title: Tolerance to the effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) on free-operant timing behaviour: interaction between behavioural and pharmacological mechanisms.
abstract: BACKGROUND
  The psychostimulant d-amphetamine, the D(2/3) dopamine receptor agonist quinpirole and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behaviour. There is evidence that tolerance develops to the effects of psychostimulants on timing performance during chronic treatment; this tolerance is generally attributed to behavioural adaptation rather than to pharmacological desensitisation. There have been no previous investigations of tolerance to the effect of DOI on free-operant timing behaviour.
  
  
  OBJECTIVE
  To demonstrate tolerance to DOI's effect on timing performance and to examine the nature of this tolerance.
  
  
  METHODS
  Rats were trained under the free-operant psychophysical procedure to press two levers (A and B) in 80-s trials in which reinforcement was provided intermittently for responding on A in the first half and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 8-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices (T (50) [time corresponding to %B = 50]; Weber fraction).
  
  
  RESULTS
  In experiment 1, DOI (0.25 mg kg(-1)) reduced T (50) compared to vehicle; tolerance to this effect was seen after repeated daily treatments with DOI if the rats were exposed to behavioural training during the period of treatment but not if the repeated treatments took place during a 'holiday' from behavioural training. In experiment 2, repeated treatment with DOI resulted in tolerance to the effect of DOI on T (50) and cross-tolerance to the effect of d-amphetamine (0.4 mg kg(-1)), but no cross-tolerance was seen to the effect of quinpirole (0.08 mg kg(-1)).
  
  
  CONCLUSIONS
  The results indicate that behavioural adaptation is involved in the development of tolerance to DOI's effect on timing. The finding of cross-tolerance to d-amphetamine but not to quinpirole suggests that the reduction of T (50) in the free-operant psychophysical procedure may be brought about by two distinct pharmacological mechanisms, one activated by DOI and d-amphetamine, and the other by quinpirole.
authors.affiliation: Psychopharmacology Section, Division of Psychiatry, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK. c.m.bradshaw@nottingham.ac.uk.
authors.forename: T H C
authors.initials: TH
authors.lastname: Cheung
authors.forename: G
authors.initials: G
authors.lastname: Bezzina
authors.forename: S
authors.initials: S
authors.lastname: Body
authors.forename: K C F
authors.initials: KC
authors.lastname: Fone
authors.forename: C M
authors.initials: CM
authors.lastname: Bradshaw
authors.forename: E
authors.initials: E
authors.lastname: Szabadi
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004361:Drug Tolerance; D005260:Female; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013998:Time Perception / Q000187:drug effects*
chemical_list: D000662:Amphetamines; D015259:Dopamine Agents; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017366:Serotonin Receptor Agonists; D019257:Quinpirole; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003913:Dextroamphetamine