Behavioral Effects of d‐Methamphetamine and sin vivo microdialysis in rats

Abstract

The present studies were conducted to examine the relationship between locomotor stimulant effects of d‐methamphetamine (d‐MA) and its ability to increase extracellular concentrations of d‐MA, its active metabolite d‐amphetamine (d‐AMP), dopamine (DA), serotonin (5‐HT), norepinephrine (NE), γ‐aminobutyric acid (GABA), and glutamate (GLU) in dialysate samples obtained from the rat nucleus accumbens (nAcc) shell. First, the effects of cumulatively administered d‐MA (0.3–5.6 mg/kg) on locomotor activity were determined in rats. In other studies, in vivo microdialysis and LC/MS analysis of dialysate samples were used to determine the effects of cumulatively administered d‐MA (0.3–5.6 mg/kg) on extracellular levels of d‐MA, d‐AMP, DA, 5‐HT, NE, GABA, and GLU in the nAcc shell. d‐MA produced dose‐related effects on locomotor activity, characterized by an inverted‐U dose‐response curve; 0.3–3 mg/kg increased activity, whereas 5.6 mg/kg suppressed activity (induced stereotypy). Results from microdialysis studies show that levels of d‐MA (0.3–5.6 mg/kg i.p.) in the nAcc shell increased in a dose‐ and time‐dependent manner with concentrations ranging from 12–319 nM, respectively; peak levels (334 nM) detected 20 min after 5.6 mg/kg slowly declined over the next hour. An increase in d‐AMP was also observed with concentrations ranging from 4.5–130 nM after 0.3–5.6 mg/kg d‐MA; peak levels of d‐AMP were detected 20 min (164 nM) after 5.6 mg/kg d‐MA and remained at this level for more than the next hour 100 min. d‐MA produced dose‐ and time‐dependent increases in DA, 5‐HT, and NE efflux in the nAcc shell to maxima of approximately 642% (17 nM), 582% (1.2 nM), and 422% (0.7 nM) of control values, respectively. In contrast, d‐MA did not produce significant changes in GABA or GLU levels. Time course and dose‐response analysis show that increases in d‐MA levels after 0.3–3.0 mg/kg are concordant with increases in DA, 5‐HT, and NE efflux. However, levels of d‐MA after 5.6 mg/kg appear to reflect increases in DA and 5‐HT but not NE. Correlation analysis revealed an inverse relationship between d‐MA‐induced increases in locomotor activity and in vivo extracellular levels of 5‐HT and d‐AMP. Although not statistically significant, a trend towards an inverse relationship was also observed between d‐MA‐induced increases in locomotor activity and extracellular levels of d‐MA and other neurotransmitters in the nAcc shell. Taken together, the ability to detect and correlate the presence and clearance of in vivo brain levels of d‐MA, and its active metabolite d‐AMP in the nAcc shell of rats to neurochemical and behavioral effects can provide insight into the neuropharmacological effects of d‐MA.