Previous Exposure to Δ⁹-Tetrahydrocannibinol Enhances Locomotor Responding to but Not Self-Administration of Amphetamine

Abstract

Previous exposure to amphetamine leads to enhanced locomotor and nucleus accumbens (NAcc) dopamine (DA) responding to the drug as well as enhanced amphetamine self-administration. Here, we investigated the effects of exposure to ⌬ 9 -tetrahydrocannibinol (⌬ 9 -THC) on behavioral and biochemical responding to amphetamine. Rats in different groups received five exposure injections of vehicle or one of five doses of ⌬ 9 -THC (0.4, 0.75, 1.5, 3.0, and 6.0 mg/kg i.p.) and were tested 2 days and 2 weeks later. Exposure to all but the lowest and highest doses of ⌬ 9 -THC enhanced the locomotor response to amphetamine (0.75 mg/kg i.p.), but all failed to enhance NAcc DA overflow in response to the drug. Moreover, exposure to 3.0 mg/kg i.p. ⌬ 9 -THC increased forskolin-evoked adenylyl cyclase activity in the NAcc and rats' locomotor response to the direct DA receptor agonist apomorphine (1.0 mg/kg s.c.), suggesting that ⌬ 9 -THC sensitized locomotor responding to amphetamine by up-regulating postsynaptic DA receptor signaling in the NAcc. Finally, amphetamine self-administration (200 g/kg/infusion i.v.) was enhanced in amphetamine (5 ϫ 1.5 mg/kg i.p.)-exposed rats, but not in rats exposed to ⌬ 9 -THC (5 ϫ 3.0 mg/kg i.p.). Previous exposure to this dose of ⌬ 9 -THC modestly increased apomorphine SA (0.5 mg/kg/infusion i.v.). Thus, unlike amphetamine exposure, exposure to ⌬ 9 -THC does not enhance the subsequent NAcc DA response to amphetamine or promote amphetamine self-administration. Although ⌬ 9 -THC leads to alterations in postsynaptic DA receptor signaling in the NAcc and these can affect the generation of locomotion, these neuroadaptations do not seem to be linked to the expression of enhanced amphetamine self-administration.

Exposure to nicotine enhances its subsequent self-administration: Contribution of nicotine-associated contextual stimuli

“…They are also consistent with other reports supporting a relation between sensitized midbrain dopamine neuron reactivity and enhanced stimulant self-administration [5, 9, 16, 17, 33]. Together with these findings, the present results support an incentive motivational view of enhanced nicotine intake [8, 9, 34, 35] and the suggestion by some that it is the changes in mesoaccumbens dopamine function induced by previous exposure to nicotine [1] that predisposes individuals to pursue this drug [2, 3].…”

The effects of Δ9-tetrahydrocannabinol on the dopamine system

“…There is further evidence of downstream dopaminergic effects of THC, as one study in rats78 reported up-regulated postsynaptic dopamine receptor signalling in the NAc via increased adenylyl cyclase activity, which was proposed to underlie THC-induced changes in amphetamine-induced locomotive behaviour. These findings suggest that repeated THC dosing results in altered dopamine receptor signal transduction.…”

Interactions of Cannabis and Amphetamine-Type Stimulants

“…Indeed, while pre-exposure to THC does not appear to affect the self-administration of AMPH in rats [178], the blockade of CB 1 receptors attenuates METH self-administration [179,180]. Notably, this effect may not reflect an intrinsic reduction of the rewarding properties of METH, but rather the acquisition and consolidation of the preference for this drug [181,182], suggesting that the key effect of cannabis may modulate the plastic and adaptive response to repeated administrations of ATSs.…”