Evidence for bidirectional cues as a function of time following treatment with amphetamine: implications for understanding tolerance and withdrawal.
BACKGROUND
Previous drug-discrimination studies have focused on characterizing the cue properties associated with amphetamine's (AMPH) primary effect. Results from recent experiments indicate that equally prominent cues are associated with AMPH withdrawal.


OBJECTIVE
The purpose of the present study was to investigate the extent to which AMPH-induced withdrawal cues, opposite to those associated with AMPH's primary effect are observed.


METHODS
Since dopamine (DA) has been implicated in mediating the AMPH cue, rats were trained to discriminate between 0.25 mg/kg AMPH, an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) providing a behavioral baseline sensitive to assessing AMPH-related bidirectional changes in cue state. Following acquisition of the discrimination, rats were tested for choice of responding on the AMPH and HAL levers at intervals from 6 to 72 h following treatment with a single dose of 3.0 mg/AMPH. Also, in order to investigate the relationship between withdrawal and tolerance to AMPH's cue properties, AMPH dose-response curves were determined 24 h following treatment with SAL, 1.5 and 3.0 mg/kg AMPH.


RESULTS
At short intervals after treatment with 3.0 mg/kg AMPH, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16-30 h post-treatment, before returning to predrug levels. Treatment with 1.5 and 3.0 mg/kg AMPH produced parallel dose-response curve shifts to the right.


CONCLUSIONS
Following a single dose of AMPH, robust cues associated with AMPH withdrawal were observed that lasted approximately three times longer than the cues associated with the drug's primary effects. Furthermore, results from the tolerance tests indicate that tolerance reflects a baseline shift rather than a loss in drug efficacy.
Barrett
Robert J
RJ
Veterans Administration Medical Center, Departments of Psychology and Pharmacology, Vanderbilt University, Research Service (151), 1310 24th Avenue South, Nashville, TN 37212-2637, USA. r2k2@comcast.net
Caul
William F
WF
Smith
Randy L
RL
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D003463:Cues; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000523:psychology*; D013997:Time Factors
D000661:Amphetamine