Neonatal quinpirole treatment enhances locomotor activation and dopamine release in the nucleus accumbens core in response to amphetamine treatment in adulthood

Abstract

Neonatal quinpirole treatment to rats produces long-term increases in D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon referred to as D(2) priming. Male and female Sprague-dawley rats were administered quinpirole (1 mg kg(-1)) or saline from postnatal days (P)1-11. At P60, all animals were given an injection of quinpirole (100 microg kg(-1)), and results showed that rats neonatally treated with quinpirole demonstrated enhanced yawning in response to quinprole, verifying D(2) receptor priming because yawning is a D(2) receptor mediated event. Beginning 1-3 days later, locomotor sensitization was tested through administration of d-amphetamine (1 mg kg(-1)) or saline every other day over 14 days, and horizontal activity and turning behavior were analyzed. Findings indicated that D(2)-priming enhanced horizontal activity in response to amphetamine in females compared to males at Days 1 and 4 of locomotor sensitization testing, and D(2)-priming enhanced turning in response to amphetamine. Seven to ten days after sensitization was complete, microdialysis of the NAcc core was performed using a cumulative dosing regimen of amphetamine (0.1-3.0 mg kg(-1)). D(2)-primed rats administered amphetamine demonstrated a 500% increase in accumbal DA overflow compared to control rats administered amphetamine. Additionally, amphetamine produced a significant increase in NE overflow compared to controls, but this was unaffected by D(2) priming. These results indicate that D(2) receptor priming as is produced by neonatal quinpirole treatment robustly enhances behavioral activation and accumbal DA overflow in response to amphetamine, which may underlie increases in psychostimulant use and abuse within the psychotic population where increased D(2) receptor sensitivity is a hallmark.

Figure 1

Yawning behavior is presented as a function of sex and neonatal drug treatment. Quinpirole-treated males demonstrated significantly higher levels of yawning than all other groups (indicated by **), and quinpirole-treated females demonstrated higher levels of yawning as compared to saline-treated females (indicated by *).

Figure 2

(a). Horizontal activity is presented as a function of neonatal and adulthood drug treatment for females. Group QA demonstrated significantly higher levels of horizontal activity compared to all other groups (indicated by **). Group SA demonstrated significantly higher levels of horizontal activity compared to female Group SS (indicated by *). (b). Horizontal activity is presented as a function of neonatal and adulthood drug treatment for males. Group QA demonstrated significantly higher levels of horizontal activity compared to all other male groups (indicated by **), and Group SA demonstrated significantly higher levels of horizontal activity compared male Group SS.

Figure 3

The number of turns is presented as function of neonatal and adulthood drug treatment. Group QA demonstrated significantly higher levels of horizontal activity compared to all other groups (indicated by **). Group SA demonstrated significantly higher levels of horizontal activity compared to Group SS at days 4 and 7 (indicated by *).

Figure 4

Rat brain stereotaxic atlas for_(a) 1.0 mm anterior to bregma, and (b) 1.2 mm anterior to bregma. Note that AcbC in this figure represents the nucleus accumbens core. The two lines on either figure indicate the furthest lateral and medial a probe was placed at each location for the left and right hemisphere. Note that all probes intersected the nucleus accumbens core. A total of 46 of the 52 probes intersected the NAcc core at 1.0 mm anterior to bregma, and the other 6 probes intersected the NAcc core at 1.2 mm anterior to bregma. Figure was adapted from The Rat Brain in Stereotaxic Coordinates, 5^th edition (Paxinos and Watson, 2006).

Figure 5

(a). Dopamine (DA) is presented as a percentage of baseline as a function of minutes post adulthood drug treatment and group. The arrows along the × axis indicate the dose of d-amphetamine injected at these time points. Group QA demonstrated a significant increase in accumbal core DA overflow compared to all other groups (indicated by **). Group SA demonstrated a significant increase in accumbal DA overflow compared to controls (Group SS; indicated by *). (b) DOPAC is presented as a percentage of baseline as a function of mines post drug treatment and group. Although it appears that Group QS demonstrated an absolute increase in DOPAC levels from time points 80 through 160, there were no significant group differences. (c) Homovanillic acid (HVA) is presented as a percentage of baseline as a function of minutes post adulthood drug treatment and group. Likewise, Group QA demonstrated an absolute increase towards the end of testing, but statistically, there were no significant group differences.

Figure 6

Norepinephrine (NE) is presented as a percentage of baseline as a function of mniutes post adulthood drug treatment and group. Groups QA and SA demonstrated a significant increase in accumbal core NE overflow at time points 80, 100, and 120 compared to Groups SS and QS (indicated by *). Group SS demonstrated a slight but significant increase in NE concentrations at time point 20 (indicated by **).