Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics

Abstract

Using in vivo microdialysis, the caudate and nucleus accumbens dopamine (DA) responses to the psychomotor stimulants amphetamine (AMPH), cocaine (COC), and fencamfamine (FCF) were evaluated in rats concurrent with characterization of their behavioral response profiles. Doses of each stimulant that produced either enhanced locomotion or a prolonged period of intense focused stereotypies were examined to evaluate the quantitative relationships between stimulant-induced behaviors and changes in DA dynamics and to test the hypothesis that a balance between mesostriatal and mesolimbic DA activity contributes to the appearance of specific stimulant-induced behaviors. Although 10 mg/kg COC and 1.7 mg/kg FCF promoted levels of locomotor activity substantially greater than 0.5 mg/kg AMPH, the magnitude of the DA increases in both caudate and accumbens were markedly less than was obtained following AMPH. Thus, stimulant-induced locomotion appears to be dissociated from the quantitative DA response in both brain regions. This behavioral/DA dissociation was also apparent at higher doses of AMPH (2.5 mg/kg), COC (40 mg/kg), and FCF (6 mg/kg), doses that promoted a behavioral pattern that included a prolonged period of intense stereotypy. Indeed, the regional DA responses to these high doses of COC and FCF were substantially less than the response to 0.5 mg/kg AMPH. Furthermore, there were no differences in the ratio of the caudate and accumbens DA responses as a function of dose for any of the three drugs. Thus, the balance between the regional DA activation does not appear to regulate the expression of the behavioral response. Additionally, the effects of these stimulants on regional DA metabolite concentrations were compared. The results indicate that AMPH promoted an identical pattern of effects on caudate and accumbens DA metabolites, suggesting that similar mechanisms govern the dynamics of DA in response to AMPH in both brain regions. In contrast, the DA uptake blockers promoted some region-specific effects on DA metabolites that may be due to regional differences in the DA metabolism and rates of impulse flow.

Effects of Cocaine in Rats Exposed to Heroin

“…Here it should be noted that, in our locomotion study (Figure 4,panel b), cocaine (20 mg/ kg) significantly enhanced locomotion in rats in acute withdrawal from the heroin. Thus, taken together, our results indicate that cocaine-induced DA activity in the Acb and cocaine-induced elevation of locomotor activity can be dissociated (Kuczenski et al, 1991). Interestingly, others have found that when the activity of the mesolimbic DA systems is tested in animals at later time points after withdrawal, repeated exposure to opioid drugs augments the DA response to electrically evoked release (Nestby et al, 1997) and to the administration of morphine (Spanagel et al, 1993).…”

Protracted ‘Pro-Addictive’ Phenotype Produced in Mice by Pre-Adolescent Phenylpropanolamine

“…Thus, perhaps a converse mechanism may be invoked to account for our data; pre-adolescent PPA administration may facilitate the development of cocaine-conditioned reward by reducing either the unconditioned or the conditioned aversive effects of cocaine. Although this mechanism is under intense investigation by our laboratory, our present observation that juvenile PPA treatment prevented the development of cocaine-induced locomotor sensitization, a classic animal model of psychosis (eg, Scheel-Kruger et al, 1977;Kuczenski et al, 1991;Post and Kopanda, 1976;Segal and Kuczenski, 1997), is consistent with this hypothesis.…”

“…In addition to a sensitization of horizontal locomotion, the repeated administration of psychomotor stimulant drugs, such as cocaine, can induce a sensitization of intensely focused, stereotyped behaviors in rodents (including grooming, rearing, and sniffing) that can interfere with the expression of horizontal locomotion (eg, Kuczenski et al, 1991). Moreover, the expression of both stimulantinduced locomotion and stereotypy can become conditioned to the environment in which the drug is administered with repeated drug administration (Badiani et al, 2000;Badiani and Robinson, 2004;Browman et al, 1998;Pert et al, 1990;Robinson et al, 1998;Szumlinski et al, 1997).…”

SPECT imaging of D2 dopamine receptors and endogenous dopamine release in mice

“…In all animals, ex vivo measurements gave higher specific striatal binding than in vivo measurements ( [7]. The 27% reduction in specific binding after administration of a dose of 2.5 mg/kg amphetamine seems rather minor compared to the massive dopamine release after amphetamine administration measured using microdialysis in previous studies [1,11]. The SPECT measurement is performed 2 h after amphetamine administration at that moment the effect of the amphetamine administration may already be reduced.…”