Sensitivity to self-administered cocaine within the lateral preoptic-rostral lateral hypothalamic continuum

Abstract

The lateral preoptic-rostral lateral hypothalamic continuum (LPH) receives projections from the nucleus accumbens and is believed to be one route by which nucleus accumbens signaling affects motivated behaviors. While accumbens firing patterns are known to be modulated by fluctuating levels of cocaine, studies of the LPH's drug-related firing are absent from the literature. The present study sought to electrophysiologically test whether drug-related tonic and slow-phasic patterns exist in the firing of LPH neurons during a free-access cocaine self-administration task. Results demonstrated that a majority of neurons in the LPH exhibited changes in both tonic and slow-phasic firing rates during fluctuating drug levels. During the maintenance phase of self-administration, 69.6% of neurons exhibited at least a twofold change in tonic firing rate when compared to their pre-drug firing rates. Moreover, 54.4% of LPH neurons demonstrated slow-phasic patterns, specifically "progressive reversal" patterns, which have been shown to be related to pharmacological changes across the inter-infusion interval. Firing rate was correlated with calculated drug level in 58.7% of recorded cells. Typically, a negative correlation between drug level and firing rate was observed, with a majority of neurons showing decreases in firing during cocaine self-administration. A small percentage of LPH neurons also exhibited correlations between locomotor behavior and firing rate; however, correlations with drug level in these same neurons were always stronger. Thus, the weak relationships between LPH firing and locomotor behaviors during cocaine self-administration do not account for the observed changes in firing. Overall, these findings suggest that a proportion of LPH neurons are sensitive to fluctuations in cocaine concentration and may contribute to neural activity that controls drug taking.

Figure 1

A diagram of wire placements within the lateral preoptic-rostral lateral hypothalamic continuum (LPH) for wires exhibiting a single unit. Each blue dot represents a single localized microwire tip. The inset shows a representative histological slice with wires localized in the LPH. Arrows point to the lesions created at the microwire tips. The section is stained for antibodies raised against Calbindin D28k.

Figure 2

Calculated drug levels and the corresponding firing rate for a neuron that shows an inhibitory response to cocaine self-administration and a negative correlation between calculated drug level and firing rate. Red lines demarcate the start and end of self-administration while the blue line designates the end of the loading phase and start of the maintenance phase.

Figure 3

Top: Heatmaps showing firing rate change scores for all individual neurons (neurons 1-46; y-axes) across the load up, maintenance, and recovery periods. For each of these epochs, change scores for individual neurons [Δ firing rate (FR)= (EpochFR/ (Pre-drug BaselineFR + EpochFR))-0.5] are shown across ten bins (x-axes), each representing 10% of that epoch. Change scores below 0 represent decreases in firing rate when compared to the pre-drug baseline, while those above 0 represent increases in firing rate compared to baseline. Bottom: Frequency histogram displaying tonic firing rate changes across load up, maintenance and recovery. Histograms show the fold change when comparing each portion of the recording session (Load, Maintenance, Post-Drug) to the pre-drug baseline period. Change scores are normally distributed around no change during the loading period, but show a pronounced change during the maintenance period. Changes in firing then begin to normalize again during the post-drug recovery period.

Figure 4

Examples of raw firing patterns of individual neurons for the observed progressive (A & B) and late reversal (C & D) patterns. Time in relation to the infusion offset (seconds) is shown on the x-axis (infusion offset at time zero), the window around the inter-infusion intervals spans between -4 minutes prior to the infusion and +4 minutes following the infusion. Examples of post-infusion increases are shown in panels A &C, while post-infusion decreases are shown in panels B & D. Decrease/progressive reversals (B) were the most commonly observed pattern and were more common than increase/progressive reversals. In contrast, increase/late reversal patterns were more common than decrease/late reversal patterns.

Figure 5

The taxonomy of firing patterns as determined by the principle components analysis. The representative pattern for each taxon is shown in blue for post-infusion decreases and red for post-infusion increases. Gray traces represent individual neurons assigned to each taxon. Time in relation to the infusion offset (seconds) is shown on the x-axis (infusion offset at time zero) and the Z-score for each factor score (taxa) and firing pattern (neuron) is shown on the y-axis. Principal components analysis categorized neurons as increase/ or decrease/progressive reversals patterns (PR; A-F), or increase/ or decrease/late reversal patterns (LR; G-H). Available evidence indicates that progressive reversal patterns are related to pharmacological changes across the inter-infusion interval. Hybrid component loadings (C-F) represent variations in the progressive reversal pattern, perhaps owing to differences in the timing of pharmacological effects or differences in the integration of upstream neuronal signals.

Figure 6

The distribution of observed correlations between calculated drug level and firing rate (top) and locomotion and firing rate (bottom). More neurons exhibited significant negative correlations between drug level and firing rate than between locomotor behaviors and firing rate. The magnitude of correlations with drug level, on the average, was also greater.