Behavioural and biochemical effects of subchronic treatment with raclopride in the rat: tolerance and brain monoamine receptor sensitivity.
Male Sprague-Dawley rats were treated with the dopamine (DA) D2 receptor blocking agent raclopride 0.5 or 8.0 mg kg-1 subcutaneously (1.0 and 16.0 mumol kg-1, respectively), twice daily for 21 days. The animals treated with raclopride gained weight at the same rate as saline controls, and gross observation did not indicate any behavioural abnormalities due to the subchronic raclopride treatment. Possible changes in brain DA receptor sensitivity due to prolonged blockade of DA receptors were evaluated in behavioural and biochemical models. There were no effects on locomotor activity, as observed by means of photobeam-equipped activity cages, 24 hr or 72 hr after withdrawal of 0.5 or 8.0 mg kg-1 subchronic raclopride treatment. Twenty-four hr after withdrawal of the raclopride treatment there was an increased post-synaptic DA receptor sensitivity as evidenced by increased behavioural and biochemical responses to apomorphine, and by an attenuated response to acute raclopride treatment, 0.1 mg kg-1. Thus, there was an increase in locomotor activity by the apomorphine treatment in animals pretreated with the 8 mg kg-1 dose, as compared to the response obtained in saline controls. Furthermore, the suppression of locomotor activity in saline controls produced by acute raclopride treatment was dose-dependently antagonized by the raclopride pretreatment and this also applied to the increase in striatal DOPAC levels produced by acute raclopride treatment. Finally, there was an increased DA receptor sensitivity presynaptically as evidenced by an enhanced effect on striatal DOPA levels by apomorphine in rats treated with NSD 1015 and reserpine.(ABSTRACT TRUNCATED AT 250 WORDS)
Ahlenius
S
S
Department of Neuropharmacology, Astra Research Centre AB, Södertälje, Sweden.
Ericson
E L
EL
Högberg
K
K
Wijkström
A
A
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D018492:Dopamine Antagonists; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D020891:Raclopride; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D012457:Salicylamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013997:Time Factors
D018492:Dopamine Antagonists; D012457:Salicylamides; D020891:Raclopride; D004295:Dihydroxyphenylalanine; D012110:Reserpine; D001058:Apomorphine