An assessment of the effects of psychoactive drugs and electrical stimulatin of the ventral tegmental area on the stimulus properties of amphetamine
Creators: name: Druhan, Jonathan Peter
Publisher: name: University of British Columbia
Year: 2010

description: The discriminative stimulus properties of amphetamine are thought to result from the facilitatory actions of this drug on dopamine neurotransmission within the nucleus accumbens. As such actions within the nucleus accumbens also are hypothesized to be responsible for amphetamine's rewarding effects, the stimulus properties of amphetamine may be related to the hedonic effects of the drug. If these conclusions are correct, then tests for generalization with the stimulus properties of amphetamine might be useful either to determine the dopaminergic actions of drugs, or to screen newly developed compounds for their abuse potential. In the present thesis rats were trained to discriminate 1.0 mg/kg amphetamine from saline, and then tested for stimulus generalization to a range of amphetamine doses (0.0, 0.25, 0.50 and 1.0 mg/kg) injected either alone or in combination with either cocaine, apomorphine, haloperidol, nicotine, morphine, midazolam, ethanol or electrical stimulation of the ventral tegmental area (VTA). Comparisons were then made between the amphetamine stimulus generalization functions obtained in the presence and absence of the test stimuli, to determine whether the functions were altered in a manner consistent with the known dopaminergic actions or hedonic effects of the drugs and VTA stimulation. It was predicted that test stimuli that could enhance dopamine neurotransmission or produce positive hedonic effects might augment the stimulus properties of amphetamine and elevate stimulus generalization functions relative to a control curve. Conversely, test stimuli that inhibited dopamine neurotransmission or reduced positive affect might interfere with the amphetamine stimuli and lower the generalization functions. The results indicated that amphetamine stimulus generalization functions were altered in a manner that generally reflected the known actions of each test stimulus on dopamine neurotransmission. Thus, the generalization functions were elevated by stimuli that enhanced dopamine neurotransmission (cocaine, a dose of apomorphine affecting post-synaptic dopamine receptor sites, nicotine and VTA stimulation) and lowered by stimuli that interfered with dopamine neurotransmission (haloperidol, midazolam, and a dose of apomorphine that acts preferentially at presynaptic dopamine autoreceptors). Ethanol, which has not been found to consistently affect dopamine neurotransmission, did not generalize with the stimulus properties of amphetamine. Only morphine was found to affect amphetamine stimulus generalization functions (a lowering) in a manner that was inconsistent with the drug's facilitatory actions on dopamine neurotransmission. The amphetamine stimulus generalization functions were not affected in a manner consistent with the hedonic actions of each test stimulus. Certain drugs that could produce positive hedonic effects (morphine, midazolam and ethanol) failed to elevate the generalization functions. In fact, the functions were elevated only by stimuli that appear to produce most of their rewarding effects by enhancing mesoaccumbens dopamine neurotransmission (cocaine, apomorphine, nicotine, and VTA stimulation). Two additional experiments suggested that this property could have been responsible for the ability of VTA stimulation to elevate amphetamine stimulus generalization functions. In one experiment, the ability of the VTA stimulation to substitute for the stimulus properties of amphetamine was found to be correlated positively with its rewarding efficacy measured during ICSS tests. A subsequent experiment indicated that dopamine neurons could indeed mediate discriminative stimuli produced by VTA stimulation, as the brain stimulation cues were augmented by amphetamine and attenuated by the dopamine receptor antagonist, haloperidol. Together, the findings of this thesis indicated that amphetamine stimulus generalization paradigms might be useful for detecting the dopaminergic actions of certain psychoactive drugs. However, such procedures may not detect the abuse potential of all compounds. This latter result indicates that certain drugs of abuse do not produce amphetamine-like stimulus properties, and that this may be due to differences in the neural mechanisms that mediate their positive hedonic effects.