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The glycine/NMDA receptor antagonist, R‐(+)‐HA‐966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK‐801) in rodents
Author(s) -
Bristow L.J.,
Hutson P.H.,
Thorn L.,
Tricklebank M.D.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13520.x
Subject(s) - nucleus accumbens , dizocilpine , chemistry , dopamine , phencyclidine , nmda receptor , pharmacology , striatum , endocrinology , medicine , mesolimbic pathway , agonist , dopaminergic , receptor , ventral tegmental area , biochemistry
1 The effects of the glycine/N‐methyl‐ d ‐aspartate (NMDA) receptor antagonist, R‐(+)‐HA‐966 on the neurochemical and behavioural responses to phencyclidine (PCP) and dizocilpine (MK‐801) have been determined in rodents. 2 In rats, pretreatment with PCP (5 and 10 mg kg −1 ) or MK‐801 (0.25 and 0.5 mg kg −1 ) dose‐dependently stimulated dopamine turnover in nucleus accumbens, amygdala and medial prefrontal cortex, but had no effect in striatum. In contrast, pretreatment with (+)‐HA‐966 (10 and 30 mg kg −1 ) did not affect dopamine turnover in any brain region investigated. 3 Pretreatment with (+)‐HA‐966 (10 and 30 mg kg −1 ) significantly antagonized the stimulation of dopamine turnover induced by both PCP (10 mg kg −1 ) and MK‐801 (0.5 mg kg −1 ) in rat nucleus accumbens, amygdala and medial prefrontal cortex. 4 Intracerebral dialysis studies in conscious rats demonstrated that systemic injection of PCP (10 mg kg −1 ) markedly stimulated dopamine release from the nucleus accumbens, an effect that was abolished by pretreatment with (+)‐HA‐966 (30 mg kg −1 ). 5 Pretreatment with PCP (3–30 mg kg −1 ) or MK‐801 (0.1–1.6 mg kg −1 ) significantly increased locomotor activity in mice. In contrast, subcutaneous injection of (+)‐HA‐966 (10–100 mg kg −1 ) failed to stimulate activity. 6 Pretreatment with (+)‐HA‐966 (10 and 30 mg kg −1 ) dose‐dependently antagonized both PCP (10 mg kg −1 ) and MK‐801 (0.4 mg kg −1 ) induced hyperactivity in mice. 7 Blockade of PCP‐induced hyperactivity by (+)‐HA‐966 is unlikely to be explained by the induction or potentiation of sedation/ataxia since PCP‐induced rotarod deficits were not significantly different in mice pretreated with (+)‐HA‐966 (30 mg kg −1 ) or saline. 8 The results demonstrate that (+)‐HA‐966 antagonizes both the neurochemical and behavioural effects of PCP and MK‐801, possibly through interactions at the glycine/NMDA receptor.