chronic Neuroleptic Treatment

Abstract

1 The behavioural responses of drugs known to act through central 5-hydroxytryptamine (5-HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months. 2 5-Hydroxytryptophan (5-HTP) induced 5-HT-dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and 'wet-dog' shakes. In doses of 50 to 150 mg/kg, 5-HTP induced more intense behavioural effects in neuroleptic-treated rats than in the control animals. 3 Similarly the putative 5-HT agonist. quipazine (I to 20 mg/kg) and the 5-HT releasing drug. fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic-treated rats. 4 A 5-HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine-treated rats. 5 Total specific high-affinity binding of radiolabelled 5-HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic-treated rats compared to control animals. 6 High-affinity uptake of radiolabelled 5-HT into striatal slices was similar in experimental and control animals. 7 Behavioural and biochemical data would indicate that postsynaptic 5-HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5-HT receptor supersensitivity in addition to the well-documented cerebral dopamine receptor supersensitivity.

Evaluation of sex differences in cannabinoid dependence

“…Retropulsion usually occurs with higher inducing doses of THC and has been reported only rarely during withdrawal (Aceto et al, 1996; Gonzalez et al, 2004). Retropulsion is associated with imbalance between dopamine and serotonin neurotransmission (Curzon et al, 1979; Dawbarn et al, 1981; Andrews et al, 1982), as may occur in THC-dependent rats due to decreases in mesolimbic dopamine neurotransmission (Diana et al, 1998; Tanda et al, 1999). Dopamine function may also be affected via dependence-induced changes in the endocannabinoid system (Spiga et al, 2011), which interacts with dopamine neurotransmission indirectly (Patel et al, 2003; Melis et al, 2004).…”

Increased platelet membrane [3H]‐LSD binding in patients on chronic neuroleptic treatment.

“…On the other hand, Green (1977) had reported enhanced behavioural responses to 5-HT agonists in rats treated with chlorpromazine for 4 days. Dawbarn et al (1981) treated rats for 4 to 6 months with trifluoperazine and observed intensification of 5-HTP-induced behaviours at the end of this period. There was also an increased number of [3H]-5-HT binding sites in the cortex: these sites correspond to 5-HT1 sites according to Peroutka & Snyder's (1979) classification, whereas platelet 5-HT receptors are of the 5-HT2 type (see also Leysen et al, 1983).…”

“…On the other hand, Green (1977) had reported enhanced behavioural responses to 5-HT agonists in rats treated with chlorpromazine for 4 days. Dawbarn et al (1981) treated rats for 4 to 6 months with trifluoperazine and observed intensification of 5-HTP-induced behaviours at the end of this period. There was also an increased number of…”

Phenylalanine kinetics are associated with tardive dyskinesia in men but not in women

“…For heuristic purposes, a possible model for the altered kinetics of Phe in TD development in men is as follows : (1) our men with TD responded to dietary challenges of Phe with higher levels of plasma Phe than those without the disorder, (2) the challenge experience of our study may mimic real life in that men who eventually develop TD experience higher levels of plasma Phe in response to their normal dietary intake (i.e., protein sources, aspartame), (3) these chronically higher levels of plasma Phe and resultant chronically higher plasma Phe / LNAA ratios may lead to a chronically reduced DA, NE and 5-HT neurochemical tone, (4) this reduced tone can produce a vulnerability to the development of supersensitivities to catecholamines and indolamines brought on by chronic neuroleptic treatment (Heal et al 1976;Burt et al 1977;Muller and Seeman 1977;Dawbarn et al 1981), thus providing the Þnal stimulus to TD development.…”