Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter

Abstract

The dopamine transporter (DAT) is responsible for terminating dopamine (DA) signaling and is the primary site of cocaine's reinforcing actions. Cocaine self-administration has been shown previously to result in changes in cocaine potency at the DAT. To determine whether the DAT changes associated with self-administration are due to differences in intake levels or temporal patterns of cocaine-induced DAT inhibition, we manipulated cocaine access to produce either continuous or intermittent elevations in cocaine brain levels. Long-access (LgA, 6 h) and short-access (ShA, 2 h) continuous self-administration produced similar temporal profiles of cocaine intake that were sustained throughout the session; however, LgA had greater intake. ShA and intermittent-access (IntA, 6 h) produced the same intake, but different temporal profiles, with 'spiking' brain levels in IntA compared with constant levels in ShA. IntA consisted of 5-min access periods alternating with 25-min timeouts, which resulted in bursts of high responding followed by periods of no responding. DA release and uptake, as well as the potency of cocaine for DAT inhibition, were assessed by voltammetry in the nucleus accumbens slices following control, IntA, ShA, and LgA self-administration. Continuous-access protocols (LgA and ShA) did not change DA parameters, but the 'spiking' protocol (IntA) increased both release and uptake of DA. In addition, high continuous intake (LgA) produced tolerance to cocaine, while 'spiking' (IntA) produced sensitization, relative to ShA and naive controls. Thus, intake and pattern can both influence cocaine potency, and tolerance seems to be produced by high intake, while sensitization is produced by intermittent temporal patterns of intake.

Figure 1

Short-access (ShA), Intermittent-access (IntA), and long-access (LgA) cocaine self-administration result in different patterns of self-administration. (a) Plots demonstrating representative self-administration behavior throughout each session for individual rats self-administering cocaine. Tick marks represent infusions/responses on the lever earned on a fixed ratio one schedule of reinforcement. (a, top) ShA results in high consistent rates of responding over the 2-h session. (a, middle) IntA is achieved by giving 5-min access followed by 25-min forced timeouts. This results in bursts of high responding followed by no responding. (a, bottom) LgA results in high consistent rates of responding over the 6-h session. (b) Group data plotting total intake over the 14 days of self-administration for each paradigm. ***P<0.001 vs ShA; ^###p<0.001 vs IntA.

Figure 2

Differential effects of intermittent-access (IntA), short-access (ShA), and long-access (LgA) self-administration on presynaptic dopamine system kinetics. (a) Representative traces from control (left), IntA (center, left), LgA (center, right), and ShA (right) animals. Traces are represented as concentration (μM) in dopamine (DA) over time. (b) Stimulated DA release in μM across LgA, IntA, ShA, and control groups. (c) Maximal rate of DA uptake (V_max) across groups. (d) Group data indicating that the K_m of DA for the dopamine transporter is unchanged following all self-administration paradigms. **P<0.01 vs control; ***p<0.001 vs control; ^&&&p<0.001 vs LgA.

Figure 3

Intermittent-access (IntA) self-administration results in sensitization to the neurochemical effects of cocaine, while long-access (LgA) results in tolerance. (a) Representative traces highlighting the uptake inhibition induced by 10 μM cocaine in control (black) and short-access (ShA, green) animals. Traces are represented as concentration (μM) in dopamine (DA) over time and smaller signals were shifted to the right in order to match the peak-height of the small signal to equivalent concentration of the larger signal. This allows for direct comparison of dopamine uptake in signals with different peak-heights. (b) Representative traces highlighting the uptake inhibition induced by 10 μM cocaine in control (black), IntA (blue), and LgA (red) animals. (c) Cumulative cocaine (0.3–30 μM) dose–response curves in slices containing the nucleus accumbens core. Cocaine potency is decreased following LgA, unchanged following ShA, and increased following IntA. (d) Group data of K_i values for cocaine in control, LgA, ShA, and IntA groups. K_i values are a measure of the concentration of drug at which 50% inhibition is achieved. *P<0.5 vs control; **p<0.01 vs control; and ^#p<0.01 vs ShA.

Figure 4

Cocaine-induced increases in dopamine (DA) did not differ across groups. Stimulated DA release was measured across a dose–response curve for cocaine, and expressed as a percent pre-cocaine stimulated DA release. There were no differences in cocaine-induced DA elevations between control, intermittent-access (IntA), long-access (LgA), or short-access (ShA) cocaine self-administration groups.