Amphetamine and LSD as discriminative stimuli: alterations following neonatal monoamine reductions

Male adult Sprague-Dawley rats (70 days of age), neonatally depleted of either 5-hydroxytryptamine (5HT) via 5,7-dihydroxytryptamine (5,7-DHT; ICS) + desmethylimipramine (DMI; IP) at 3 days of age or dopamine (DA) via 6-hydroxydopamine (6-OHDA; ICS) + DMI at 14 days of age, were trained to discriminate either d-LSD-tartrate (80 micrograms/kg; IP) or d-amphetamine (d-AMPH) sulfate (0.90 mg/kg; IP) from saline utilizing a two lever drug discrimination paradigm. A neurochemical analysis at the termination of these studies revealed the following in terms of %DA or %5HT (presented in that order) depleted with respect to the appropriate vehicle control group: telencephalon; 96 and 96%, diencephalon; 51 and 31%, and brain stem; 76 and 80%. Rats learned to discriminate either d-AMPH or LSD regardless of amine depleted. In addition, the depletion of 5HT had little effects on dose or drug generalizations, or the ability of known antagonists to antagonize the discrimination stimulus (DS) effects of either LSD or d-AMPH. The effect of DA depletion, on the other hand, was to increase the sensitivity of the LSD DS at low doses, while decreasing the sensitivity of the d-amphetamine DS. DA depletion also had the effect of reducing the effectiveness of the LSD-antagonists, pizotifen maleate (BC105), while the opposite was observed for the d-AMPH antagonist, trifluoperazine HCI. These data suggest that: (1) LSD and d-amphetamine discrimination stimuli are not mediated and/or influenced via the compromised aspects of the 5HT systems (other central mechanisms may have compromised for these 5HT deficits); (2) the LSD DS is mediated or influenced both by serotonergic and dopaminergic mechanisms; and (3) the d-amphetamine DS is mediated by certain aspects of the dopaminergic system with little evidence for the involvement of 5HT systems.